US 20170035784A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0035784 A1 Lancaster et al. (43) Pub. Date: Feb. 9, 2017
(54) COMPOSITIONS OF OBETICHOLIC ACID (22) Filed: Apr. 26, 2016 AND METHODS OF USE Related U.S. Application Data (71) Applicants: Intercept Pharmaceuticals, Inc., New York, NY (US); Sumitomo Dainippon (60) Provisional application No. 62/153,040, filed on Apr. Pharma Co., Ltd., Osaka (JP) 27, 2015, provisional application No. 62/317,933, filed on Apr. 4, 2016. (72) Inventors: Richard Gail Lancaster, San Diego, CA (US); Kay K. Olmstead, Publication Classification Escondido, CA (US); Masashi Kagihiro, Osaka (JP); Mitsuhiro (51) Int. Cl. Matono, Osaka (JP); Ikuko Taoka, A 6LX 3/575 (2006.01) Osaka (JP); Mark Pruzanski, New A6II 45/06 (2006.01) York, NY (US); David Shapiro, A69/20 (2006.01) Rancho Sante Fe, CA (US); Roya (52) U.S. Cl. Hooshmand-Rad, San Diego, CA (US); CPC ...... A61K3I/575 (2013.01); A61K 9/2059 Richard Pencek, San Diego, CA (US); (2013.01); A61 K9/2054 (2013.01); A61 K Cathi Sciacca, San Diego, CA (US); 45/06 (2013.01); A61K 9/2072 (2013.01) Lise Eliot, San Diego, CA (US); Jeffrey Edwards, San Diego, CA (US); (57) ABSTRACT Leigh A. MacConell, Encinitas, CA (US); Tonya K. Marmon, San Diego, The disclosure relates to obeticholic acid formulations with CA (US) improved stability, dissolution, and/or solubility, methods of preparing the same for use and methods of treating various (21) Appl. No.: 15/139,138 diseases and conditions. Patent Application Publication Feb. 9, 2017. Sheet 1 of 37 US 2017/0035784 A1
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os 8 an cs 9 CD 5 c Ois qs O ne OO v - H v H qs O ve C c. c. c. c. c. N N Cn vs O (%) (SueO eunON Patent Application Publication Feb. 9, 2017. Sheet 2 of 37 US 2017/0035784 A1 C O O O O ve C O O O ve OO 92 O 92 O O v g - N S2 E 5 S, CN aOO 5 CN 2 ccS 32t as CD s S n S - 75 .9 s 9 s O O H MO H d ve C C C C e O s CN O (%) (Sued eunON Patent Application Publication Feb. 9, 2017. Sheet 3 of 37 US 2017/0035784 A1 pact of AP Agglomeration and Jet Willing on the Dissolution of OCA fablets, 10 ng (900 in dissolution volune) G. &O. :-38.-- 8.------* Unmilled Non-Agglomerated AP (OCA) & Unmilled. Agglomerated AP (OCA) ... Jeti-MiEled AP (OCA) Patent Application Publication Feb. 9, 2017. Sheet 4 of 37 US 2017/0035784 A1 FG. 4 Patent Application Publication Feb. 9, 2017. Sheet 5 of 37 US 2017/0035784 A1 Buffers Dissolutioi Vedium Free acid BCS imit (5 mg) BCS imit (10 mg) F.G. 5 Patent Application Publication Feb. 9, 2017. Sheet 6 of 37 US 2017/0035784 A1 ------ Biorelevant buffers Proposed disso medium Free acid BCS imit (5 mg) BCS imit (10 mg) 0.O O ------ F.G. 6 Patent Application Publication Feb. 9, 2017. Sheet 7 of 37 US 2017/0035784 A1 |sodTs 90UDpunqW 9ADey e3UDPunqW eN.De Patent Application Publication Feb. 9, 2017. Sheet 8 of 37 US 2017/0035784 A1 000|| Z/UU 8/'5)|–| 08 09 07 0Z 00|| 08 09 07 OZ e3UDpundy eNDey 00600800/00900900,700200Z Patent Application Publication Feb. 9, 2017. Sheet 10 of 37 US 2017/0035784 A1 090||000|09600609800809/100/09900909G097007099,009, (z/u.)96JD?.0-01-SSDWºsasjun00 Patent Application Publication Feb. 9, 2017. Sheet 11 of 37 US 2017/0035784 A1 09 / 99 07 Sdo (Sueu Patent Application Publication Feb. 9, 2017. Sheet 12 of 37 US 2017/0035784 A1 0960' (Z)?ODI?qnSpº?deudy#6]IgNHWNOGLI=fidu!(SuDOSÇZ‘uluuLLZ'yl-G60'y])uDOSISEH n) OO N. co r n CN Patent Application Publication Feb. 9, 2017. Sheet 13 of 37 US 2017/0035784 A1 * 3: 8 : : {x : & & & & & as 3. it g 2 is at 3 38 : : is 38 x s & is 38 FIG. 10 Patent Application Publication Feb. 9, 2017. Sheet 16 of 37 US 2017/0035784 A1 3. FIG. 13 Patent Application Publication Feb. 9, 2017. Sheet 17 of 37 US 2017/0035784 A1 & 2 S E 3i 3 Baselirie LP is FIG. 14A Patent Application Publication Feb. 9, 2017. Sheet 18 of 37 US 2017/0035784 A1 Titti s 2 . s" so st Baselire 8, Pi: F.G. 14B Patent Application Publication Feb. 9, 2017. Sheet 19 of 37 US 2017/0035784 A1 i.s t - 3 3 8 Baseline 8, Pil F.G. 14C Patent Application Publication Feb. 9, 2017. Sheet 20 of 37 US 2017/0035784 A1 e SE All : 3: AP Nixia Rate s Time entis F.G. 15A Patent Application Publication Feb. 9, 2017. Sheet 21 of 37 US 2017/0035784 A1 eat SE fotai Esilii is: x *ise: it is: 8s 33 : 383, itratigrit 3E30: 3: ; 38, i8 regit}E 8:3 Title initis FIG. 15B Patent Application Publication Feb. 9, 2017. Sheet 22 of 37 US 2017/0035784 A1 s 8:338 8:38: 388:8g F.G. 16 Patent Application Publication Feb. 9, 2017. Sheet 23 of 37 US 2017/0035784 A1 S tear (SE {{ { } {g actiherapy {{A : rig -- is A. ** 8 x : :a::seisse 883 : F.G. 17A Patent Application Publication Feb. 9, 2017. Sheet 24 of 37 US 2017/0035784 A1 Mono : +UCA = 6 r = : r = 1 n = 9. Mean BLALP 401 (UIL) 445 (UL : 307 (UL) 304 (UFL) - - 250- : O Placebo -30- OCA 10 mg FIG. 17B Patent Application Publication Feb. 9, 2017. Sheet 25 of 37 US 2017/0035784 A1 §§***** 88%(5948 Patent Application Publication US 2017/0035784 A1 woo-oinel-----…-…-…-- w Siempsa peaf et JOIlluo e Siempse Sufia:A lot OC WOO-OOÁIÐ o s: SerpSociate CIOO uOeuueuOO eul Patent Application Publication Feb. 9, 2017. Sheet 27 of 37 US 2017/0035784 A1 VOOfiuGZVOO6uuO|VOOG eSOO-efuS eSOO-ed nW Patent Application Publication Feb. 9, 2017. Sheet 28 of 37 US 2017/0035784 A1 ------fas: 30: 38 s cs :::::::32: Y:3: 888 *------3------+------#------+---+---+------&------+------&------+------+------+------* $33A 8,883 w : ers -o- Ole Patent Application Publication Feb. 9, 2017. Sheet 29 of 37 US 2017/0035784 A1 8: 8. w 33:83 :X: 3883. yO ful O. Patent Application Publication Feb. 9, 2017. Sheet 30 of 37 US 2017/0035784 A1 g N (D as -.2 g d 2 O b s e ge Se se (u?u-Ju) (931&O'onw s 2 t 3. 3. E w l C HH Y (5N HH. . . . HIH s (u/5u-Ju) (93.200nw Patent Application Publication Feb. 9, 2017. Sheet 31 of 37 US 2017/0035784 A1 Off Treatment 0.2 O 24 48 72 96 Weeks -H OCA -e- Placebo FIG. 24A Patent Application Publication Feb. 9, 2017. Sheet 32 of 37 US 2017/0035784 A1 Off Treatment O 24 48 72 96 Weeks -- OCA -e- Placebo FIG. 24B Patent Application Publication Feb. 9, 2017. Sheet 33 of 37 US 2017/0035784 A1 s Off Treatment O 0.4 - SS up 0.2 9,E?) is LL 0.063...... C Z O -0.2 v -0.4 u O 24 48 72 96 Weeks -- OCA -e Placebo FIG. 24C Patent Application Publication Feb. 9, 2017. Sheet 34 of 37 US 2017/0035784 A1 isia: {}{A :8: - s a s : s ; :8: wisc 3&c. s is C3 V ???oddÁëO9 {{i;82; wago. 383. Olde pode Patent Application Publication Feb. 9, 2017. Sheet 35 of 37 US 2017/0035784 A1 ra | | s: Patent Application Publication Feb. 9, 2017. Sheet 36 of 37 US 2017/0035784 A1 38: 8 &A 8883 s ::::::::::38 23: aSOO-efuS asochrad, Patent Application Publication Feb. 9, 2017. Sheet 37 of 37 US 2017/0035784 A1 4. :-***·*** 3******************************************************************************••••••••••••••• *::::::::} : 3323:33. WOO ful ga. US 2017/0035784 A1 Feb. 9, 2017 COMPOSITIONS OF OBETICHOLIC ACID wherein obeticholic acid or a pharmaceutically acceptable AND METHODS OF USE salt, ester, or amino acid conjugate thereof is in the form of particles, and wherein at least 50% of the particles have a BACKGROUND diameter of less than 200 um. Such compositions include all those described herein. 0001. The farnesoid X receptor (FXR), also known as the 0005. Another aspect of the disclosure relates to treating bile acid receptor (BAR) or NR1H4, is a member of the a disease or condition described herein in a patient in need nuclear receptor Superfamily of ligand-activated transcrip thereof by administering a composition that includes obet tion factors. FXR forms with retinoid X receptor (RXR) a icholic acid, or a pharmaceutically acceptable salt, ester, or heterodimer receptor crucial for bile acid homeostasis. FXR amino acid conjugate thereof, where the obeticholic acid or is expressed in various tissues including the liver, kidney, a pharmaceutically acceptable salt, ester, or amino acid intestine, colon, ovary, and adrenal gland, and is activated by conjugate thereof is in the form of particles. a variety of naturally occurring bile acids, including the 0006 Another aspect of the disclosure relates to treating primary bile acid chenodeoxycholic acid (CDCA) and its a disease or condition described herein in a patient in need taurine and glycine conjugates. Upon activation, the FXR thereof by administering a composition that includes obet RXRheterodimer binds the promoter region of target genes icholic acid, or a pharmaceutically acceptable salt, ester, or and regulates their expression. amino acid conjugate thereof, where the obeticholic acid or 0002 6-Ethyl-chenodeoxycholic acid (6-ECDCA, or a pharmaceutically acceptable salt, ester, or amino acid obeticholic acid, or OCA), a bile acid derivative, shows a conjugate thereof is in the form of particles, and wherein at potent FXR activating activity, and accordingly offers great least 50% of the particles have a diameter of 200 um or less. promise for the treatment of FXR-mediated diseases or 0007 Another aspect of the disclosure relates to treating conditions. Thus, there is a need to develop obeticholic acid primary biliary cirrhosis (PBC) in a patient in need thereof compositions having desirable dissolution profile and solu by administering a composition that includes obeticholic bility, and possessing advantageous storage stability. acid, or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof, optionally in a titration period, where SUMMARY the obeticholic acid or a pharmaceutically acceptable salt, 0003. The present disclosure relates to novel formula ester, or amino acid conjugate thereof is in the form of tions of obeticholic acid, an FXR agonist, with improved particles, and wherein at least 50% of the particles have a stability, dissolution, and solubility, methods of preparing diameter of 200 um or less. the same and methods of using the novel formulations for 0008. In still another aspect of the disclosure is a method treating a disease or condition. In certain instances, the of treating primary Sclerosing cholangitis (PSC), chronic disease or condition is primary biliary cirrhosis (PBC), also liver disease, nonalcoholic fatty liver disease (NAFLD), known as primary biliary cholangitis. In other instances, the nonalcoholic steatohepatitis (NASH), hepatitis C infection, disease or condition is primary Sclerosing cholangitis (PSC), alcoholic liver disease, liver damage due to progressive chronic liver disease, nonalcoholic fatty liver disease (NA fibrosis, or liver fibrosis in a patient in need thereof by FLD), nonalcoholic steatohepatitis (NASH), hepatitis C administering a composition that includes obeticholic acid, infection, alcoholic liver disease, liver damage due to pro or a pharmaceutically acceptable salt, ester, or amino acid gressive fibrosis, or liver fibrosis. In another instance, the conjugate thereof, optionally in a titration period, where the disease is NASH. In still other instances, the disease or obeticholic acid or a pharmaceutically acceptable salt, ester, condition is solid-tumor cancer Such as, for example, or amino acid conjugate thereof is in the form of particles. hepatocellular carcinoma (HCC), colorectal cancer, gastric In one example, at least 50% of the particles have a diameter cancer, liver cancer, breast cancer, kidney cancer, or pan of 200 um or less. creatic cancer. Further provided herein are novel dosing 0009. In yet another aspect of the disclosure is a method regimens for administration of obeticholic acid for treatment of treating a solid-tumor cancer in a patient in need thereof of the diseases or conditions described herein. by administering a composition that includes obeticholic acid, or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof, optionally in a titration period, where the obeticholic acid or a pharmaceutically acceptable salt, CO2H ester, or amino acid conjugate thereof is in the form of particles. In one example, at least 50% of the particles have a diameter of 200 um or less. 0010. In another aspect of the disclosure is a method of treating an autoimmune disease in a patient in need thereof by administering a composition that obeticholic acid, or a pharmaceutically acceptable salt, ester, or amino acid con jugate thereof, optionally in a titration period, where the obeticholic acid or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof is in the form of particles. obeticholic acid In one example, at least 50% of the particles have a diameter (also known as INT-747) of 200 um or less. 0011. In another aspect of the disclosure are methods of 0004. A first aspect of the disclosure relates to a compo treating a disease or condition described herein by admin sition comprising obeticholic acid, or a pharmaceutically istering a obeticholic acid composition described herein acceptable salt, ester, or amino acid conjugate thereof, where the obeticholic acid composition is administered as US 2017/0035784 A1 Feb. 9, 2017 part of a treatment regimen that includes a titration period 0018. In another aspect, the disclosure relates to methods and a starting dose of the obeticholic acid composition at an for treating or preventing an FXR mediated disease or amount of about 5 mg or 10 mg. In particular instances, such condition or a disease or condition in which elevated con methods include daily (QD) administration of an obeticholic centrations of circulating lipid compounds or glucose in the acid described herein during the titration period. In particu blood, or decreased insulin level, or increased insulin resis lar instances, such methods also include administration of an tance is involved, or inhibiting or reversing fibrosis, com adjusted dose of an obeticholic acid composition described prising administering a therapeutically effective amount of a herein after the titration period. composition of the present disclosure to a Subject in need 0012 Another aspect of the disclosure relates to a com thereof. position comprising obeticholic acid, or a pharmaceutically 0019. Another aspect of the disclosure relates to use of a acceptable salt, ester, or amino acid conjugate thereof, composition of the present disclosure for treating or pre wherein obeticholic acid or a pharmaceutically acceptable venting an FXR mediated disease or condition or a disease salt, ester, or amino acid conjugate thereof is in the form of or condition in which elevated concentrations of circulating particles, and wherein at least 50% of the particles have a lipid compounds or glucose in the blood, or decreased diameter of less than 200 um. Another aspect of the disclo insulin level, or increased insulin resistance is involved, or Sure relates to a composition comprising obeticholic acid, or for inhibiting or reversing fibrosis. a pharmaceutically acceptable salt, ester, or amino acid 0020. In another aspect, the disclosure relates to use of a conjugate thereof, and a pharmaceutically acceptable excipi composition of the present disclosure in the manufacture of ent (e.g., sodium starch glycolate) having a low alcohol a medicament for treating or preventing an FXR mediated (e.g., ethanol or methanol) content (e.g., less than 5% disease or condition or a disease or condition in which (wt/wt)). elevated concentrations of circulating lipid compounds or glucose in the blood, or decreased insulin level, or increased 0013. In another aspect, the disclosure relates to a phar insulin resistance is involved, or for inhibiting or reversing maceutical composition, comprising a therapeutically effec fibrosis. tive amount of obeticholic acid, or a pharmaceutically 0021. The compositions and methods of the present dis acceptable salt, ester, or amino acid conjugate thereof, in the closure address unmet needs in the treatment or prevention form of particles, and a pharmaceutically acceptable excipi of an FXR mediated disease or a disease or disorder in which ent (e.g., sodium starch glycolate) having a low alcohol elevated concentrations of circulating lipid compounds in (e.g., ethanol or methanol) content (e.g., less than 5% the blood Such as cholesterol and triglycerides or glucose are (wt?wt)), wherein at least 50% of the particles have a involved. diameter of less than 200 um. 0022. The compositions and methods of the present dis 0014) Another aspect of the disclosure relates to a phar closure address unmet needs in the treatment of diseases and maceutical composition, comprising obeticholic acid, or a conditions described herein, including for example, PBC, pharmaceutically acceptable salt, ester, or amino acid con PSC, NAFLD, NASH, cancer, and autoimmune diseases jugate thereof, in the form of particles, wherein at least 50% described herein. of the particles have a diameter of less than 200 um, at about 1% to about 6% by weight, sodium starch glycolate at about BRIEF DESCRIPTION OF THE DRAWINGS 2% to about 8% by weight having a low alcohol (e.g., ethanol or methanol) content (e.g., less than 5% (wit/wt)), a 0023 FIG. 1 is a particle size distribution histogram of lubricant (e.g., magnesium Stearate) at about 0.1% to about obeticholic acid before jet-milling. 2.0% by weight, and a diluent (e.g., microcrystalline cellu 0024 FIG. 2 is a particle size distribution histogram of lose) at about 85% to about 95% by weight. obeticholic acid after jet-milling. 0025 FIG. 3 is a graph showing the dissolution profile of 0015. In another aspect, the disclosure relates to a method 10 mg tablets containing unmilled/non-agglomerated, for preparing a composition comprising obeticholic acid, or unmilled/agglomerated, or jet-milled obeticholic acid. a pharmaceutically acceptable salt, ester, or amino acid 0026 FIG. 4 is a graph showing the dissolution profile of conjugate thereof, in the form of particles, wherein at least 5 mg tablets containing unmilled or jet-milled obeticholic 50% of the particles have a diameter of less than 200 um, acid. comprising forming the particles through jet-milling. 0027 FIG. 5 is a graph showing solubility of obeticholic 0016. Another aspect of the disclosure relates to a tablet acid in various buffers at 37° C. over a pH range of about 1.2 comprising an intra-granular portion and an extra-granular to about 12. The dashed and dotted lines represent the portion, the intra-granular portion comprising obeticholic Biopharmaceutical Classification System (BCS) limit for 5 acid, or a pharmaceutically acceptable salt, ester, or amino mg and 10 mg doses, respectively (5 and 10 mg/250 mL) acid conjugate thereof, microcrystalline cellulose, and one 0028 FIG. 6 is a graph showing obeticholic acid solu or more additional pharmaceutical excipients, and the extra bility in various biologically relevant buffers over a pH granular portion comprising one or more pharmaceutical range of about 1.2 to about 12. The dashed and dotted lines excipients. represent the Biopharmaceutical Classification System 0017. Another aspect of the disclosure relates to a tablet (BCS) high-solubility limit for 5 mg and 10 mg doses, comprising an intra-granular portion and an extra-granular respectively (5 and 10 mg/250 mL). portion, the intra-granular portion comprising obeticholic (0029 FIG. 7A shows the LC/HRMS spectrum in the acid, or a pharmaceutically acceptable salt, ester, or amino positive mode of a sample of obeticholic acid OCA and the acid conjugate thereof, microcrystalline cellulose, and one synthesized ethyl ester of obeticholic acid OCA. FIG. 7B or more additional pharmaceutical excipients, and the extra shows the mass spectrum in the positive mode of a sample granular portion comprising microcrystalline cellulose and of obeticholic acid OCA and the synthesized ethyl ester of one or more additional pharmaceutical excipients. obeticholic acid OCA. US 2017/0035784 A1 Feb. 9, 2017 0030 FIG. 8A shows the total ion count (TIC) chromato 0044 FIG. 22 illustrates External Validation of Model in gram in the positive ion mode acquired on Q-TOF LC/MS Patients with Impaired Hepatic Function. FIG. 22A shows of a sample of obeticholic acid OCA containing the PEG the effect of 10 mg OCA in mild impairment, FIG. 20B impurity, FIG. 8B shows the mass spectra in the positive shows the effect of 10 mg OCA in moderate impairment, mode acquired on Q-TOF LC/MS of a sample of obeticholic FIG. 20O shows the effect of 10 mg OCA in severe impair acid OCA containing the PEG impurity. FIG. 8C shows the ment, FIG. 22D shows the effect of 25 mg OCA in mild total ion count (TIC) chromatogram acquired on triple quad impairment, FIG. 20E shows the effect of 25 mg OCA in (QQQ) mass spectrometer of a sample of obeticholic acid moderate impairment, and FIG. 20E shows the effect of 25 OCA containing the PEG impurity. mg OCA in severe impairment. 0031 FIG. 9 shows an enlarged spectrum of the co 004.5 FIG. 23A and FIG. 23B illustrates plasma OCA eluting peaks containing obeticholic acid OCA and the PEG Concentrations are a Poor Surrogate for Liver OCA Con impurity displaying spacing characteristics of PEG. centrations. 0032 FIG. 10 illustrates the percent Change in ALP 0046 FIG. 24A, FIG. 24B, and FIG. 24C illustrate levels from Baseline to EOS: mITT Population (N=161). changes in FIG. 4, APRI Score, and NFS during the course 0033 FIG. 11 illustrates ALP Concentration (U/L) over of treating NASH using the obeticholic acid compositions duration of treatment. described herein, respectively. *p-0.05, **p<0.01, ***p<0. 0034 FIG. 12 illustrates TB Concentration (umol/L) over 0001; P-values were calculated using ANCOVA models, duration of treatment. regressing change from baseline at each post-baseline visit on treatment group and baseline value of the outcome. 0035 FIG. 13 illustrates proposed metabolic pathways of 0047 FIG. 25 illustrates a Visual Predictive Check of PK OCA in human plasma. Model in Subjects with Normal Hepatic Function where 0036 FIG. 14 illustrates Observed Individual Patient FIG. 25A shows a 6-day profile, FIG. 25B shows a 24-hour Level Change in ALP from Baseline at Month for responders profile, FIG. 25C shows a 6-day profile over period 2 and and non-responders by treatment group (Placebo (FIG. FIG. 25D shows a 24-hour profile over period 2. 14A), for OCA titration (FIG. 14B) and for OCA 10 mg 0048 FIG. 26 shows Visual Predictive Check of PK (FIG. 14C)). model in Patients with Normal and Impaired Hepatic Func 0037 FIG. 15A illustrates mean ALP over time and FIG. tion where FIG. 26A shows normal function, FIG. 26B 15B illustrates mean total bilirubin (TB) over time. shows mild impairment, FIG. 26C shows moderate impair 0038 FIG. 16 illustrates the mean plasma concentration ment and FIG. 26D shows severe impairment. time profile (Semi-log) of total OCA following a single oral 0049 FIG. 27 shows External Validation of Model in dose of 10 mg OCA (inset shows expanded view of first 24 Subjects with Normal Hepatic Function where FIG. 27A hours). shows a single dose of OCA 5 mg, FIG. 27B shows a single 0039 FIG. 17A illustrates ALP levels and FIG. 17 B dose of OCA 10 mg, FIG. 27C shows a single dose of OCA illustrates change in ALP from baseline with OCA mono 25 mg, FIG. 27D shows a multiple dose of OCA 5 mg, FIG. therapy and combination therapy with UDCA, based on 27E shows a multiple dose of OCA 10 mg, and FIG. 27F pooled data from study 747-201, study 747-202 and Phase shows a multiple dose of OCA 25 mg. 3 study 747-301. 0050 FIG. 28 shows External Validation of Model in 0040 FIG. 18 illustrates the Goodness of Fit: Observed Patients with Impaired Hepatic Function where FIG. 28A Concentrations vs Predicted Concentrations of OCA. FIG. shows mild impairment of OCA 10 mg, FIG. 28B shows 18A shows the individual glyco-OCA group, FIG. 18B moderate impairment of OCA 10 mg, FIG. 28C shows shows the individual unconjugated OCA group, FIG. 18C severe impairment of OCA 10 mg, FIG. 28D shows mild shows individual tauro-OCA group, FIG. 18D shows the impairment of OCA 25 mg, FIG. 28E shows moderate population glyco-OCA group, FIG. 18.E shows the popula impairment of OCA 25 mg, and FIG. 28F shows severe tion unconjugated OCA group, and FIG. 18F shows the impairment of OCA 25 mg. population tauro-OCA group. 0041 FIG. 19 illustrates the Goodness of Fit: Residuals. DETAILED DESCRIPTION FIG. 19A shows the glyco-OCA group vs. concentration, 0051 Pharmaceutical preparations containing a poorly FIG. 19B shows the unconjugated OCA group vs. concen water-soluble drug require some tools for improving the tration, FIG. 19C shows the tauro-OCA group vs. concen dissolution property of the drug, for example, adding a tration, FIG. 19D shows the glyco-OCA group vs. time, FIG. Surfactant or other additive, or amorphizing the drug. How 19E shows the unconjugated OCA group vs. time, and FIG. ever, the addition of the surfactant or other additive can 19E shows the tauro-OCA group vs. time. chemically destabilize the drug, and methods of amorphiz 0042 FIG. 20 illustrates External Validation of Model in ing the drug may require changing the crystal form. Subjects with Normal Hepatic Function. FIG. 20A shows the 0052. When compositions containing a high concentra single dose of 5 mg OCA, FIG. 20B shows the single dose tion of a poorly water-soluble drug are produced, usually, of 10 mg OCA, FIG. 20O shows the single dose of 25 mg powders are tableted by direct compression or granules are OCA, FIG.20D shows the multiple dose of 5 mg OCA, FIG. produced by dry or wet granulation methods and tableted. 20E shows the multiple dose of 10 mg OCA, and FIG. 20F However, tableting by direct compression and granulation shows the multiple dose of 25 mg OCA. are largely affected by the physical properties of the drug 0043 FIG. 21 illustrates External Validation of Model in and often have great weight variations and poor content Subjects with Normal Hepatic Function. FIG. 21A shows the uniformity at the time of tableting, resulting in poor manu 6 day profile in Period 1, FIG.21B shows the 24 hour profile facturability in consideration of productivity. Moreover, in Period 1, FIG. 21C shows the 6 day profile in Period 2, these approaches can provide a drug product with poor and FIG. 21D shows the 24 hour profile in Period 2. dissolution. US 2017/0035784 A1 Feb. 9, 2017 0053. The present application is directed to compositions 0058. The term “preservative,” as used herein, refers to and formulations of obeticholic acid, a pharmaceutically an agent or mixture of agents that is used to protect a active ingredient (also known as INT-747) having the chemi composition against antimicrobial (e.g., yeast, mold, bacte cal structure: ria) activity. Preservatives include, but are not limited to, Sodium benzoate, benzoic acid, ethylenediaminetetraacetic acid, Sorbic acid, benzethonium chloride, benzalkonium chloride, bronopol, butyl paraben, methyl paraben, ethylpa COH, raben, propyl paraben, thiomerosol, Sodium propionate, chlorhexidine, chlorobutanol, chlorocresol, cresol, imidurea, phenol, phenylmercuric salts, potassium Sorbate, propylene glycol, and mixtures thereof. In one embodiment, the pre servative can be any preservative known in the art. 0059. The term “organ” refers to a differentiated structure (as in a heart, lung, kidney, liver, etc.) consisting of cells and tissues and performing some specific function in an organ ism. This term also encompasses bodily parts performing a function or cooperating in an activity (e.g., an eye and obeticholic acid related structures that make up the visual organs). The term (also known as INT-747) “organ further encompasses any partial structure of differ entiated cells and tissues that is potentially capable of or a pharmaceutically acceptable salt, ester, or amino acid developing into a complete structure (e.g., a lobe or a section conjugate (such as, e.g., glycine, taurine or sarcosine con of a liver). jugate) thereof having improved dissolution, Solubility, and 0060. As used herein the term “6-ethyl chenodeoxycholic stability for the treatment of a disease or condition described acid”, “6-ECDCA”, “obeticholic acid' or “OCA' refers to a herein. compound having the chemical structure: 0054 The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and sci entific terms used herein have the same meaning as com monly understood by one of ordinary skill in the art to which this disclosure belongs. In the case of conflict, the present specification will control. All patents and publications cited in this specification are incorporated herein by reference in 0061. Other chemical names for obeticholic acid include: their entireties. 3C,7C.-dihydroxy-6C.-ethyl-5B-cholan-24-oic acid, 0055 All percentages and ratios used herein, unless oth 6O-ethyl-chenodeoxycholic acid, 6-ethyl-CDCA, 6ECDCA, erwise indicated, are by weight. cholan-24-oic acid, 6-ethyl-3,7-dihydroxy-(3C,5B,6O.7C)- 0056. The term “viscosity enhancer, as used herein, and INT-747. The CAS registry number for obeticholic acid refers to an agent or a mixture of agents that increases the is 459789-99-2. This term refers to all forms of obeticholic thickness of a liquid thereby keeping the active ingredient acid, e.g., non-crystalline, crystalline and Substantially pure. Suspended to allow accurate dosing. Viscosity enhancers 0062 An “obeticholic acid composition” described include, but are not limited to, Xantham gum, guar gum, herein refers to obeticholic acid administered to a patient in acacia, alginic acid, Sodium alginate, propylene glycol alg any form described herein including as a component of a inate, povidone, carbomer, salts of carboxymethylcellulose, pharmaceutical composition. methylcellulose, ethylcellulose, hydroxyethyl cellulose, 0063. The articles “a” and “an are used in this disclosure hydroxypropyl cellulose, hydroxypropyl methylcellulose, to refer to one or more than one (i.e., to at least one) of the bentonite, polydextrose, carrageenan, Sucrose, Sorbitol. Xyli grammatical object of the article. By way of example, “an tol, dextrose, fructose, malitol, gelatin, tragacanth, a poly element’ means one element or more than one element. vinyl alcohol, cetearyl alcohol, colloidal silicon dioxide and 0064. The term “and/or is used in this disclosure to mixtures thereof. In one embodiment, the Viscosity enhancer mean either “and” or 'or' unless indicated otherwise. can be any viscosity enhancer known in the art. 0065. As used herein, the term “purity” refers to a chemi 0057 The term “flavoring agent, as used herein, refers cal analysis of a compound obtained from, e.g., HPLC. In to an agent or a mixture of agents that adds flavor to a one embodiment, the purity of a compound is compared to mixture. Flavoring agents include, but are not limited to, the purity of the reference standard, e.g., obeticholic acid, artificial strawberry flavor, art banana flavor and artificial via the area under their respective peak for comparisons. In cream flavor. In one embodiment, the flavoring agent can be one embodiment, purity accounts for the organic impurities any flavoring agent known in the art. in a sample. US 2017/0035784 A1 Feb. 9, 2017 0066 “Treating, includes any effect, e.g., lessening, embodiments, obeticholic acid prepared in accordance with reducing, modulating, or eliminating, that results in the the present disclosure can be used to coat or impregnate a improvement of the condition, disease, disorder, etc. “Treat medical device, e.g., a stent. ing or “treatment of a disease state includes: inhibiting the 0075 For any compound, the therapeutically effective disease state, i.e., arresting the development of the disease amount can be estimated initially either in cell culture assays state or its clinical symptoms; or relieving the disease state, or in animal models, usually rats, mice, rabbits, dogs, or i.e., causing temporary or permanent regression of the pigs. The animal model may also be used to determine the disease state or its clinical symptoms. appropriate concentration range and route of administration. 0067. The term “regimen” refers to a protocol for dosing Such information can then be used to determine useful doses and/or timing the administration of one or more therapies and routes for administration in humans. Therapeutic/pro (e.g., an obeticholic acid composition described herein or phylactic efficacy and toxicity may be determined by stan another active agent Such as for example UDCA) for treating dard pharmaceutical procedures in cell cultures or experi a disease, disorder, or condition described herein. A regimen mental animals, e.g., ED50 (the dose therapeutically can include periods of active administration and periods of effective in 50% of the population) and LD50 (the dose rest as known in the art. Active administration periods lethal to 50% of the population). The dose ratio between include administration of the obeticholic acid compositions toxic and therapeutic effects is the therapeutic index, and it described herein in a defined course of time, including, for can be expressed as the ratio, LD50/ED50. Pharmaceutical example, the number of and timing of dosages of the compositions that exhibit large therapeutic indices are pre compositions. In some regimens, one or more rest periods ferred. The dosage may vary within this range depending can be included where no compound is actively adminis upon the dosage form employed, sensitivity of the patient, tered, and in certain instances, includes time periods where and the route of administration. the efficacy of Such compounds can be minimal. 0076 Dosage and administration are adjusted to provide 0068. The term "enhance” refers to an increase or Sufficient levels of the active agent(s) or to maintain the improvement in the function or activity of a protein or cell desired effect. Factors which may be taken into account after administration or contacting with a combination include the severity of the disease state, general health of the described herein compared to the protein or cell prior to such Subject, age, weight, and gender of the Subject, diet, time and administration or contact. frequency of administration, drug combination(s), reaction 0069. “Preventing the disease state includes causing the sensitivities, and tolerance/response to therapy. clinical symptoms of the disease state not to develop in a 0077. A “starting dose” as used herein refers to an initial Subject that may be exposed to or predisposed to the disease dose provided to a patient to provide a clinical effect while state, but does not yet experience or display symptoms of the minimizing onset or occurrence of an adverse effect. A disease state. starting dose can, in certain instances, be less than an amount 0070. The term “inhibiting or “inhibition,” as used typically administered to a patient. A starting dose is pro herein, refers to any detectable positive effect on the devel vided in an amount that is titrated or gradually increased opment or progression of a disease or condition. Such a over the course of a titration period or during the course of positive effect may include the delay or prevention of the treatment with an obeticholic acid composition described onset of at least one symptom or sign of the disease or herein. condition, alleviation or reversal of the symptom(s) or (0078. A “titration period” refers to a length of time for sign(s), and slowing or prevention of the further worsening which a starting dose is administered to a patient. A titration of the symptom(s) or sign(s). period continues for a specified length of time, where the 0071 “Disease state' means any disease, disorder, con patient is often monitored for liver function and/or liver dition, symptom, or indication. biochemistry as described herein. In one embodiment a 0072. The term “effective amount as used herein refers titration period concludes when a patient tolerates an obet to an amount of obeticholic acid (e.g., an FXR-activating icholic acid composition described herein but has a ligand) that produces an acute or chronic therapeutic effect decreased or minimal reduction in alkaline phosphatase. upon appropriate dose administration. The effect includes 0079 An “adjusted dose” as used herein refers to a dose the prevention, correction, inhibition, or reversal of the of an obeticholic acid composition described herein admin symptoms, signs and underlying pathology of a diseasef istered after the termination of a titration period. An adjusted condition (e.g., fibrosis of the liver, kidney, or intestine) and dose is often increased compared to a starting dose but, as related complications to any detectable extent. provided herein, patient tolerance and other factors 0073. “A therapeutically effective amount’ means the described herein determine the dosage amount of an amount of obeticholic acid that, when administered to a adjusted dose. A “re-adjusted dose' as used herein refers to mammal for treating a disease, is Sufficient to effect Such any changed dosage amount or dose frequency of an treatment for the disease. The “therapeutically effective adjusted dose in a patient. amount will vary depending on obeticholic acid, the dis 0080) “Hepatic impairment” is used in accordance with ease and its severity and the age, weight, etc., of the mammal its standard meaning(s) in the art and can, in certain embodi to be treated. A therapeutically effective amount can refer to ments herein refer to scoring based upon the Child-Pugh a starting dose or adjusted dose as set forth herein. Score of A, B, and C. 0074. A therapeutically effective amount of obeticholic I0081. The term “administering refers to the act of deliv acid can be formulated with a pharmaceutically acceptable ering an obeticholic acid composition described herein into carrier for administration to a human or an animal. Accord a subject by Such routes as oral, mucosal, topical, Supposi ingly, obeticholic acid or its formulations can be adminis tory, intravenous, parenteral, intraperitoneal, intramuscular, tered, for example, via oral, parenteral, or topical routes, to intralesional, intrathecal, intranasal or Subcutaneous admin provide an effective amount of the compound. In alternative istration. Parenteral administration includes intravenous, US 2017/0035784 A1 Feb. 9, 2017 intramuscular, intra-arterial, intradermal, Subcutaneous, solvent. Obeticholic acid may have a tendency to trap a fixed intraperitoneal, intraventricular, and intracranial administra molar ratio of solvent molecules in the crystalline solid state, tion. The term can also refer to the frequency (e.g., daily, thus forming a solvate. If the solvent is water the solvate weekly, monthly, etc.) of providing an obeticholic acid formed is a hydrate, when the solvent is alcohol, the solvate composition described herein to a patient. Administration formed is an alcoholate. Hydrates are formed by the com generally occurs after the onset of the disease, disorder, or bination of one or more molecules of water with one of the condition, or its symptoms but, in certain instances, can Substances in which the water retains its molecular state as occur before the onset of the disease, disorder, or condition, H2O, such combination being able to form one or more or its symptoms (e.g., administration for patients prone to hydrate. Additionally, the compounds of the present disclo Such a disease, disorder, or condition). In certain embodi Sure, for example, the salts of the compounds, can exist in ments, administration as used herein refers to oral admin either hydrated or unhydrated (the anhydrous) form or as istration. solvates with other solvent molecules. Non-limiting 0082. The term “co-administration” refers to administra examples of hydrates include monohydrates, dihydrates, etc. tion of two or more agents (e.g., an obeticholic acid com Non-limiting examples of Solvates include ethanol Solvates, position described herein and another active agent such as acetone Solvates, etc. UDCA or an anti-cancer agent described herein). The timing I0087. “Tautomers' refers to compounds whose structures of co-administration depends in part of the combination and differ markedly in arrangement of atoms, but which exist in the compositions administered and can include administra easy and rapid equilibrium. It is to be understood that tion at the same time, prior to, or after the administration of obeticholic acid may be depicted as different tautomers. It one or more additional therapies. An obeticholic acid com should also be understood that when obeticholic acid and position of the instant invention can be administered alone synthetic intermediates of the disclosure have tautomeric or can be coadministered to the patient. Co-administration is forms, all tautomeric forms are intended to be within the meant to include simultaneous or sequential administration Scope of the disclosure, and the naming of obeticholic acid of an obeticholic acid composition individually or in com does not exclude any tautomer form. obeticholic acid and bination (more than one compound or agent). Thus, the synthetic intermediates of the disclosure can exist in several preparations can also be combined, when desired, with other tautomeric forms, including the keto-enol. For example, in active Substances (e.g., to reduce metabolic degradation). keto-enol tautomerism a simultaneous shift of electrons and The obeticholic acid compositions described herein can be a hydrogen atom occurs. Tautomers exist as mixtures of a used in combination with each other (i.e., two different tautomeric set in solution. In solid form, usually one tau obeticholic acid compositions), with other active agents tomer predominates. Even though one tautomer may be known to be useful in treating a disease, or with adjunctive described, the present disclosure includes all tautomers of agents that are not effective alone, but can contribute to or the present compounds. enhance the efficacy of the active agent. I0088. It is to be understood accordingly that the isomers 0083. The term “anti-cancer agent' is used in accordance arising from asymmetric carbon atoms (e.g., all enantiomers with its plain ordinary meaning and refers to a composition and diastereomers) are included within the scope of the having anti-neoplastic properties or the ability to inhibit the disclosure, unless indicated otherwise. Such isomers can be growth or proliferation of cells. In embodiments, an anti obtained in Substantially pure form by classical separation cancer agent is a chemotherapeutic agent. In embodiments, techniques and by Stereochemically controlled synthesis. an anti-cancer agent is an agent identified herein having Furthermore, the structures and other compounds and moi utility in methods of treating cancer. In embodiments, an eties discussed in this application also include all tautomers anti-cancer agent is an agent approved by the FDA or similar thereof. Alkenes can include either the E- or Z-geometry, regulatory agency of a country other than the USA, for where appropriate. Obeticholic acid and synthetic interme treating cancer. diates may exist in stereoisomeric form, and therefore can be 0084) “Pharmacological effect” as used herein encom produced as individual stereoisomers or as mixtures. passes effects produced in the subject that achieve the I0089. A “pharmaceutical composition' is a formulation intended purpose of a therapy. In one embodiment, a phar containing obeticholic acid in a form Suitable for adminis macological effect means that primary indications of the tration to a Subject. In one embodiment, the pharmaceutical Subject being treated are prevented, alleviated, or reduced. composition is in bulk or in unit dosage form. It is can be For example, a pharmacological effect would be one that advantageous to formulate compositions in dosage unit form results in the prevention, alleviation or reduction of primary for ease of administration and uniformity of dosage. Dosage indications in a treated Subject. In another embodiment, a unit form, as used herein, refers to physically discrete units pharmacological effect means that disorders or symptoms of Suited as unitary dosages for the Subject to be treated; each the primary indications of the Subject being treated are unit containing a predetermined quantity of active reagent prevented, alleviated, or reduced. For example, a pharma calculated to produce the desired therapeutic effect in asso cological effect would be one that results in the prevention ciation with the required pharmaceutical carrier. The speci or reduction of primary indications in a treated Subject. fication for the dosage unit forms of the disclosure are 0085 “Geometric Isomers’ means the diastereomers that dictated by and directly dependent on the unique character owe their existence to hindered rotation about double bonds. istics of the active reagent and the particular therapeutic These configurations are differentiated in their names by the effect to be achieved, and the limitations inherent in the art prefixes cis and trans, or Z and E, which indicate that the of compounding Such an active agent for the treatment of groups are on the same or opposite side of the double bond individuals. in the molecule according to the Cahn-Ingold-Prelog rules. 0090 The term “unit dosage form” refers to physically 0.086 “Solvates' means solvent addition forms that con discrete units Suitable as unitary dosages for human Subjects tain either stoichiometric or non-stoichiometric amounts of and other mammals, each unit containing a predetermined US 2017/0035784 A1 Feb. 9, 2017 quantity of active material calculated to produce the desired 0097. A pharmaceutical composition of the disclosure is therapeutic effect, in association with a Suitable pharmaceu formulated to be compatible with its intended route of tical excipient as described above. administration. Examples of routes of administration include 0091. The unit dosage form is any of a variety of forms, parenteral, e.g., intravenous, intradermal, Subcutaneous, oral including, for example, a capsule, an IV bag, a tablet, a (e.g., inhalation), transdermal (topical), and transmucosal single pump on an aerosol inhaler, or a vial. The quantity administration. Solutions or Suspensions used for parenteral, obeticholic acid (e.g., a formulation of obeticholic acid, or a intradermal, or Subcutaneous application can include the pharmaceutically acceptable salt, Solvate, or amino acid following components: a sterile diluent Such as water for conjugate thereof) in a unit dose of composition is an injection, Saline solution, fixed oils, polyethylene glycols, effective amount and is varied according to the particular glycerine, propylene glycol or other synthetic solvents; treatment involved. One skilled in the art will appreciate that antibacterial agents such as benzyl alcohol or methyl para it is sometimes necessary to make routine variations to the bens; antioxidants such as ascorbic acid or sodium bisulfite: dosage, depending on the age and condition of the patient. chelating agents such as ethylenediaminetetraacetic acid The dosage will also depend on the route of administration. (EDTA); buffers such as acetates, citrates or phosphates, and A variety of routes are contemplated, including oral, pull agents for the adjustment of tonicity Such as Sodium chloride monary, rectal, parenteral, transdermal, Subcutaneous, intra or dextrose. The pH can be adjusted with acids or bases, such venous, intramuscular, intraperitoneal, inhalational, buccal, as hydrochloric acid or sodium hydroxide. The parenteral Sublingual, intrapleural, intrathecal, intranasal, and the like. preparation can be enclosed in ampoules, disposable Dosage forms for the topical or transdermal administration Syringes or multiple dose vials made of glass or plastic. of a compound of this disclosure include powders, sprays, 0098 “Process of the disclosure refers to a method for ointments, pastes, creams, lotions, gels, solutions, patches preparing obeticholic acid as described herein, wherein the and inhalants. In one embodiment, obeticholic acid is mixed method comprises preparing a crystalline form of obet under Sterile conditions with a pharmaceutically acceptable icholic acid. carrier, and with any preservatives, buffers, or propellants 0099. A “control as used herein refers to a baseline level that are required. determined on a patient-by-patient basis, an amount or level 0092. The term “flash dose” refers to obeticholic acid considered by those skilled in the art as a normal value, or formulations that are rapidly dispersing dosage forms. any level or measure of a condition or biomarker described herein taken from a patient or population of patients at any 0093. The term “immediate release' is defined as a given time for a given condition. release of obeticholic acid from a dosage form in a relatively 0100 “Fibrosis” refers to a condition involving the devel brief period of time, generally up to about 60 minutes. The opment of excessive fibrous connective tissue, e.g., Scar term “modified release' is defined to include delayed tissue, in a tissue or organ. Such generation of Scar tissue release, extended release, and pulsed release. The term may occur in response to infection, inflammation, or injury “pulsed release' is defined as a series of releases of drug of the organ due to a disease, trauma, chemical toxicity, and from a dosage form. The term “sustained release' or so on. Fibrosis may develop in a variety of different tissues “extended release' is defined as continuous release of obet and organs, including the liver, kidney, intestine, lung, heart, icholic acid from a dosage form over a prolonged period. etc. 0094. A “subject' or “patient includes mammals, e.g., 0101. As used herein, a “cholestatic condition” refers to humans, companion animals (e.g., dogs, cats, birds, and the any disease or condition in which bile excretion from the like), farm animals (e.g., cows, sheep, pigs, horses, fowl, and liver is impaired or blocked, which can occur either in the the like) and laboratory animals (e.g., rats, mice, guinea liver or in the bile ducts. Intrahepatic cholestasis and extra pigs, birds, and the like). In one embodiment, the patient is hepatic cholestasis are the two types of cholestatic condi human. In one embodiment, the Subject is human child (e.g., tions. Intrahepatic cholestasis (which occurs inside the liver) between about 30 kg to about 70 kg). In one embodiment, is most commonly seen in primary biliary cirrhosis, primary the human child has had a Kasai procedure, where the Kasai Sclerosing cholangitis, sepsis (generalized infection), acute procedure effectively gives them a functional bile duct when alcoholic hepatitis, drug toxicity, total parenteral nutrition they are born either without a bile duct or a bile duct that is (being fed intravenously), malignancy, cystic fibrosis, and completely blocked at birth. pregnancy. Extrahepatic cholestasis (which occurs outside 0095. As used herein, the phrase “pharmaceutically the liver) can be caused by bile duct tumors, strictures, cysts, acceptable' refers to those compounds, materials, composi diverticula, Stone formation in the common bile duct, pan tions, carriers, and/or dosage forms which are, within the creatitis, pancreatic tumor or pseudocyst, and compression Scope of sound medical judgment, Suitable for use in contact due to a mass or tumor in a nearby organ. with the tissues of human beings and animals without 0102 Clinical symptoms and signs of a cholestatic con excessive toxicity, irritation, allergic response, or other dition include: itching (pruritus), fatigue, jaundiced skin or problem or complication, commensurate with a reasonable eyes, inability to digest certain foods, nausea, vomiting, pale benefit/risk ratio. stools, dark urine, and right upper quadrant abdominal pain. 0096 “Pharmaceutically acceptable excipient’ means an A patient with a cholestatic condition can be diagnosed and excipient that is useful in preparing a pharmaceutical com followed clinically based on a set of standard clinical position that is generally safe, non-toxic and neither bio laboratory tests, including measurement of levels of alkaline logically nor otherwise undesirable, and includes excipient phosphatase, Y-glutamyl transpeptidase (GGT), 5' nucleoti that is acceptable for veterinary use as well as human dase, bilirubin, bile acids, and cholesterol in a patients pharmaceutical use. A "pharmaceutically acceptable excipi blood serum. Generally, a patient is diagnosed as having a ent as used in the specification and claims includes both one cholestatic condition if serum levels of all three of the and more than one such excipient. diagnostic markers alkaline phosphatase, GGT, and 5' US 2017/0035784 A1 Feb. 9, 2017 nucleotidase, are considered abnormally elevated. The nor diameter of 200 um or less, and 10% of the particles have a mal serum level of these markers may vary to Some degree diameter of 5 um or less. In a further embodiment, 90% of from laboratory to laboratory and from procedure to proce the particles have a diameter of 300 um or less, 50% of the dure, depending on the testing protocol. Thus, a physician particles have a diameter of 150 um or less, and 10% of the will be able to determine, based on the specific laboratory particles have a diameter of 5 um or less. In another and test procedure, what an abnormally elevated blood level embodiment, 90% of the particles have a diameter of 100 um is for each of the markers. For example, a patient Suffering or less, 50% of the particles have a diameter of 50 m or less, from a cholestatic condition generally has greater than about and 10% of the particles have a diameter of 5 um or less. In 125 IU/L alkaline phosphatase, greater than about 65 IU/L another embodiment, 90% of the particles have a diameter GGT, and greater than about 17 NIL 5' nucleotidase in the of 100 um or less, 50% of the particles have a diameter of blood. Because of the variability in the level of serum 20 um or less, and 10% of the particles have a diameter of markers, a cholestatic condition may be diagnosed on the 5 um or less. basis of abnormal levels of these three markers in addition 0108. In yet another embodiment, 90% of the particles to at least one of the symptoms mentioned above, such as have a diameter of 100 um or less, 50% of the particles have itching (pruritus). a diameter of 10 um or less, and 10% of the particles have 0103) In one aspect, the disclosure provides a composi a diameter of 5 um or less. In yet another embodiment, 90% tion comprising obeticholic acid, or a pharmaceutically of the particles have a diameter of 90 um or less, 50% of the acceptable salt, ester, or amino acid conjugate thereof, particles have a diameter of 10 um or less, and 10% of the wherein obeticholic acid or a pharmaceutically acceptable particles have a diameter of 5 um or less. In another salt, ester, or amino acid conjugate thereof is in the form of embodiment, 90% of the particles have a diameter of 50 um particles, and wherein at least 50% of the particles have a or less, 50% of the particles have a diameter of 10 um or less, diameter of less than 200 um. The composition of the and 10% of the particles have a diameter of 5 um or less. In disclosure possesses advantageous properties, including a further embodiment, 90% of the particles have a diameter improved dissolution profile and solubility. of 50 um or less, 50% of the particles have a diameter of 5 0104. In one embodiment, 90% of the particles have a um or less, and 10% of the particles have a diameter of 1 um diameter of 400 um or less, 300 um or less, 200 um or less, or less. In a further embodiment, 90% of the particles have 100 um or less, 90 Lum or less, 80 um or less, 70 um or less, a diameter of 25 um or less, 50% of the particles have a 60 um or less, 50 um or less, 25 um or less. In a further diameter of 5 um or less, and 10% of the particles have a embodiment, 90% of the particles have a diameter of 300 um diameter of 1 Lim or less. or less, such as 200 um or less, 100 um or less, 90 um or less, 0109. In one embodiment, 99% of the particles have a 80 um or less, 70 um or less, 60 um or less, 50 um or less, diameter of 200 um or less, such as 1 um to 100 um, and 1 25um or less. In a further embodiment, 90% of the particles um to 80 um: 90% of the particles have a diameter of 200 have a diameter of 100 um or less, such as 90 m or less, 80 um or less, such as 2 um to 100 um, and 2 um to 80 Lum; and um or less, 70 um or less, more preferably 60 um or less, 50% of the particles have a diameter of 200 um or less, such more preferably 50 m or less, 25 um or less. In a further as 7 um to 100 um, 8 um to 100 um, and 9 um to 80 Lum. embodiment, 90% of the particles have a diameter of 90 um Furthermore preferably 90% of the particles have a diameter or less, such as 80 um or less, 70 um or less, 60 um or less, of 100 um or less, and 50% of the particles have a diameter 50 um or less, 25um or less. In a further embodiment, 90% of 90 um or less. of the particles have a diameter of 50 um or less, such as 25 0110. In one embodiment, 50% of the particles have a um or less. In a further embodiment, 90% of the particles diameter of 100 um or less, such as 5 um to 100 um, and 5 have a diameter of 25 um or less. um to 50 um: 90% of the particles have a diameter of 200 0105. In one embodiment, 50% of the particles have a um or less, Such as 3 um to 200 um, and 3 um to 150 um; diameter of 200 um or less, such as 150 um or less, 100 um and 99% of the particles have a diameter of 300 um or less, or less, 80 um or less, 60 um or less, 40 um or less, 20 Jum such as 1 um to 300 um, and 1 um to 200 um. In a further or less, 15um or less, 10um or less, 5um or less. In a further embodiment, 90% of the particles have a diameter of 150 um embodiment, 50% of the particles have a diameter of 100 um or less, such as 3 um to 150 um, and 3 um to 100 um; and or less, such as 80 um or less, 60 um or less, 40 um or less, 99% of the particles have a diameter of 200 um or less, such 20 um or less, 15um or less, more preferably 10 um or less, as 1 um to 200 um, and 1 um to 150 lum. In a further 5um or less. In a further embodiment, 50% of the particles embodiment, 99% of the particles have a diameter of 150 um have a diameter of 20 Lum or less, such as 15 um or less, 10 or less, preferably 2 um to 150 lum, and more preferably 2 um or less, 5 um or less. In a further embodiment, 50% of um to 100 um. the particles have a diameter of 10 um or less, such as 5um 0111. In the present disclosure, the “particle size reduc or less. In a further embodiment, 50% of the particles have tion' is carried out for the purpose of crushing Solid particles a diameter of 5 um or less. by the application of mechanical force Such as impact, 0106. In one embodiment, 10% of the particles have a shearing, or friction thereto to reduce the particle sizes, diameter of 5 um or less, such as 4 um or less, 3 um or less, thereby facilitating the formation of a homogeneous mixed 2 um or less, 1 um or less. In a further embodiment, 10% of state and improving the dissolution rate and bioavailability the particles have a diameter of 3 um or less, 2 um or less, of the drug owing to the increased Surface area (which refers or 1 um or less. In a further embodiment, 10% of the to as specific surface area, or “SSA) of the drug. Known particles have a diameter of 2 um or less, such as, e.g., 1 um particle size reduction methods include, but are not limited or less. In a further embodiment, 10% of the particles have to: high-speed rotating impact mills (hammer mills and a diameter of 1 um or less. impact mills), which reduce particle size by means of the 0107. In one embodiment, 90% of the particles have a impact force of a high-speed rotating hammer or pin in a diameter of 400 um or less, 50% of the particles have a chamber; carrier mills (ball mills or vibration mills) which US 2017/0035784 A1 Feb. 9, 2017 reduce particle size powder by means of impact force or observed at pH 6.8 to 10, the particle size distribution of friction force in a rotating cylinder in which the powder and OCA is believed to impact its dissolution rate. magnetic balls are placed; and fluid energy mills (jet mills), (0123. In one embodiment, in vitro dissolution rates or which reduce particle size by jetting compressed air and raw profiles of the entire active ingredient of the pharmaceutical material particles from a nozzle and colliding the particles composition are measured from the entire pharmaceutical accelerated by the jet of air with swirling particles in a composition according to the steps and conditions in chamber. In one embodiment, the particle size of obeticholic Example 3. The dissolution rate can be measured in a variety acid is reduced using a jet mill. “Micronization, as defined of buffers, which optionally contains one or more surfac herein, is a reduction of particle size of an active ingredient, tants. Non-limiting examples of buffers include acetate i.e., obeticholic acid, to a diameter that is less than about 200 buffer, phosphate buffers, and alkaline borate buffers, or a um, Such as less than about 100 um, less than about 50 um, combination thereof. Non-limiting examples of Surfactants and less than 25 Lum. include, polysorbate 80 (Tween 80R), potassium laurate, 0112. In some examples, obeticholic acid has a particle Sodium laurate, triethanol ammonium laurate, potassium size distribution with a Ds of not more than 100 um. In myristate, Sodium myristate, triethanol ammonium specific embodiments, the Dso is not more than 50 Lim, not myristate, sodium lauryl Sulfate, polyoxyethylene alkyl more than 20 Jum, or not more than 10 Jum. In other ether sodium sulfate, Sodium alkyl 3-alanine, sodium Sul examples, the Doo is not more than 200 um, or not more than foSuccinate, acylmethyl taurine, sodium alkylethane Sui 100 um. In still other examples, the Do is not more than 20 fonate, polyoxyethylene alkyl ether Sodium carboxylate, um, not more than 10 um, or not more than 5 Jum. trimethyl ammonium chloride, benzalkonium chloride, lau 0113 Particle size analysis can be carried out via differ ryl amine oxide, amide propyl betaine coconut fatty add, ent methods. Non-limiting examples of the methods include, amide propyl betaine laurate, amide propyl betaine but are not limited to, sieve technique, wet dispersion myristate, Sorbitan monolaurate, Sorbitan monopalmitate, method with laser diffraction analysis, dry dispersion Sorbitan sesquioleate, polyoxyethylene Sorbitan monolau method with laser diffraction analysis, or a combination rate, polyethylene glycol monooleate, polyoxyethylene alkyl thereof. Particle size analysis is not limited to the methods ether, polyglycol diester, lauroyl diethanol amide, fatty acid described herein and can be carried out using any method isopropanol amide, maltitol hydroxy fatty acid alkyl ether, known to one skilled in the art. In one embodiment, particle alkylated polysaccharide, alkyl glucoside, and Sucrose fatty size analysis can be performed via a sieve technique. In acid ester or a combination thereof. In one embodiment, the another embodiment, particle size analysis can be performed dissolution rate is measured in Disodium Hydrogen Phos using a wet dispersion method (e.g., water as the dispersing phate Buffer (NaHPO). In another embodiment, the dis agent, and analysis by laser diffraction using, e.g., Sympatec Solution rate is measured in a buffer containing a Surfactant equipment). In yet another embodiment, particle size analy (e.g., 0.01-0.1% wt/wt). In one embodiment, the surfactant sis can be performed using a dry dispersion method and is polysorbate 80 (Tween 80R). analyzed by laser diffraction using, e.g., Sympatec equip 0.124. In one embodiment, in vitro dissolution rates or ment. profiles are measured by using a using USP II paddle 0114. In one embodiment, particle size distribution (% apparatus in Disodium Hydrogen Phosphate Buffer Volume at each particle size) is measured via a Sympatec (NaHPO) at a temperature of about 37+0.5° C. and laser diffraction analyzer (e.g., Helos/KF-Magic F71000 paddles rotation between about 50 rpm to about 100 rpm. In with Rodos Dispersing Unit, Vibri sampling unit with another embodiment, in vitro dissolution rates or profiles are Sniffer rotation, Nilfisk exhaustion, or equivalent). In measured by using a using USP II paddle apparatus in another embodiment, particle size distribution (% volume at Disodium Hydrogen Phosphate Buffer (NaHPO) contain each particle size) is measured via a Malvern laser diffrac ing polysorbate 80 (Tween 80R) (e.g., 0.01-0.1% wt/wt) at tion analyzer. a temperature of about 37+0.5° C. and paddles rotation 0115 For example, particles can be measured using the between about 50 rpm to about 100 rpm. The entire phar following: maceutical composition includes the entire active ingredient 0116 Particle diameter distribution measurement appa and if the pharmaceutical composition contains a capsule ratus: HELOS (KF-Magic F71000) & RODOS System shell, carrier, excipient, diluent, disintegrating agent, lubri (manufactured by Sympatec GmbH): cant, binder or any additional agent described in the Phar 0117. Measurement range of laser diffraction apparatus: maceutical Composition Section below, the measurement is 0.5/0.9 to 175 um; performed with those components. 0118 Calculation mode of laser diffraction apparatus: 0.125. In one embodiment, in vitro dissolution is con Fraunhofer HRLD (v3.2 Rel. 2); ducted at about 75 rpm using Disodium Hydrogen Phos 0119) Disperser: RODOS, dry dispersion system: phate Buffer (NaHPO). In another embodiment, in vitro 0120 Dispersive pressure: 1.0 bar. dissolution is conducted at 75 rpm using about 900 mL of a 0121 The composition of the present disclosure compris Disodium Hydrogen Phosphate Buffer (NaHPO). Solu ing obeticholic acid or a pharmaceutically acceptable salt, tions are collected at 15 minutes, 30 minutes, 45 minutes, 60 ester, or amino acid conjugate thereof, in the form of minutes, and 75 minutes after the start of the dissolution. particles, offers improved dissolution and solubility. The dissolution rate of the compound is measured by 0122) Without any intent to be bound by theory, obet high-performance liquid chromatography (HPLC) with icholic acid (OCA) (pK-4.82) exhibits a pH-solubility Corona Charged Aerosol Detection (CAD). profile consistent with that of a weak acid. Solutions of OCA 0.126 In one embodiment, the concentration for OCA at pH 6.8 to 10 produce clear solutions. However, recovery (e.g., in a Disodium Hydrogen Phosphate Buffer, optionally of OCA steadily diminishes at pH higher than 8.0, indicating containing a surfactant, Such as polysorbate 80 (Tween basic decomposition of OCA. Despite the solubility 80R)), after dissolution is between about 0.001 mg/mL to US 2017/0035784 A1 Feb. 9, 2017 about 0.01 mg/mL, or between about 0.001 mg/mL to about or about 65% to about 95% is dissolved within about 30 0.03 mg/mL. Above pH 6.8, the solubility of OCA is well minutes, or about 80% to about 95% is dissolved within above 0.01 mg/mL. about 45 minutes, or about 87% to about 97% is dissolved 0127. In one embodiment, the concentration for dissolved within about 60 minutes, or about 87% to about 99% is 5 mg tablets of OCA is between about 0.001 mg/mL to about dissolved within about 75 minutes. For example, about 60% 0.02 mg/mL. In another embodiment, the concentration for to about 84% of obeticholic acid or a pharmaceutically dissolved 5 mg tablets of OCA is between about 0.003 acceptable salt, ester, or amino acid conjugate thereof in the mg/mL to about 0.01 mg/mL. In yet another embodiment, particle composition of the present disclosure is dissolved the concentration for dissolved 5 mg tablets of OCA is within about 15 minutes, or about 75% to about 91% is between about 0.004 mg/mL to about 0.009 mg/mL. In dissolved within about 30 minutes, or about 85% to about another embodiment, the concentration for dissolved 5 mg 93% is dissolved within about 45 minutes, or about 90% to tablets of OCA is between about 0.005 mg/mL to about about 96% is dissolved within about 60 minutes, or about 0.008 mg/mL. In yet another embodiment, the concentration 90% to about 97% is dissolved within about 75 minutes. For for dissolved 5 mg tablets of OCA is between about 0.006 example, about 62% to about 83% of obeticholic acid or a mg/mL to about 0.007 mg/mL. In another embodiment, the pharmaceutically acceptable salt, ester, or amino acid con concentration for dissolved 5 mg tablets of OCA is about jugate thereof in the particle composition of the present 0.006 mg/mL. In yet another embodiment, the concentration disclosure is dissolved within about 15 minutes, or about for dissolved 5 mg tablets of OCA is about 0.0056 mg/mL. 80% to about 90% is dissolved within about 30 minutes, or 0128. In one embodiment, the concentration for dissolved about 87% to about 94% is dissolved within about 45 10 mg tablets of OCA is between about 0.001 mg/mL to minutes, or about 92% to about 96% is dissolved within about 0.03 mg/mL. In another embodiment, the concentra about 60 minutes, or about 91% to about 97% is dissolved tion for dissolved 10 mg tablets of OCA is between about within about 75 minutes. For example, about 60% to about 0.005 mg/mL to about 0.025 mg/mL. In yet another embodi 84% obeticholic acid or a pharmaceutically acceptable salt, ment, the concentration for dissolved 10 mg tablets of OCA ester, or amino acid conjugate thereof in the particle com is between about 0.008 mg/mL to about 0.02 mg/mL. In position of the present disclosure is dissolved within about another embodiment, the concentration for dissolved 10 mg 15 minutes, or about 70% to about 90% is dissolved within tablets of OCA is between about 0.009 mg/mL to about about 30 minutes, or about 85% to about 92% is dissolved 0.015 mg/mL. In yet another embodiment, the concentration within about 45 minutes, or about 89% to about 96% is for dissolved 10 mg tablets of OCA is about 0.011 mg/mL. dissolved within about 60 minutes, or about 90% to about In another embodiment, the concentration for dissolved 10 96% is dissolved within about 75 minutes. For example, at mg tablets of OCA is about 0.010 mg/mL. least about 60% obeticholic acid or a pharmaceutically 0129. In one embodiment, the concentration for dissolved acceptable salt, ester, or amino acid conjugate thereof in the 25 mg tablets of OCA is between about 0.001 mg/mL to particle composition of the present disclosure is dissolved about 0.05 mg/mL. In another embodiment, the concentra within about 15 minutes, or at least about 90% is dissolved tion for dissolved 25 mg tablets of OCA is between about within about 60 minutes. For example, obeticholic acid or a 0.01 mg/mL to about 0.08 mg/mL. In yet another embodi pharmaceutically acceptable salt, ester, or amino acid con ment, the concentration for dissolved 25 mg tablets of OCA jugate thereof in the particle composition of the present is between about 0.02 mg/mL to about 0.06 mg/mL. In disclosure has an in vitro dissolution profile of about 51% another embodiment, the concentration for dissolved 25 mg dissolved within about 15 minutes, or about 66% dissolved tablets of OCA is between about 0.025 mg/mL to about 0.04 within about 30 minutes, or about 79% dissolved within mg/mL. In yet another embodiment, the concentration for about 45 minutes, or about 85% dissolved within about 60 dissolved 25 mg tablets of OCA is about 0.026 mg/mL to minutes. about 0.03 mg/mL. In another embodiment, the concentra 0.132. In one embodiment, the composition of the present tion for dissolved 25 mg tablets of OCA is about 0.028 disclosure comprising obeticholic acid or a pharmaceuti mg/mL. cally acceptable salt, ester, or amino acid conjugate thereof, 0130. In one embodiment, the composition of the present in the form of particles, provides improved solubility of disclosure comprising obeticholic acid or a pharmaceuti obeticholic acid or a pharmaceutically acceptable salt, ester, cally acceptable salt, ester, or amino acid conjugate thereof, or amino acid conjugate thereof. For example, obeticholic in the form of particles, provides improved dissolution of acid or a pharmaceutically acceptable salt, ester, or amino obeticholic acid or a pharmaceutically acceptable salt, ester, acid conjugate thereof in the particle composition of the or amino acid conjugate thereof. For example, obeticholic present disclosure has a solubility (e.g., in a Disodium acid or a pharmaceutically acceptable salt, ester, or amino Hydrogen Phosphate Buffer) that is at least 2%. 3%, 4%, acid conjugate thereof in the particle composition of the 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50%, present disclosure dissolves (e.g., in a Disodium Hydrogen 80%, or 100% higher than the solubility when obeticholic Phosphate Buffer) at a rate that is at least 2%. 3%, 4%. 5%, acid or a pharmaceutically acceptable salt, ester, or amino 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50%, 80%, acid conjugate thereof is not present in the particle compo or 100% faster than the dissolution rate when obeticholic sition of the present disclosure. For example, obeticholic acid or a pharmaceutically acceptable salt, ester, or amino acid or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof is not present in the particle compo acid conjugate thereof in the particle composition of the sition of the present disclosure. present disclosure has a solubility (e.g., in a Disodium 0131) For example, about 55% to about 95% of obet Hydrogen Phosphate Buffer) that is at least 2%. 3%, 4%, icholic acid or a pharmaceutically acceptable salt, ester, or 5%, 6%, 7%, 8%, 9%, 10%, 15%, or 20% higher than the amino acid conjugate thereof in the particle composition of solubility when obeticholic acid or a pharmaceutically the present disclosure is dissolved within about 15 minutes, acceptable salt, ester, or amino acid conjugate thereof is not US 2017/0035784 A1 Feb. 9, 2017 present in the particle composition of the present disclosure conjugates thereof can generally be prepared by carrying out at a pH (e.g., pH 6.8) at which obeticholic acid has the the procedures disclosed in the Schemes and/or in the highest solubility (e.g., freely soluble) when not present in Examples of the disclosure, by Substituting a readily avail the particle composition of the present disclosure. able isotopically labeled reagent for a non-isotopically 0133. In one embodiment, obeticholic acid, or a pharma labeled reagent. In one embodiment, obeticholic acid, or ceutically acceptable salt, ester, or amino acid conjugate pharmaceutically acceptable salts, Solvates, or amino acid thereof, and/or particles of obeticholic acid, or a pharma conjugates thereof are not isotopically labeled. In one ceutically acceptable salt, ester, or amino acid conjugate embodiment, deuterated obeticholic acid is useful for bio thereof, has a solubility of about 0.001 to about 0.600 analytical assays. In another embodiment, obeticholic acid, mg/mL. In another embodiment, obeticholic acid, or a or pharmaceutically acceptable salts, Solvates, or amino acid pharmaceutically acceptable salt, ester, or amino acid con conjugates thereof are radiolabeled. jugate thereof, and/or particles of obeticholic acid, or a pharmaceutically acceptable salt, ester, or amino acid con 0.136. In another aspect, the disclosure provides a com jugate thereof, has a solubility of about 0.02 to about 0.500 position comprising obeticholic acid, or a pharmaceutically mg/mL. In yet another embodiment, obeticholic acid, or a acceptable salt, ester, or amino acid conjugate thereof, and pharmaceutically acceptable salt, ester, or amino acid con a pharmaceutically acceptable excipient having a low alco jugate thereof, and/or particles of obeticholic acid, or a hol (e.g., an impurity having at least one primary OH group, pharmaceutically acceptable salt, ester, or amino acid con Such as ethanol or methanol) content. In one embodiment, jugate thereof, has a solubility of about 0.03 to about 0.48 the alcohol is a primary alcohol. As defined herein “primary mg/mL. In another embodiment, obeticholic acid, or a alcohol is an alcohol which has a hydroxy group connected pharmaceutically acceptable salt, ester, or amino acid con to a primary carbon atom. The composition of the disclosure jugate thereof, and/or particles of obeticholic acid, or a possesses advantageous properties, including improved sta pharmaceutically acceptable salt, ester, or amino acid con bility of obeticholic acid in the composition. jugate thereof, has a solubility of about 0.05 to about 0.46 mg/mL. In yet another embodiment, obeticholic acid, or a 0.137 The excipient can be any excipient present in the pharmaceutically acceptable salt, ester, or amino acid con composition comprising obeticholic acid, or a pharmaceu jugate thereof, and/or particles of obeticholic acid, or a tically acceptable salt, ester, or amino acid conjugate pharmaceutically acceptable salt, ester, or amino acid con thereof. Examples of excipients include, but are not limited jugate thereof, has a solubility of about 0.1 to about 0.5 to, calcium phosphate, microcrystalline cellulose, sodium mg/mL. In another embodiment, obeticholic acid, or a starch glycolate and magnesium Stearate, or a combination pharmaceutically acceptable salt, ester, or amino acid con thereof. In one embodiment, the excipient can be any jugate thereof, and/or particles of obeticholic acid, or a excipient known in the art. In another embodiment, the pharmaceutically acceptable salt, ester, or amino acid con excipient is selected from calcium phosphate, microcrystal jugate thereof, has a solubility of about 0.2 to about 0.6 line cellulose, Sodium starch glycolate and magnesium Stear mg/mL. ate. In yet another embodiment, the excipient is selected 0134. The disclosure also comprehends isotopically-la from microcrystalline cellulose, Sodium starch glycolate and beled obeticholic acid, or pharmaceutically acceptable salts, magnesium Stearate. In another embodiment, the excipient is Solvate, or amino acid conjugates thereof, which are iden the excipient is magnesium Stearate. In yet another embodi tical to those recited in formulae of the disclosure and ment, the excipient is microcrystalline cellulose. In a further following, but for the fact that one or more atoms are embodiment, the excipient is sodium starch glycolate. replaced by an atom having an atomic mass or mass number 0.138. In one embodiment, the excipient has an impurity different from the atomic mass or mass number most com having a primary alcohol group. In another embodiment, the monly found in nature. Examples of isotopes that can be impurity in the excipient is ethanol, methanol, polyvinyl incorporated into obeticholic acid, or pharmaceutically alcohol, polyethylene glycol, or a Substance having at least acceptable salts, Solvate, or amino acid conjugates thereof one primary OH moiety. include isotopes of hydrogen, carbon, nitrogen, fluorine, such as H, C, ''C and F. 0.139. In one embodiment, the total alcohol (e.g., the 0135. Obeticholic acid, or pharmaceutically acceptable impurity having at least one primary OH group) content in salts, Solvates, or amino acid conjugates thereof that contain the excipient is less than 6%. 5%, 4.5%, 4%, 3.5%, 3%, the aforementioned isotopes and/or other isotopes of other 2.5%, 2%, 1.5%, 1%, or 0.5% (wit/wt). In one embodiment, atoms are within the scope of the present disclosure. Isoto the alcohol is a Substance having at least one primary OH pically-labeled obeticholic acid, or pharmaceutically accept moiety. In one embodiment, the alcohol is ethanol, metha able salts, Solvates, or amino acid conjugates thereof, for nol, polyvinyl alcohol, polyethylene glycol, or a combina example those into which radioactive isotopes such as H. tion thereof. In one embodiment, the total content of ethanol, '''C are incorporated, are useful in drug and/or substrate methanol, polyvinyl alcohol, polyethylene glycol, or a com tissue distribution assays. Tritiated, i.e., H, and carbon-14, bination thereof in the excipient is less than 6%. 5%, 4.5%, i.e., ''C, isotopes are particularly preferred for their ease of 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% (wit/wt). preparation and detectability. Further, substitution with 0140. In one embodiment, the alcohol is ethanol. In one heavier isotopes such as deuterium, i.e., H. can afford embodiment, the total ethanol content in the excipient is less certain therapeutic advantages resulting from greater meta than 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or bolic stability, for example increased in vivo half-life or 0.5% (wit/wt). In another embodiment, the excipient is reduced dosage requirements and, hence, may be preferred Sodium starch glycolate. In one embodiment, the sodium in some circumstances, isotopically labeled obeticholic acid, starch glycolate comprises less than 6%. 5%, 4.5%, 4%, or pharmaceutically acceptable salts, Solvates, or amino acid 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% (wit/wt) ethanol. US 2017/0035784 A1 Feb. 9, 2017 0141. In one embodiment, the alcohol is methanol. In one 0149. In one embodiment, the impurity is a methyl ester embodiment, the total methanol content in the excipient is of obeticholic acid. In one embodiment, the amount of the less than 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, methyl ester of obeticholic acid is decreased by at least 10%, 1%, or 0.5% (wt?wt). 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%. 0142. In another embodiment, the alcohol is a substance In one embodiment, the amount of the methyl ester of having at least one primary OH moiety. In one embodiment, obeticholic acid is decreased by at least 50%, 60%, 70%, the total content of the Substance having at least one primary 80%, 90%, 95%, or 99%. In another embodiment, the OH moiety in the excipient is less than 6%. 5%, 4.5%, 4%, amount of the methyl ester of obeticholic acid is less than 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% (wit/wt). 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0143. In one embodiment, the alcohol is polyvinyl alco 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01% (wit/wt). hol. In one embodiment, the total polyvinyl alcohol content 0150. An analysis of the impurities in an obeticholic acid in the excipient is less than 6%, 5%, 4.5%, 4%, 3.5%, 3%, composition (e.g., the obeticholic acid composition of the 2.5%, 2%, 1.5%, 1%, or 0.5% (wit/wt). In one embodiment, present disclosure) can be conducted with methods known to the excipient is sodium starch glycolate. In one embodiment, one skilled in the art, for example, with LC/HRMS using the Sodium starch glycolate comprises less than 6%. 5%, LTQ-Orbitrap. The identities of various impurities can be 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% (wit/wt) confirmed through various techniques available in the art. polyvinyl alcohol. For example, to determine whether an ethyl ester of obet 0144. In one embodiment, the alcohol is polyethylene icholic acid is an impurity, obeticholic acid can be dissolved glycol. In one embodiment, the total polyethylene glycol in ethanol, and treated with concentrated acid and heated to content in the excipient is less than 6%. 5%, 4.5%, 4%, synthesize the ethyl ester. The retention time and mass 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5% (wit/wt). In one spectrometry of the impurity can be compared with those of embodiment, the excipient is sodium starch glycolate. In one the synthesized ethyl ester of obeticholic acid. The excipi embodiment, the Sodium starch glycolate comprises less ents were analyzed for ethanol content and excipients con than 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or taining higher ethanol content were Substituted with a low 0.5% (wit/wt) polyethylene glycol. ethanol content excipient. 0145 The composition comprising obeticholic acid, or a 0151. The composition comprising obeticholic acid, or a pharmaceutically acceptable salt, ester, or amino acid con pharmaceutically acceptable salt, ester, or amino acid con jugate thereof, and a pharmaceutically acceptable excipient jugate thereof, in the form of particles, or the composition having low alcohol content offers advantageous stability of comprising obeticholic acid, or a pharmaceutically accept obeticholic acid upon storage under various conditions. able salt, ester, or amino acid conjugate thereof, and a 0146 In one embodiment, the composition comprising pharmaceutically acceptable excipient having a low alcohol obeticholic acid, or a pharmaceutically acceptable salt, ester, content, as disclosed herein, can be incorporated into a or amino acid conjugate thereof, and a pharmaceutically pharmaceutical composition Suitable for administration acceptable excipient having a low primary alcohol content (e.g., oral administration). comprises a decreased amount of impurities, as compared to 0152 Thus, in another aspect, the present disclosure an obeticholic acid composition comprising an excipient provides a pharmaceutical composition, comprising a thera having a high alcohol (e.g., greater than or equal to 6% peutically effective amount of obeticholic acid, or a phar (wt/wt) content). maceutically acceptable salt, ester, or amino acid conjugate 0147 In one embodiment, the impurity is an ester of thereof, and a pharmaceutically acceptable excipient having obeticholic acid. In one embodiment, the amount of the ester a low alcohol content. In one embodiment, the pharmaceu of obeticholic acid is decreased by at least 10%, 20%, 30%, tical composition has a low alcohol content as described 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%. In one herein. In another embodiment, the pharmaceutical compo embodiment, the amount of the ester of obeticholic acid is sition comprises Sodium starch glycolate comprising less decreased by at least 50%, 60%, 70%, 80%, 90%. 95%, or than 5% alcohol (e.g., ethanol). 99%. 0153. In another embodiment, the pharmaceutical com 0148. In one embodiment, the impurity is an ethyl ester position comprises a therapeutically effective amount of of obeticholic acid. In one embodiment, the amount of the obeticholic acid, or a pharmaceutically acceptable salt, ester, ethyl ester of obeticholic acid is decreased by at least 10%, or amino acid conjugate thereof, and a pharmaceutically 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%. acceptable excipient having a low alcohol content, wherein In one embodiment, the amount of the ethyl ester of obet obeticholic acid is in the form of particles. In one embodi icholic acid is decreased by at least 50%, 60%, 70%, 80%, ment, the particles have a size distribution as described 90%. 95%, or 99%. In another embodiment, the amount of herein. the ethyl ester of obeticholic acid is less than 0.5%, 0.4%, 0154) In one embodiment, the pharmaceutical composi 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, tion further comprises one or more pharmaceutical excipi 0.04%, 0.03%, 0.02%, or 0.01% (wit/wt). In a further ents. The excipient can be one or more selected from the embodiment, the amount of the ethyl ester of obeticholic group consisting of diluents, Sweeteners, viscosity enhanc acid is less than 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, ing agents, dispersing agents, preservatives, flavoring agents 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or and the like. One excipient can perform more than one 0.01% (wit/wt) at the storage condition of 40° C., 75% RH function. In one embodiment, the one or more pharmaceu for 4 weeks. In a further embodiment, the amount of the tical excipients include a lubricant and/or a diluent. ethyl ester of obeticholic acid is less than 0.2%, 0.1%, 0.155. Non-limiting examples of sweeteners include natu 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, ral Sweeteners such as Sugars, e.g., fructose, glucose, 0.02%, or 0.01% (wit/wt) at the storage condition of 40°C., Sucrose, Sugar alcohols such as mannitol, Sorbitol or mix 75% RH for 4 weeks. tures thereof and artificial Sweeteners such as sodium sac US 2017/0035784 A1 Feb. 9, 2017 charine, Sodium cyclamate and aspartame. In one embodi hydroxypropyl methyl cellulose, hydroxyethyl cellulose, ment, the Sweetener can be any Sweetener known in the art. methyl hydroxyethyl cellulose, sodium carboxymethyl cel In another embodiment, the sweetener is selected from lulose, polyvinyl acetal diethyl amino acetate, polyvinyl fructose, glucose, Sucrose, mannitol, and Sorbitol, or a alcohol, polyethylene glycol, and lecithin, or a combination combination thereof. thereof. In another embodiment, the coating agent is 0156 Dispersing agents include, but are not limited to, Opadry(R) II (e.g., Opadry(R) II green, white, yellow, etc.). colloidal silicon dioxide and Surfactants, wherein the Sur 0160. In one embodiment, the pharmaceutical composi factant is used alone or as an admixture with one or more tion comprising obeticholic acid, or a pharmaceutically Surfactant. In one embodiment, the dispersing agent can be acceptable salt, ester, or amino acid conjugate thereof, in the any dispersing agent known in the art. Combinations of form of particles, at about 1% to about 6% by weight, colloidal silicon dioxide with one or more surfactants can sodium starch glycolate at about 2% to about 8% by weight also be used. having a low alcohol content, a lubricant (e.g., magnesium 0157. In one embodiment, the lubricant can be any lubri stearate) at about 0.1% to about 2.0% by weight, and a cant known in the art. Non-limiting examples of lubricants diluent (e.g., microcrystalline cellulose) at about 85% to include magnesium Stearate, calcium Stearate, Stearic acid, about 95% by weight. In one embodiment, the sodium starch glyceryl behenate, hydrogenated vegetable oil, and glycer glycolate comprises less than 6% (wt/wt) ethanol. ine fumarate, and/or a combination thereof. In another 0.161. In one embodiment, the pharmaceutically compo embodiment, the lubricant is selected from magnesium sition is in Solid particle form. Any inert excipient that is Stearate, calcium Stearate, Stearic acid, glyceryl behenate, commonly used as a carrier or diluent may be used in the hydrogenated vegetable oil, and glycerine fumarate. In pharmaceutical composition of the present disclosure. Such another embodiment, the lubricant is calcium Stearate. In yet as for example, a gum, a starch, a Sugar, a cellulosic another embodiment, the lubricant is stearic acid. In further material, a glycolate, an acrylate, or mixtures thereof. In one embodiment, the lubricant is magnesium Stearate. embodiment, the filler/diluent is microcrystalline cellulose. 0158. In one embodiment, the diluent can be any diluent The pharmaceutical composition may further comprise a known in the art. Non-limiting examples of diluents include disintegrating agent (e.g., sodium starch glycolate) and/or a starch, pregelatinized starch, microcrystalline cellulose, cal lubricant (e.g., magnesium Stearate). Also, the pharmaceu cium carbonate, dibasic calcium phosphate, tribasic calcium tical composition may comprise one or more additives phosphate, calcium phosphate, lactose, dextrose, fructose, selected from a buffer, a Surfactant, a solubilizing agent, a lactitol, lactose, magnesium carbonate, magnesium oxide, plasticizer, an emulsifier, a stabilizing agent, a Viscosity maltitol, maltodextrin, maltose, simethicone, Sodium chlo increasing agent, a Sweetener, a film forming agent, or any ride, talc, Xylitol, Sorbitol, mannitol, and Sucrose, and/or a combination thereof. Furthermore, the pharmaceutical com combination thereof. In another embodiment, the diluent is position of the present disclosure may be in the form of selected from starch, pregelatinized starch, microcrystalline controlled release of immediate release formulations. cellulose, calcium phosphate, lactose, Sorbitol, mannitol, 0162 The percentage of the active ingredient (i.e., obet and Sucrose. In another embodiment, the diluent is calcium icholic acid, or a pharmaceutically acceptable salt, ester, or phosphate. In yet another embodiment, the diluent is man amino acid conjugate thereof) and various excipients in the nitol. In further embodiment, the diluent is microcrystalline pharmaceutical composition of the present disclosure may cellulose. vary. For example, the composition may comprise between 0159. In one embodiment, the pharmaceutical composi about 0.1 and about 99%, between about 1-50%, between tion may further comprise a coating agent Such as Sugar about 1-25%, or about 1-6% by weight of active ingredient. based coating agents, water-soluble film coating agents, Furthermore, the composition may comprise between about enteric coating agents and delayed release coating agents or 20-99%, between about 45-97%, between about 65-96%, or a coating composition comprising any combination thereof. between about 85-95% by weight microcrystalline cellulose In another embodiment, the coating agent can be any coating as a filler or diluent. Furthermore, the composition may agent known in the art. Examples of coating agents include, comprise between about 1-30%, between about 1-20%, or but are not limited to, saccharose used alone or together with between about 2-8% by weight sodium starch glycolate as a any of the agents such as talc, calcium carbonate, calcium disintegrant. Furthermore, the composition may comprise phosphate, calcium Sulphate, gelatine, gum arabic, polyvi between about 0.1-5% or about 0.5-2.0% by weight mag nylpyrrolidone and pullulan or any combination thereof. nesium Stearate as a lubricant. cellulose derivatives Such as hydroxypropyl cellulose, 0163. In one embodiment, the pharmaceutical composi hydroxypropyl methyl cellulose, hydroxyethyl cellulose, tion of the present disclosure is about 0.1% to about 10% by methyl hydroxyethyl cellulose and sodium carboxymethyl weight of active ingredient (i.e., obeticholic acid, or a cellulose; synthetic polymers such as polyvinyl acetal pharmaceutically acceptable salt, ester, or amino acid con diethyl amino acetate, aminoalkyl methacrylate copolymers jugate thereof), about 0.1% to about 20% by weight of and polyvinylpyrrolidone; polysaccharides such as pullulan; sodium starch glycolate, about 0.01% to about 8.0% by hydroxypropyl methyl cellulose phthalate: hydroxypropyl weight of magnesium stearate, and about 65% to about 99% methyl cellulose acetate Succinate; carboxymethyl ethyl by weight of microcrystalline cellulose. In another embodi cellulose; cellulose acetate phthalate; acrylic acid deriva ment, the pharmaceutical composition of the present disclo tives such as methacrylic acid copolymer L. methacrylic sure is about 0.5% to about 8% by weight of active ingre acid copolymer LD and methacrylic acid copolymer S. dient, about 1% to about 10% by weight of sodium starch natural Substances such as shellac, titanium dioxide; poly glycolate, about 0.05% to about 4.0% by weight of magne vinyl alcohol (e.g., Opadry(R); polyethylene glycol; talc; sium stearate, and about 75% to about 97% by weight of lecithin; and/or combinations thereof. In one embodiment, microcrystalline cellulose. In yet another embodiment, the the coating agent is selected from hydroxypropyl cellulose, pharmaceutical composition of the present disclosure is US 2017/0035784 A1 Feb. 9, 2017 about 1% to about 6% by weight of active ingredient, about amino acid conjugate thereof until at least 90% of the 2% to about 8% by weight of sodium starch glycolate, about particles have a diameter of less than 100 um, preferably less 0.1% to about 2.0% by weight of magnesium stearate, and than 90 um, less than 50 m, less than 25 um, less than 20 about 85% to about 95% by weight of microcrystalline um, less than 15 um, less than 10 um, less than 5 Jum, less cellulose. In one embodiment, obeticholic acid, or a phar than 1 um; at least 50% of the particles have a diameter of maceutically acceptable salt, ester, or amino acid conjugate less than 10 Lim, less than 5um, less than 1 um; and at least thereof, in the pharmaceutical composition is in the form of 10% of the particles have a diameter of less than 5um, or particles, as described herein. less than 1 Jum, and ii) combining the micronized obeticholic 0164. In another aspect, the present disclosure provides a acid particles with at least one pharmaceutically acceptable pharmaceutical composition, comprising a therapeutically excipient. In one embodiment, the micronizing is carried out effective amount of obeticholic acid, or a pharmaceutically using a jet-mill. acceptable salt, ester, or amino acid conjugate thereof, in the 0169. In another aspect, the present disclosure provides a form of particles, and a pharmaceutically acceptable excipi method for preparing a pharmaceutical composition con ent having a low alcohol content. In one embodiment, the taining a therapeutically effective amount of obeticholic obeticholic acid particle composition is an obeticholic acid acid, or a pharmaceutically acceptable salt, ester, or amino particle composition described herein. In one embodiment, acid conjugate thereof, in the form of particles, comprising the pharmaceutical composition has a low alcohol content as i) micronizing obeticholic acid acceptable salt, ester, or described herein. In one embodiment, the pharmaceutical amino acid conjugate thereof until at least 90% of the composition comprises sodium starch glycolate comprising particles have a diameter of less than 100 um, at least 50% less than 6% alcohol (e.g., ethanol). of the particles have a diameter of less than 10 um, and at 0.165. In another aspect, the present disclosure provides a least 10% of the particles have a diameter of less than 5um, method for preparing a pharmaceutical composition con and ii) combining the micronized obeticholic acid particles taining a therapeutically effective amount of obeticholic with at least one pharmaceutically acceptable excipient. In acid, or a pharmaceutically acceptable salt, ester, or amino one embodiment, the micronizing is carried out using a acid conjugate thereof, in the form of particles, comprising jet-mill. i) micronizing obeticholic acid acceptable salt, ester, or 0170 In another aspect, the present disclosure provides a amino acid conjugate thereof until at least 90% of the method for preparing a pharmaceutical composition con particles have a diameter of less than 100 um, Such as less taining a therapeutically effective amount of obeticholic than 90 um, less than 50 um, less than 25um, less than 20 acid, or a pharmaceutically acceptable salt, ester, or amino um, less than 15 um, less than 10 um, less than 5um, or less acid conjugate thereof, in the form of particles, comprising than 1 um, and ii) combining the micronized obeticholic acid i) micronizing obeticholic acid acceptable salt, ester, or particles with at least one pharmaceutically acceptable amino acid conjugate thereof until at least 90% of the excipient. In one embodiment, the micronizing is carried out particles have a diameter of less than 25 um, at least 50% of using a jet-mill. the particles have a diameter of less than 5um, and at least 0166 In another aspect, the present disclosure provides a 10% of the particles have a diameter of less than 1 um, and method for preparing a pharmaceutical composition con ii) combining the micronized obeticholic acid particles with taining a therapeutically effective amount of obeticholic at least one pharmaceutically acceptable excipient. In one acid, or a pharmaceutically acceptable salt, ester, or amino embodiment, the micronizing is carried out using a jet-mill. acid conjugate thereof, in the form of particles, comprising 0171 In another aspect the present disclosure provides a i) micronizing obeticholic acid acceptable salt, ester, or method for treating or preventing a disease or condition, amino acid conjugate thereof until at least 50% of the comprising administering an effective amount of an obet particles have a diameter of less than 10 Lim, i.e., less than icholic acid composition of the present disclosure to a 5 um, and ii) combining the micronized obeticholic acid patient in need thereof. particles with at least one pharmaceutically acceptable 0172. In one aspect, the present disclosure provides a excipient. In one embodiment, the micronizing is carried out method for treating a disease or condition by administering using a jet-mill. an effective amount of an obeticholic acid composition 0167. In another aspect, the present disclosure provides a described herein to a patient in need thereof. In certain method for preparing a pharmaceutical composition con embodiments herein the effective amount refers to a titrated taining a therapeutically effective amount of obeticholic dosage administered during a titration period as set forth acid, or a pharmaceutically acceptable salt, ester, or amino herein. In other embodiments, the effective amount refers to acid conjugate thereof, in the form of particles, comprising an adjusted or re-adjusted dosage administered after a titra i) micronizing obeticholic acid acceptable salt, ester, or tion period as set forth herein. amino acid conjugate thereof until at least 10% of the (0173 It is to be understood that the methods described particles have a diameter of less than 5um, i.e., less than 1 herein refer generally to the obeticholic acid compositions um, and ii) combining the micronized obeticholic acid set forth herein. The methods described herein can include particles with at least one pharmaceutically acceptable any specific formulation provided herein, for example, that excipient. In one embodiment, the micronizing is carried out provided in Example 11. In one embodiment, the obeticholic using a jet-mill. acid composition useful in the methods of treating described 0.168. In another aspect, the present disclosure provides a herein is a composition provided in Example 11. In another method for preparing a pharmaceutical composition con embodiment, the obeticholic acid composition useful in the taining a therapeutically effective amount of obeticholic methods of treating described herein is a composition that acid, or a pharmaceutically acceptable salt, ester, or amino includes microcrystalline cellulose, sodium starch glycolate, acid conjugate thereof, in the form of particles, comprising and magnesium Stearate as excipients. Such a composition i) micronizing obeticholic acid acceptable salt, ester, or can be provided in a dosage form set forth herein, e.g., an US 2017/0035784 A1 Feb. 9, 2017 oral dosage form such as a tablet or coated tablet. Thus, in obeticholic acid composition described above. In yet another certain instances, the obeticholic acid composition useful in embodiment, the method is a method of treating fibrosis the methods is a tablet or coated tablet for oral administra (e.g., progressive or liver fibrosis) by administering an tion. In one embodiment, the oral dosage form of the effective amount of an obeticholic acid composition obeticholic acid composition includes a film coating that described above. In yet another embodiment, the method is includes one or more excipients selected from polyvinyl a method of treating cirrhosis by administering an effective alcohol (part hydrolyzed), titanium dioxide, macrogol (poly amount of an obeticholic acid composition described above. ethylene glycol 3350), talc, and iron oxide. 0.179 NAFLD is a medical condition that is characterized 0174. In one embodiment, the disease or condition is an by the buildup of fat (called fatty infiltration) in the liver. FXR mediated disease or condition. Examples of the FXR NAFLD is one of the most common causes of chronic liver mediated diseases or conditions include, but not limited to, disease, and encompasses a spectrum of conditions associ liver diseases such as a cholestatic liver disease such as ated with lipid deposition in hepatocytes. It ranges from primary biliary cirrhosis (PBC) also known as primary Steatosis (simple fatty liver), to nonalcoholic Steatohepatitis biliary cholangitis (PBC), primary Sclerosing cholangitis (NASH), to advanced fibrosis and cirrhosis. The disease is (PSC), chronic liver disease, nonalcoholic fatty liver disease mostly silent and is often discovered through incidentally (NAFLD), nonalcoholic steatohepatitis (NASH), hepatitis C elevated liver enzyme levels. NAFLD is strongly associated infection, alcoholic liver disease, liver damage due to pro with obesity and insulin resistance and is currently consid gressive fibrosis, and liver fibrosis. Examples of FXR medi ered by many as the hepatic component of the metabolic ated diseases also include portal hypertension, bile acid syndrome. diarrhea, hyperlipidemia, high LDL-cholesterol, high HDL 0180. Nonalcoholic steatohepatitis (NASH) is a condi cholesterol, high triglycerides, and cardiovascular disease. tion that causes inflammation and accumulation of fat and 0.175. In another aspect, the present disclosure provides fibrous (scar) tissue in the liver. Liver enzyme levels in the methods of treating or preventing a disease or condition blood may be more elevated than the mild elevations seen described herein by administering an obeticholic acid com with nonalcoholic fatty liver (NAFL). Although similar position described herein (e.g., obeticholic acid or a phar conditions can occur in people who abuse alcohol, NASH maceutically acceptable salt, ester, or amino acid conjugate occurs in those who drink little to no alcohol. NASH affects thereof, where the obeticholic acid or a pharmaceutically 2 to 5 percent of Americans, and is most frequently seen in acceptable salt, ester, or amino acid conjugate thereof is in people with one of more of the following conditions: obe the form of particles, and wherein at least 50% of the sity, diabetes, hyperlipidemia, insulin resistance, uses of particles have a diameter of 200 um or less). certain medications, and exposure to toxins. NASH is an 0176). In still another aspect the present disclosure pro increasingly common cause of chronic liver disease world vides a method of treating primary biliary cirrhosis (PBC) wide and is associated with increased liver-related mortality by administering an obeticholic acid composition described and hepatocellular carcinoma, even in the absence of cir herein (e.g., obeticholic acid or a pharmaceutically accept rhosis. NASH progresses to cirrhosis in 15-20% of affected able salt, ester, or amino acid conjugate thereof, where the individuals and is now one of the leading indications for obeticholic acid or a pharmaceutically acceptable salt, ester, liver transplantation in the United States. At present there are or amino acid conjugate thereof is in the form of particles, no approved therapies for NASH. and wherein at least 50% of the particles have a diameter of 0181. In one embodiment, the method is a method of 200 um or less), optionally in a titration period. In some treating NASH by administering an obeticholic acid com examples, the method comprise administering a starting position described herein, optionally in a titration period as dose in a titration period. The starting dose, adjusted dose, described herein. The NASH patient can be a high risk and titration period are as described below. NASH patient. A “high risk NASH patient” refers to char (0177. The PBC can be advanced stage PBC. “Advanced acterization by one or more of NAS4; baseline fibrosis stage PBC refers to PBC characterized by one or more of stage 2 or 3; or baseline fibrosis stage 1 with a comorbidity the following: Baseline total bilirubin-upper liming of nor (type 2 diabetes, BMI-30 kg/m2 or ALT-60 U/L). mal (ULN); Baseline total ALP>5xULN; Baseline transient 0182. In one embodiment, the disease or condition is elastography (TE)>10.7 kPa; Cirrhosis based on an initial or hyperlipidemia. In one embodiment, the disease or condition baseline biopsy result or patient having an Ishak score 6 is a cholestatic liver disease. In one embodiment, the disease (cirrhosis) or Ludwig/Scheuer PBC Stage 4: or Medical or condition is PBC. In another embodiment, the disease or history of ascites, hepatic cirrhosis, jaundice, portal hyper condition is a cardiovascular disease. In another embodi tension, portal hypertensive gastropathy or varices esopha ment, the cardiovascular disease is atherosclerosis, hyperc geal. holesteremia, or hypertriglyceridemia. 0178. Further provided herein are methods of treating 0183 The present disclosure also provides a method for primary Sclerosing cholangitis (PSC), chronic liver disease, treating or preventing NAFLD or NASH. In one embodi nonalcoholic fatty liver disease (NAFLD), nonalcoholic ment, the present disclosure provides a method for treating steatohepatitis (NASH), hepatitis C infection, alcoholic liver or preventing NAFLD or NASH that is associated with disease, liver damage due to progressive fibrosis, or liver hyperlipidemia. In one embodiment, the present disclosure fibrosis in a patient in need thereof by administering an provides a method for treating or preventing NASH. In one effective amount of an obeticholic acid composition embodiment, the present disclosure provides a method for described above. In another embodiment, the method is a treating or preventing NASH that is associated with hyper method of treating NAFLD by administering an effective lipidemia. amount of an obeticholic acid composition described above. 0184. In another aspect, the present disclosure also pro In still another embodiment, the method is a method of vides a method for decreasing liver enzymes, comprising treating PSC by administering an effective amount of an administering a therapeutically effective amount of the com US 2017/0035784 A1 Feb. 9, 2017 position of the present disclosure to a subject in need patient has an ALP level greater than about 1.5xULN. In one thereof. In one embodiment, the subject is not suffering from embodiment, a patient has an ALP level greater than about a cholestatic condition. In another embodiment, the Subject 2xULN. In one embodiment, a patient has a ALP level is suffering from a cholestatic condition. In one embodi greater than about 5xULN. In one embodiment, a patient has ment, the liver enzyme is alkaline phosphatase, 7-glutamyl an ALP level greater than about 10xULN. In one embodi transpeptidase (GGT), and/or 5' nucleotidase. ment, a patient has a bilirubin level greater than about 0185. In certain instances, the methods described herein 15XULN. also include assessing, monitoring, measuring, or otherwise 0191 In another example, the liver biomarker assessed, detecting liver function. Assessing, monitoring, measuring, monitored, measured, or detected can be bilirubin. The or otherwise detecting liver function can be performed bilirubin level can be a measure of ULN. In one embodi before, during, or after a titration period described herein, or ment, a patient before treatment can have abilirubin level of in other instances, performed during the course of any at least 1.1 xULN to at least 20xULN; at least 1.1 xULN to treatment described herein. Liver function can be deter at least 15xULN; at least 1.1 xULN to at least 12xULN; at mined by, for example, assessing, monitoring, measuring, or least 1.1 xULN to at least 10xULN; at least 1.1 xULN to at otherwise detecting a level of one or more liver biomarkers least 8xULN; at least 1.1 xULN to at least 6xULN; at least compared to a control. In certain instances the control is a 1.1 xULN to at least 5xULN; at least 1.1 xULN to at least baseline taken from the patient before beginning treatment. 4xULN; at least 1.1 xULN to at least 3xULN; or at least In other instances the control is preestablished baseline 1.1XULN to at least 2xULN. considered as a normal value. 0.192 A patient before a treatment described herein can 0186 Values for measure or detection of liver function have abilirubin level of about 1.5xULN to about 20xULN; biomarkers and controls can be expressed as a comparison about 1.5xULN to about 15xULN; about 1.5xULN to about to Upper Limit of Normal (ULN). 10 ULN; about 1.5xULN to about 5xULN; or about 1.5x 0187 Liver biomarkers can be used to ascertain, quantify ULN to about 3xULN. In another example a patient before the efficacy of the course of treatment with an obeticholic a treatment described herein can have a bilirubin level of acid composition described herein. In other instances, liver about 2xULN to about 20xULN; about 2xULN to about biomarkers described herein can be used to ascertain, quan 15xULN; about 2xULN to about 10 ULN; about 2xULN to tify liver function during the course of treatment with an about 5xULN; or about 2xULN to about 3xULN. In another obeticholic acid composition described herein. Liver bio example a patient before a treatment described herein can markers can also be used to predict whether a patient or have abilirubin level of greater than about 2xULN to greater patient population will be susceptible to treatment with an than about 20xULN; greater than about 2xULN to greater obeticholic acid composition described herein. In one than about 15xULN; greater than about 2xULN to greater embodiment, the liver biomarkers include assessing, moni than about 10 ULN; greater than about 2xULN to greater toring, measuring or otherwise detecting an amount or level than about 5xULN; or greater than about 2xULN to greater of aspartate transaminase (AST), alanine transaminase than about 3XULN. (ALT), alkaline phosphatase (ALP), bilirubin, glycine con 0193 A patient before treatment can have a bilirubin jugated obeticholic acid, taurine conjugated obeticholic level before a treatment described herein of about 1.5.x, 2x, acid, a bile acid, a bile acid glycine conjugate, or a bile acid 3x, 4x, 5x, 8x. 10x. 15x, or 20xULN. A patient before taurine conjugate. For example, the liver biomarker treatment can have a bilirubin level before a treatment assessed, monitored, measured, or detected can be ALP. described herein of greater than about 1.5.x, 2x, 3x, 4x, 5x, 0188 The ALP level can be a measure of ULN. In one 8x, 10x. 15x, or 20xULN. In one embodiment, a patient has embodiment, a patient before treatment can have an ALP abilirubin level greater than about 2xULN. In one embodi level of at least 1.1 xULN to at least 20xULN; at least ment, a patient has a bilirubin level greater than about 1.1 xULN to at least 15xULN; at least 1.1 xULN to at least 5xULN. In one embodiment, a patient has a bilirubin level 12xULN; at least 1.1 xULN to at least 10xULN; at least greater than about 10xULN. In one embodiment, a patient 1.1 xULN to at least 8xULN; at least 1.1 xULN to at least has a bilirubin level greater than about 15xULN. In one 6xULN; at least 1.1 xULN to at least 5xULN; at least embodiment, a patient has a bilirubin level less than about 1.1 xULN to at least 4xULN; at least 1.1 xULN to at least 2xULN. In one embodiment, a patient has a bilirubin level 3xULN; or at least 1.1 xULN to at least 2xULN. less than about 5xULN. In one embodiment, a patient has a 0189 A patient before a treatment described herein can bilirubin level less than about 10xULN. In one embodiment, have an ALP level of about 1.5xULN to about 20xULN; a patient has a bilirubin level less than about 15xULN. about 1.5xULN to about 15xULN; about 1.5xULN to about 0.194. In some instances it can be useful to assess, moni 10 ULN; about 1.5xULN to about 5xULN; or about 1.5x tor, measure, or detect ALP and bilirubin to assess, monitor, ULN to about 3xULN. A patient before treatment can have measure, or otherwise detect liver function or changes in an ALP level before a treatment described herein of about liver function during treatment with an obeticholic acid 1.5.x, 2x, 3x, 4x, 5x, 8x, 10x, 15x, or 20xULN. composition described herein. In certain instances, a patient 0190. A patient before treatment can have an ALP level has an ALP level as provided above (e.g., about 1.5xULN to before a treatment described herein of greater than about about 10xULN) and a bilirubin level as provided above 1.5.x, 2x, 3x, 4x, 5x, 8x, 10x, 15x, or 20xULN. In one (e.g., less than about 5xULN). In one embodiment, the embodiment, a patient has an ALP level of about 1.5xULN. patient has an ALP level between about 1.5xULN to about In one embodiment, a patient has an ALP level of about 10xULN and a bilirubin level less than about 2xULN. 2xULN. In one embodiment, a patient has a ALP level of 0.195 Treatment with a obeticholic acid composition about 5xULN. In one embodiment, a patient has an ALP described herein can reduce the levels of ALP and/or bili level of about 10xULN. In one embodiment, a patient has a rubin in a patient described herein. For example, treatment bilirubin level of about 15xULN. In one embodiment, a of a disease or condition described herein (e.g., PBC) with US 2017/0035784 A1 Feb. 9, 2017 an obeticholic acid composition described herein can reduce reduced by at least 40%. The level of bilirubin can be the level of ALP by 2, 4, 5, 6, 8, 9, 10, 12, 15, 18, 20, 21, reduced by at least 35%. The level of bilirubin can be 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, reduced by at least 30%. The level of bilirubin can be 70, 75, 80, 85, 88,90, 92,94, 96, 97,98, 99,99.2, 99.4, 99.6, reduced by at least 27%. The level of bilirubin can be 99.7, 99.8, 99.9, or 100%. In another example, the level of reduced by at least 25%. The level of bilirubin can be ALP can be reduced by at least 100%, at least 125%, at least reduced by at least 20%. 150%, at least 175%, at least 200%, at least 225%, at least 25.0% or at least 300%. 0201 The reduction of bilirubin levels can be represented 0196. In another example, the level of ALP can be by the fold change over ULN. For example, treatment with reduced by about 5% to about 50%; about 10% to about an obeticholic acid described herein can reduce the bilirubin 55%; about 10% to about 45%; about 10% to about 40%: level of a patient described herein to less than about 5xULN; about 10% to about 33%, about 10% to about 30%; about less than about 4xULN, less than about 3xULN, less than 15% to about 30%; about 15% to about 25%; about 20% to about 2xULN, less than about 1.7xULN, less than about about 50%, about 20% to about 40%; about 20% to about 1.5xULN, less than about 1.25xULN, or less than about 35%; about 20% to about 30%; 20% to about 27%; or about ULN. 20% to about 27%. In another example, the level of ALP can 0202 In another example, the bilirubin level is reduced be reduced by at least 50%. The level of ALP can be reduced by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, or by at least 40%. The level of ALP can be reduced by at least 50 fold compared to a baseline value. For example, the 35%. The level of ALP can be reduced by at least 30%. The bilirubin level after treatment with an obeticholic acid level of ALP can be reduced by at least 27%. The level of composition described herein can be reduced by 1, 1.2, 1.4. ALP can be reduced by at least 25%. The level of ALP can 1.6., 1.8, or 2 fold, including intervening values therein, be reduced by at least 20%. compared to a baseline value. In another example, the (0197) The reduction of ALP levels can be represented by bilirubin level can be reduced by 2, 2.2, 2.4, 2.6, 2.8, or 3 the fold change over ULN. For example, treatment with an fold, including intervening values therein, compared to a obeticholic acid described herein can reduce the ALP level baseline value. In another example, the bilirubin level can be of a patient described herein to less than about 5xULN; less reduced 3, 4, or 5 fold, including intervening values therein, than about 4xULN, less than about 3xULN, less than about compared to a baseline value. In another example, the 2xULN, less than about 1.7xULN, less than about 1.5x bilirubin level can be reduced 5, 7, 9, or 10 fold, including ULN, less than about 1.25xULN, or less than about ULN. intervening values therein, compared to a baseline value. In 0198 In another example, the ALP level is reduced by at another example, the bilirubin level can be reduced 10, 12, least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, or 50 fold 15, or 20 fold, including intervening values therein, com compared to a baseline value. For example, the ALP level pared to a baseline value. after treatment with an obeticholic acid composition 0203. In another embodiment, one or more biomarkers described herein can be reduced by 1, 1.2, 1.4, 1.6, 1.8, or can stratify a patient population undergoing or who will 2 fold, including intervening values therein, compared to a undergo treatment with an obeticholic acid composition baseline value. In another example, the ALP level can be described herein. For example, a PBC patient can be strati reduced by 2, 2.2, 2.4, 2.6, 2.8, or 3 fold, including inter fied for the risk of hepatocellular carcinoma (HCC). vening values therein, compared to a baseline value. In another example, the ALP level can be reduced 3, 4, or 5 0204. In yet another embodiment, liver biomarkers useful fold, including intervening values therein, compared to a for detection can include metabolites and bile acids. For baseline value. In another example, the ALP level can be example, assessing, monitoring, measuring, or otherwise reduced 5, 7, 9, or 10 fold, including intervening values detecting levels of glycine and taurine conjugates of obet therein, compared to a baseline value. In another example, icholic acid can be useful for measuring efficacy of a the ALP level can be reduced 10, 12, 15, or 20 fold, treatment regimen described herein. For example, assessing, including intervening values therein, compared to a baseline monitoring, measuring, or otherwise detecting levels or value. detecting plasma levels of bile acids including cholic acid, 0199 Treatment of a disease or condition described chenodeoxycholic acid, deoxycholic acid, lithocholic acid, herein (e.g., PBC) with an obeticholic acid composition and urosodeoxycholic acid, including glycine and taurine described herein can reduce the level of bilirubin by 2, 4, 5, conjugates thereof, and optionally comparing the levels to a 6, 8, 9, 10, 12, 15, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, control, can be useful for measuring efficacy of a treatment 30, 35, 4-, 45, 50, 55, 60, 65, 70, 75, 80, 85, 88,90, 92,94, regimen described herein. 96, 97,98, 99, 99.2, 99.4, 99.6, 99.7, 99.8, 99.9, or 100%. 0205. In still other embodiments, calculating an AST to In another example, the level of bilirubin can be reduced by platelet index (APRI) can be useful for assessing, monitor at least 100%, at least 125%, at least 150%, at least 175%, ing, measuring, or otherwise detecting liver function (in at least 200%, at least 225%, at least 250% or at least 300%. cluding changes thereof). The obeticholic acid compositions 0200. In another example, the level of bilirubin can be described herein can reduce the APRI of a patient described reduced by about 5% to about 50%; about 10% to about herein. In certain instances, monitoring or measuring the 55%; about 10% to about 45%; about 10% to about 40%: APRI can be used to determine efficacy of treatment with an about 10% to about 33%, about 10% to about 30%; about obeticholic acid composition described herein. In some 15% to about 30%; about 15% to about 25%; about 20% to embodiments, a reduction in APRI is observed in a patient about 50%, about 20% to about 40%; about 20% to about (e.g., a PBC or NASH patient) after administration of an 35%; about 20% to about 30%; 20% to about 27%; or about obeticholic acid composition described herein. For example, 20% to about 27%. In another example, the level of bilirubin the APRI may be reduced by about 5% to about 50% in can be reduced by at least 50%. The level of bilirubin can be patients treated with obeticholic acid relative to baseline US 2017/0035784 A1 Feb. 9, 2017 levels measured before dose administration. The reduction linked immunosorbent assay (ELISA) method. The plasma may be up to about 5%, 10%, 15%, 20%, 25%, 30%, 35%, concentrations of FGF-19 may be quantitated at predose and 40%, 45% or 50%. after administration of dose. 0206. Further provided herein is a method for treating 0211. In some examples, a monoclonal antibody specific PBC in a patient in need thereof by administering a starting for FGF-19 is pre-coated onto a microplate. Standards, dose of an obeticholic acid composition described herein in quality controls and samples are pipetted into the wells and a titration period. The method includes assessing liver any FGF-19 present is bound by the immobilized antibody. function of the patient before, during, and after said titration After washing away any unbound Substances, an enzyme period by either calculating an APRI score for said patient; linked polyclonal antibody specific for FGF-19 is added to or by measuring the level of one or more liver biomarker the wells. Following a wash to remove any unbound anti selected from ALP. bilirubin, AST, ALT, glycine conjugated body-enzyme reagent, a Substrate Solution is added to the obeticholic acid, taurine conjugated obeticholic acid, a bile wells and color develops in the proportion to the amount of acid, a bile acid glycine conjugate, or a bile acid taurine FGF-19 bound in the initial step. The color development is conjugate, where a reduced APRI score compared to a stopped and the intensity of the color is measured. The control or a reduced level of the one or more liver biomark calibration range of the method is 15.625 pg/ml to 1000 ers compared to a control indicates non-impaired liver pg/ml for FGF-19 using a 100 ul aliquot of standard curve, function. The method further includes assessing tolerance of quality control and sample. In some embodiments, no mini the patient to the starting dose by grading the severity of one mum required dilution is used. In other embodiments, or more adverse effects, if present, and administering an samples may be subjected to a 3x minimum required dilu adjusted dose of the obeticholic acid composition, where the tion. adjusted dose includes an amount equal to or greater than an 0212. Also provided herein are methods to reduce or amount of the starting dose. The starting dose, adjusted dose, eliminate rejection failure of a liver transplant by adminis and titration period are as described below. For example, the tering an effective amount of an obeticholic acid composi starting dose can be about 5 to about 50 mg (e.g., 5 mg) and tion described above. In certain instances, administration of the adjusted dose can be about 5 to about 50 mg (e.g., 5 mg. an obeticholic acid composition described herein reduces 10 mg. or 25 mg) and the titration period can be a time of expression or levels of ALP and/or bilirubin. In one embodi about 1 to about 6 months, e.g., 1 month, 2 months, 3 ment, administration of an obeticholic acid composition months, 4 months, 5 months, or 6 months. described herein reduces ALP and bilirubin levels, thereby 0207. Also provided herein are methods to reduce or reducing transplant complications or rejection. In another eliminate rejection failure of a liver transplant by adminis embodiment, administration of an effective amount of an tering an effective amount of an obeticholic acid composi obeticholic acid composition described herein increases tion described above. In certain instances administration of post-transplantation Survival rate of a liver transplantee. an obeticholic acid composition described herein reduces 0213. In another aspect of the disclosure is a method of expression or levels of ALP and/or bilirubin. In one embodi treating a solid-tumor cancer by administering an effective ment, administration of an obeticholic acid composition amount of an obeticholic acid composition as described described herein reduces ALP and bilirubin levels, thereby herein. In another aspect, Such methods include treating reducing transplant complications or rejection. In another hepatocellular carcinoma (HCC), colorectal cancer, gastric embodiment, administration of an effective amount of an cancer, liver cancer, breast cancer, renal cancer, or pancre obeticholic acid composition described herein increases atic cancer by administering an obeticholic acid composition post-transplantation Survival rate of a liver transplantee. as described herein. In one embodiment is a method of 0208. In one aspect, obeticholic acid may mediate its treating HCC by administering an effective amount of an action primarily via FXR agonism, wherein FGF-19 obeticholic acid composition as described herein. In one released from gut enterocytes (in response to FXR agonist) embodiment is a method of treating colorectal cancer by into portal circulation down regulates endogenous bile acid administering an effective amount of an obeticholic acid synthesis in the liver. The present disclosure comprehends a composition as described herein. In another embodiment is method of measuring FXR agonist activity by, for example, a method of treating gastric cancer by administering an measuring release of FGF-19 into the bloodstream or cir effective amount of an obeticholic acid composition as culation of a patient administered with OCA. Levels of described herein. In another embodiment is a method of FGF-19 may be measured by methods known in the art, such treating liver cancer by administering an effective amount of as those described herein. an obeticholic acid composition as described herein. In still 0209 Obeticholic acid administration may lead to a sig another embodiment is a method of treating renal cancer by nificant and a dose-dependent increase in the levels of administering an effective amount of an obeticholic acid FGF-19 and in some embodiments, a decrease in the levels composition as described herein. In still another embodi of endogenous bile acids and C4 (a bile acid precursor). In ment is a method of treating pancreatic cancer by adminis some embodiments, a significant increase in FGF-19 levels tering an effective amount of an obeticholic acid composi may be observed from baseline to month 3, month 6 and tion as described herein. It is understood that the treatment month 12 after dose administration. In some examples, the of a cancer described herein can be performed by adminis FGF-19 levels may increase from about 5% to about 200%. tering an effective amount of an obeticholic acid composi In specific embodiments, the levels may increase by about tion described herein in combination with one or more 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, anticancer agents, such as those described herein. In some 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%. embodiments, the effective amount administered is a starting 0210. In some embodiments, the plasma levels of FGF dose as described herein. 19, a marker of FXR activation, are determined using a 0214 Still further provided herein are methods of treating qualified method and a validated method using an enzyme an autoimmune disease in a patient in need thereof by US 2017/0035784 A1 Feb. 9, 2017 administering an effective amount of an obeticholic acid 0218. In one embodiment, the fibrosis is selected from composition as described herein. In one instance, the auto the group consisting of liver fibrosis, kidney fibrosis, and immune disease is selected from multiple Sclerosis, rheu intestinal fibrosis. matoid arthritis, and type I diabetes. In one embodiment is 0219. In one embodiment, the subject has liver fibrosis a method of treating multiple Sclerosis by administering an associated with a disease selected from the group consisting effective amount of an obeticholic acid composition as of hepatitis B; hepatitis C; parasitic liver diseases; post described herein. In another embodiment is a method of transplant bacterial, viral and fungal infections; alcoholic treating rheumatoid arthritis by administering an effective liver disease (ALD); non-alcoholic fatty liver disease (NA amount of an obeticholic acid composition as described FLD); non-alcoholic steatohepatitis (NASH); liver diseases herein. In still another embodiment is a method of treating induced by methotrexate, isoniazid, oxyphenistatin, meth type I diabetes by administering an effective amount of an yldopa, chlorpromazine, tolbutamide, or amiodarone; auto obeticholic acid composition as described herein. In certain immune hepatitis; sarcoidosis; Wilson's disease; hemochro instances, the treatment of the autoimmune disease includes matosis; Gaucher's disease; types III, IV, VI, IX and X further administering another active agent useful for the glycogen storage diseases; C.-antitrypsin deficiency; Zell treatment, such as without limitation, non-steroidal anti weger syndrome; tyrosinemia; fructosemia; galactosemia; inflammatory agents (NSAIDs) such as ibuprofen, vascular derangement associated with Budd-Chiari Syn naproxen, corticosteroids, disease-modifying anti-rheumatic drome, veno-occlusive disease, or portal vein thrombosis: drugs such as methotrexate (Trexall, Otrexup, Rasuvo), and congenital hepatic fibrosis. leflunomide (Arava), hydroxychloroquine (Plaquenil) and 0220. In another embodiment, the subject has intestinal SulfaSalazine (AZulfidine), biologic agents such as abatacept fibrosis associated with a disease selected from the group (Orencia), adalimumab (Humira), anakinra (Kineret), cer consisting of Crohn's disease, ulcerative colitis, post-radia tolizumab (Cimzia), etanercept (Enbrel), golimumab (Sim tion colitis, and microscopic colitis. poni), infliximab (Remicade), rituximab (Rituxan), tocili Zumab (Actemra) and tofacitinib (Xeljanz), interferons. Such 0221. In another embodiment, the subject has renal fibro as interferon alpha, interferon beta, interferon gamma, and sis associated with a disease selected from the group con PEGylated versions thereof, glatiramer acetate (also known sisting of diabetic nephropathy, hypertensive nephrosclero in the art as Copaxone), dimethyl fumarate (also known in sis, chronic glomerulonephritis, chronic transplant the art as Tecifidera), fingolimod (also known in the art as glomerulopathy, chronic interstitial nephritis, and polycystic Gilenya), teriflunomide (also known in the art as Aubagio), kidney disease. natalizumab (also known in the art as TySabri), alemtuzumab 0222. In another aspect, the present disclosure also pro (also known in the art as Lemtrada), and mitoxantrone. For vides a method for treating or preventing all forms of example, an obeticholic acid composition described herein conditions related to elevated lipid levels. In one embodi can be administered in combination with metformin, insulin, ment, the condition is hyperlipidemia where it is associated insulin mimetic, or any other known anti-diabetic or anti with a condition selected from resistant primary biliary glycemic agent for treatment of diabetes. In some embodi cirrhosis: primary biliary cirrhosis where there is associated ments, the effective amount administered is a starting dose liver function test elevation and hyperlipidemia, primary as described herein. Sclerosing cholangitis, non-alcohol-induced steatohepatitis; and chronic liver disease associated with hepatitis B, C or 0215. In another aspect, the present disclosure also pro alcohol. In another embodiment, the present disclosure vides a method for inhibiting or reversing fibrosis, compris provides a method for treating or preventing hyperlipidemia, ing administering a therapeutically effective amount of the where the hyperlipidemia is primary hyperlipidemia with or composition of the present disclosure to a Subject in need without a genetic component, or hyperlipidemia associated thereof. In one embodiment, the subject is not suffering from with coronary artery disease, cerebrovascular arterial dis a cholestatic condition. In another embodiment, the Subject ease, peripheral vascular disease, aortic aneurisms, or is Suffering from a cholestatic condition. carotid atherosclerosis. 0216. In one embodiment, the subject is not suffering 0223) In one aspect, the present disclosure provides a from a cholestatic condition associated with a disease or method for treating or preventing primary Sclerosing cho condition selected from the group consisting of cancers, langitis for similar biochemical abnormalities, as well as Such as, e.g., cancers as described herein, including primary chronic hepatitis caused by hepatitis B, C or by alcohol. In liver and biliary cancer, metastatic cancer, sepsis, chronic one aspect, the present disclosure provides a method for total parenteral nutrition, cystic fibrosis, and granulomatous treating or preventing other arterial disorders associated with liver disease. In embodiments, the fibrosis to be inhibited hyperlipidemia. In one aspect, the present disclosure pro occurs in an organ where FXR is expressed. vides a method for treating or preventing hypertriglyceri 0217. In one embodiment, a cholestatic condition is demia. defined as having an abnormally elevated serum level of 0224. Therapies with FXR agonists may produce various alkaline phosphatase, 7-glutamyl transpeptidase (GGT), side effects, one of which is pruritus. Pruritus or itch is and/or 5' nucleotidase. In another embodiment, a cholestatic defined as an unpleasant sensation of the skin that provokes condition is further defined as presenting with at least one the urge to scratch. It is a characteristic feature of many skin clinical symptom. In one embodiment, the symptom is diseases and an unusual sign of Some systemic diseases. itching (pruritus). In another embodiment, a cholestatic Pruritus may be localized or generalized and can occur as an condition is selected from the group consisting of primary acute or chronic condition. Itching lasting more than 6 biliary cirrhosis (PBC), primary sclerosing cholangitis weeks is termed chronic pruritus. Itching can be intractable (PBS), biliary atresia, drug-induced cholestasis, hereditary and incapacitating, as well as a diagnostic and therapeutic cholestasis, and intrahepatic cholestasis of pregnancy. challenge. US 2017/0035784 A1 Feb. 9, 2017 20 0225. One of the advantages of the compositions of the composition described herein as administered to a patient present disclosure includes a decrease in the incidence described herein refers to the amount of obeticholic acid in and/or severity of pruritus in subjects treated with the the composition. compositions and according to the methods of the present 0229. The amount of an obeticholic acid composition as disclosure. provided above can refer to an effective amount as described 0226. In one embodiment, the incidence of pruritus herein. In certain embodiments, an effective amount of the decreases by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, obeticholic acid composition administered to a patient 40%, 45%, or 50% in subjects treated with the compositions described herein can be 5 mg. In another embodiment, an of the present disclosure. In a further embodiment, the effective amount of the obeticholic acid composition admin incidence of pruritus decreases by at least 20%, 25%, 30%, istered to a patient described herein can be 10 mg. In still 35%, 40%, 45%, or 50% in subjects treated with the another embodiment, an effective amount of the obeticholic compositions of the present disclosure. In a further embodi acid composition administered to a patient described herein ment, the incidence of pruritus decreases by at least 5%, can be 25 mg. In yet another embodiment, an effective 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% in amount of the obeticholic acid composition administered to subjects treated with the compositions of the present disclo a patient described herein can be 50 mg. Sure during the first one month, two months, three months, 0230. The amount of an obeticholic acid composition as four months, five months, or six months after the beginning provided above can optionally refer to a starting dose of the treatment. In a further embodiment, the incidence of administered during a titration period as described herein. In pruritus decreases by at least 20%, 25%, 30%, 35%, 40%, certain embodiments, a starting dose of the obeticholic acid 45%, or 50% in subjects treated with the compositions of the composition administered to a patient described herein can present disclosure during the first one month, two months, be 5 mg. In another embodiment, a starting dose of the three months, four months, five months, or six months after obeticholic acid composition administered to a patient the beginning of the treatment. described herein can be 10 mg. In still another embodiment, 0227. In one embodiment, the severity of the pruritus a starting dose of the obeticholic acid composition admin decreases by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, istered to a patient described herein can be 25 mg. In yet 40%, 45%, or 50% in subjects treated with the compositions another embodiment, a starting dose of the obeticholic acid of the present disclosure. In a further embodiment, the composition administered to a patient described herein can severity of pruritus decreases by at least 20%, 25%, 30%, be 50 mg. 35%, 40%, 45%, or 50% in subjects treated with the 0231. The amount of an obeticholic acid composition as compositions of the present disclosure. In a further embodi provided above can refer to an adjusted dose administered ment, the severity of pruritus decreases by at least 5%, 10%, after a titration period as described herein. In certain 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% in subjects embodiments, an adjusted dose of the obeticholic acid treated with the compositions of the present disclosure composition administered to a patient described herein can during the first one month, two months, three months, four be 5 mg. In another embodiment, an adjusted dose of the months, five months, or six months after the beginning of the obeticholic acid composition administered to a patient treatment. In a further embodiment, the severity of pruritus described herein can be 10 mg. In still another embodiment, decreases by at least 20%, 25%, 30%, 35%, 40%, 45%, or an adjusted dose of the obeticholic acid composition admin 50% in subjects treated with the compositions of the present istered to a patient described herein can be 25 mg. In yet disclosure during the first one month, two months, three another embodiment, an adjusted dose of the obeticholic months, four months, five months, or six months after the acid composition administered to a patient described herein beginning of the treatment. can be 50 mg. 0228 Obeticholic acid compositions described herein 0232. The amount of an obeticholic acid composition as can be administered to a patient in an amount of between provided above can refer to a re-adjusted dose administered about: 1 mg to about 50 mg; 1 to about 40 mg; 1 to about after a titration period as described herein. In certain 30 mg, 1 to about 25 mg, 1 to about 20 mg, 1 mg to about embodiments, a re-adjusted dose of the obeticholic acid 10 mg; or 1 mg to about 5 mg. In one embodiment, the composition administered to a patient described herein can obeticholic acid composition can be administered to a be 5 mg. In another embodiment, a re-adjusted dose of the patient in an amount of about: 5 to about 50 mg; 5 to about obeticholic acid composition administered to a patient 40 mg.: 5 to about 30 mg.: 5 to about 25 mg; 5 to about 20 described herein can be 10 mg. In still another embodiment, mg; or 5 to about 10 mg. In other instances, the obeticholic a re-adjusted dose of the obeticholic acid composition acid composition can be administered in an amount of about administered to a patient described herein can be 25 mg. In 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, yet another embodiment, a re-adjusted dose of the obet 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, or 50 mg. In still other icholic acid composition administered to a patient described instances, the obeticholic acid composition described herein herein can be 50 mg. can be administered at an amount of about 5 mg, 10 mg, 15 0233 While it is possible to administer obeticholic acid mg, 25 mg. or 50 mg. For example, an effective amount of directly without any formulation, obeticholic acid is usually a obeticholic acid composition described herein can be about administered in the form of pharmaceutical formulations 5 mg, 10 mg, 25 mg, or 50 mg. In another example, the comprising a pharmaceutically acceptable excipient and amount of a starting dose of an obeticholic acid composition obeticholic acid. These formulations can be administered by described herein can be about 5 mg, 10 mg, 25 mg, or 50 mg. a variety of routes including oral, buccal, rectal, intranasal, In another example, the amount of an adjusted dose or transdermal. Subcutaneous, intravenous, intramuscular, and re-adjusted dose of an obeticholic acid composition intranasal. Oral formulation of obeticholic acid are described herein can be about 5 mg, 10 mg, 25 mg, or 50 mg. described further herein under the section entitled “Oral It is to be understood the amount of an obeticholic acid Formulation and Administration'. US 2017/0035784 A1 Feb. 9, 2017 0234. In one embodiment, obeticholic acid can be admin applied orally and Swished and expectorated or Swallowed. istered transdermally. In order to administer transdermally, a Pharmaceutically compatible binding agents, and/or adju transdermal delivery device (“patch') is needed. Such trans vant materials can be included as part of the composition. dermal patches may be used to provide continuous or The tablets, pills, capsules, troches and the like can contain discontinuous infusion of a compound of the present dis any of the following ingredients, or compounds of a similar closure in controlled amounts. The construction and use of nature: a binder Such as microcrystalline cellulose, gum transdermal patches for the delivery of pharmaceutical tragacanth or gelatin; an excipient such as Sodium starch agents is well known in the art. See, e.g., U.S. Pat. No. glycolate, starch or lactose, a diluent such as microcrystal 5,023,252. Such patches may be constructed for continuous, line cellulose, a disintegrating agent Such as alginic acid, pulsatile, or on demand delivery of pharmaceutical agents. Primogel, or corn starch; a lubricant Such as magnesium 0235 Pharmaceutical compositions suitable for inject Stearate or Sterotes; a glidant Such as colloidal silicon able use include sterile aqueous solutions (where water dioxide; a Sweetening agent Such as Sucrose or saccharin; or soluble) or dispersions and sterile powders for the extem a flavoring agent such as peppermint, methyl salicylate, or poraneous preparation of sterile injectable solutions or dis orange flavoring. persion. For intravenous administration, Suitable carriers 0238 For administration by inhalation, the obeticholic include physiological Saline, bacteriostatic water, Cremo acid or obeticholic acid particles is delivered in the form of phor ELTM (BASF, Parsippany, N.J.) or phosphate buffered an aerosol spray from pressured container or dispenser, saline (PBS). In all cases, the composition must be sterile which contains a suitable propellant, e.g., a gas such as and should be fluid to the extent that easy syringeability carbon dioxide, or a nebulizer. exists. It must be stable under the conditions of manufacture 0239 Systemic administration can also be by transmu and storage and must be preserved against the contaminating cosal or transdermal means. For transmucosal or transder action of microorganisms such as bacteria and fungi. The mal administration, penetrants appropriate to the barrier to carrier can be a solvent or dispersion medium containing, for be permeated are used in the formulation. Such penetrants example, water, ethanol, polyol (for example, glycerol, are generally known in the art, and include, for example, for propylene glycol, and liquid polyethylene glycol, and the transmucosal administration, detergents, bile salts, and like), and suitable mixtures thereof. The proper fluidity can fusidic acid derivatives. Transmucosal administration can be be maintained, for example, by the use of a coating Such as accomplished through the use of nasal sprays or Supposito lecithin, by the maintenance of the required particle size in ries. For transdermal administration, the obeticholic acid or the case of dispersion and by the use of surfactants. Pre obeticholic acid particles is formulated into ointments, vention of the action of microorganisms can be achieved by salves, gels, or creams as generally known in the art. various antibacterial and antifungal agents, for example, 0240. The obeticholic acid or obeticholic acid particles parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, can be prepared with pharmaceutically acceptable carriers and the like. In many cases, it will be preferable to include that will protect the compound against rapid elimination isotonic agents, for example, Sugars, polyalcohols such as from the body, such as a controlled release formulation, mannitol, Sorbitol, Sodium chloride in the composition. including implants and microencapsulated delivery systems. Prolonged absorption of the injectable compositions can be Biodegradable, biocompatible polymers can be used. Such as brought about by including in the composition an agent ethylene vinyl acetate, polyanhydrides, polyglycolic acid, which delays absorption, for example, aluminum monoste collagen, polyorthoesters, and polylactic acid. Methods for arate and gelatin. preparation of Such formulations will be apparent to those 0236 Sterile injectable solutions can be prepared by skilled in the art. The materials can also be obtained com incorporating the active compound, obeticholic acid or mercially from Alza Corporation and Nova Pharmaceuticals, obeticholic acid particles, in the required amount in an Inc. Liposomal Suspensions (including liposomes targeted to appropriate solvent with one or a combination of ingredients infected cells with monoclonal antibodies to viral antigens) enumerated herein, as required, followed by filtered steril can also be used as pharmaceutically acceptable carriers. ization. Generally, dispersions are prepared by incorporating These can be prepared according to methods known to those the obeticholic acid into a sterile vehicle that contains a basic skilled in the art, for example, as described in U.S. Pat. No. dispersion medium and the required other ingredients from 4,522,811. those enumerated above. In the case of sterile powders for 0241. It is especially advantageous to formulate oral or the preparation of sterile injectable solutions, methods of parenteral compositions in dosage unit form for ease of preparation are vacuum drying and freeze-drying that yields administration and uniformity of dosage. Dosage unit form a powder of the obeticholic acid or obeticholic acid particles, as used herein refers to physically discrete units Suited as plus any additional desired ingredient from a previously unitary dosages for the Subject to be treated; each unit sterile-filtered solution thereof. containing a predetermined quantity of obeticholic acid or 0237. It can be useful to orally administer an obeticholic obeticholic acid particles calculated to produce the desired acid composition described herein. Oral compositions gen therapeutic effect in association with the required pharma erally include an inert diluent or an edible pharmaceutically ceutical carrier. The specification for the dosage unit forms acceptable carrier. They can be enclosed in gelatin capsules of the disclosure are dictated by and directly dependent on or compressed into tablets. For the purpose of oral thera the unique characteristics of the obeticholic acid or obet peutic administration, the active compound, obeticholic acid icholic acid particles and the particular therapeutic effect to or obeticholic acid particles, can be incorporated with be achieved. excipients and used in the form of tablets, troches, or 0242. In one embodiment of the present disclosure, there capsules. Oral compositions can also be prepared using a is provided a pharmaceutical formulation comprising at least fluid carrier for use as a mouthwash, wherein the obeticholic obeticholic acid as described above in a formulation adapted acid or obeticholic acid particles in the fluid carrier is for buccal and/or Sublingual, or nasal administration. This US 2017/0035784 A1 Feb. 9, 2017 22 embodiment provides administration of obeticholic acid in a another embodiment, the formulation comprises about 4 mg manner that avoids gastric complications, such as first pass to about 25 mg. In another embodiment, the formulation metabolism by the gastric system and/or through the liver. comprises about 5 mg to about 25 mg. In another embodi This administration route may also reduce adsorption times, ment, the formulation comprises about 5 mg to about 10 mg. providing more rapid onset of therapeutic benefit. The In one embodiment, the formulation comprises about 1 mg compounds of the present disclosure may provide particu to about 2 mg. In one embodiment, the formulation com larly favorable solubility profiles to facilitate sublingual/ prises about 1.2 mg to about 1.8 mg. In one embodiment, the buccal formulations. Such formulations typically require formulation comprises about 1.3 mg to about 1.7 mg. In one relatively high concentrations of active ingredients to deliver embodiment, the formulation comprises about 0.05 mg to Sufficient amounts of active ingredients to the limited Sur about 0.5 mg. In another embodiment, the formulation face area of the sublingual/buccal mucosa for the relatively comprises about 0.08 mg to about 0.8 mg. In yet another short durations the formulation is in contact with the surface embodiment, the formulation comprises about 0.1 mg to area, to allow the absorption of the active ingredient. Thus, about 0.5 mg. In another embodiment, the formulation the very high activity of obeticholic acid, combined with its comprises about 25 mg. In another embodiment, the formu high solubility, facilitates its suitability for sublingual/buccal lation comprises about 10 mg. In one embodiment, the formulation. formulation comprises about 5 mg. In another embodiment, 0243 Obeticholic acid is preferably formulated in a unit the formulation comprises about 0.25 mg. However, it will dosage form, each dosage containing from about 0.05 mg to be understood that the amount of obeticholic acid actually about 1500 mg. In another embodiment, the formulation administered will be determined by a physician, in the light comprises about 0.05 mg to about 100 mg. In yet another of the relevant circumstances, including the condition to be embodiment, the formulation comprises about 1 mg to about treated, the chosen route of administration, the form of 100 mg. In another embodiment, the formulation comprises obeticholic acid administered, the age, weight, and response about 0.05 mg to about 50 mg. In yet another embodiment, of the individual patient, and the severity of the patients the formulation comprises about 0.05 mg to about 30 mg. In symptoms, and therefore the above dosage ranges are not another embodiment, the formulation comprises about 0.05 intended to limit the scope of the disclosure in any way. In mg to about 20 mg. In yet another embodiment, the formu some instances dosage levels below the lower limit of the lation comprises about 0.5 mg to about 30 mg. In another aforesaid range may be more than adequate, while in other embodiment, the formulation comprises about 0.5 mg to cases still larger doses may be employed without causing about 25 mg. In yet another embodiment, the formulation any harmful side effect, provided that Such larger doses are comprises about 1 mg to about 25 mg. In another embodi first divided into several smaller doses for administration ment, the formulation comprises about 4 mg to about 26 mg. throughout the day. In another embodiment, the formulation comprises about 5 0246 The tablet of the present disclosure can comprise mg to about 25 mg. In yet another embodiment, the formu an intra-granular portion and an extra-granular portion. The lation comprises about 0.05 mg to about 2 mg. In another intra-granular portion can contain obeticholic acid, or a embodiment, the formulation comprises about 1 mg to about pharmaceutically acceptable salt, ester, or amino acid con 2 mg. In one embodiment, the formulation comprises about jugate thereof, and one or more pharmaceutical excipients. 1.2 mg to about 1.8 mg. In one embodiment, the formulation The extra-granular portion can contain obeticholic acid, or a comprises about 1.3 mg to about 1.7 mg. In one embodi pharmaceutically acceptable salt, ester, or amino acid con ment, the formulation comprises about 1.5 mg. In one jugate thereof, and one or more pharmaceutical excipients. embodiment, the formulation comprises about 0.05 mg to In one embodiment, the intra-granular portion and the extra about 0.5 mg. In another embodiment, the formulation granular portion of the tablet contain obeticholic acid, or a comprises about 0.08 mg to about 0.8 mg. In yet another pharmaceutically acceptable salt, ester, or amino acid con embodiment, the formulation comprises about 0.1 mg to jugate thereof, and one or more pharmaceutical excipients. about 0.5 mg. In another embodiment, the formulation In another embodiment, the intra-granular portion contains comprises about 0.25 mg. obeticholic acid, or a pharmaceutically acceptable salt, ester, 0244 Obeticholic acid is generally effective over a wide or amino acid conjugate thereof and/or the extra-granular dosage range. For examples, dosages per day normally fall portion does not contain obeticholic acid, or a pharmaceu within the range of about 0.0001 to about 30 mg/kg of body tically acceptable salt, ester, or amino acid conjugate weight. In the treatment of adult humans, the range of about thereof. 0.1 to about 15 mg/kg/day, in single or divided dose, is 0247 The presence of microcrystalline cellulose in the especially preferred. In one embodiment, the formulation intra-granular portion and/or the extra-granular portion of a comprises about 0.05 mg to about 1500 mg. In another tablet comprising obeticholic acid or a pharmaceutically embodiment, the formulation comprises about 0.05 mg to acceptable salt, ester, or amino acid conjugate thereof, can about 100 mg. In yet another embodiment, the formulation affect the properties of the tablet. In one embodiment, when comprises about 1 mg to about 100 mg. In another embodi microcrystalline cellulose is added to only the intra-granular ment, the formulation comprises about 0.05 mg to about 50 portion of the tablet, tablets of moderate hardness can be mg. In another embodiment, the formulation comprises produced. In another embodiment, when microcrystalline about 0.05 mg to about 30 mg. In yet another embodiment, cellulose is added to only the intra-granular portion of the the formulation comprises about 0.05 mg to about 20 mg. In tablet, tablets of tolerable hardness may be produced. In yet another embodiment, the formulation comprises about another embodiment, addition of microcrystalline cellulose 0.05 mg to about 10 mg. to both the intra-granular and extra-granular portions can 0245. In one embodiment, the formulation comprises provide tablets having Superior tablet hardness and an about 3 mg to about 30 mg. In another embodiment, the improved dissolution profile. In one embodiment, microc formulation comprises about 0.05 mg to about 25 mg. In rystalline cellulose is added to the intra-granular portion of US 2017/0035784 A1 Feb. 9, 2017 the tablet. In another embodiment, microcrystalline cellu conjugate thereof, is between about 20:1 to about 2:1, lose is added to both the intra-granular portion and extra between about 20:1 to about 3:1, between about 20:1 to granular portion of the tablet. about 4:1, between about 20:1 to about 5:1, between about 0248 When the microcrystalline cellulose is present in 20:1 to about 6:1, between about 20:1 to about 7:1, between the intra-granular portion it can be present in a ratio of about 20:1 to about 8:1, between about 20:1 to about 9:1, microcrystalline cellulose to obeticholic acid, or a pharma between about 20:1 to about 10:1, between about 20:1 to ceutically acceptable salt, ester, or amino acid conjugate about 11:1, between about 19:1 to about 2:1, between about thereof, between about 20:1 to about 1:5. In one embodi 19:1 to about 3:1, between about 19:1 to about 4:1, between ment, the ratio of microcrystalline cellulose to obeticholic about 19:1 to about 5:1, between about 19:1 to about 6:1, acid, or a pharmaceutically acceptable salt, ester, or amino between about 19:1 to about 7:1, between about 19:1 to acid conjugate thereof, may be, e.g., between about 19:1 to about 8:1, between about 19:1 to about 9:1, between about about 1:5, between about 19:1 to about 1:4, between about 19:1 to about 10:1, between about 19:1 to about 11:1, 19:1 to about 1:3, between about 19:1 to about 1:2, between between about 18:1 to about 2:1, between about 18:1 to about 18:1 to about 1:5, between about 18:1 to about 1:4, about 3:1, between about 18:1 to about 4:1, between about between about 18:1 to about 1:3, between about 18:1 to 18:1 to about 5:1, between about 18:1 to about 6:1, between about 1:2, between about 17:1 to about 1:5, between about about 18:1 to about 7:1, between about 18:1 to about 8:1, 17:1 to about 1:4, between about 17:1 to about 1:3, between between about 18:1 to about 9:1, between about 18:1 to about 17:1 to about 1:2, between about 16:1 to about 1:5, about 10:1, between about 18:1 to about 11:1, between about between about 16:1 to about 1:4, between about 16:1 to 17:1 to about 2:1, between about 17:1 to about 3:1, between about 1:3, between about 16:1 to about 1:2, between about about 17:1 to about 4:1, between about 17:1 to about 5:1, 15:1 to about 1:5, between about 15:1 to about 1:4, between between about 17:1 to about 6:1, between about 17:1 to about 15:1 to about 1:3, between about 15:1 to about 1:2, about 7:1, between about 17:1 to about 8:1, between about between about 14:1 to about 1:5, between about 14:1 to 17:1 to about 9:1, between about 17:1 to about 10:1, between about 1:4, between about 14:1 to about 1:3, between about about 17:1 to about 11:1, between about 16:1 to about 2:1, 14:1 to about 1:2, between about 13:1 to about 1:5, between between about 16:1 to about 3:1, between about 16:1 to about 13:1 to about 1:4, between about 13:1 to about 1:3, about 4:1, between about 16:1 to about 5:1, between about between about 13:1 to about 1:2, between about 12:1 to 16:1 to about 6:1, between about 16:1 to about 7:1, between about 1:5, between about 12:1 to about 1:4, between about about 16:1 to about 8:1, between about 16:1 to about 9:1, 12:1 to about 1:3, between about 12:1 to about 1:2, between between about 16:1 to about 10:1, between about 16:1 to about 11:1 to about 1:5, between about 11:1 to about 1:4, about 11:1, between about 15:1 to about 2:1, between about between about 11:1 to about 1:3, or between about 11:1 to 15:1 to about 3:1, between about 15:1 to about 4:1, between about 1:2. In another embodiment, the ratio of microcrys about 15:1 to about 5:1, between about 15:1 to about 6:1, talline cellulose to obeticholic acid, or a pharmaceutically between about 15:1 to about 7:1, between about 15:1 to acceptable salt, ester, or amino acid conjugate thereof, is about 8:1, between about 15:1 to about 9:1, between about between about 10:1 to about 1:5, between about 10:1 to 15:1 to about 10:1, between about 15:1 to about 11:1, about 1:4, between about 10:1 to about 1:3, or between about between about 14:1 to about 2:1, between about 14:1 to 10:1 to about 1:2. In another embodiment, the ratio of about 3:1, between about 14:1 to about 4:1, between about microcrystalline cellulose to obeticholic acid, or a pharma 14:1 to about 5:1, between about 14:1 to about 6:1, between ceutically acceptable salt, ester, or amino acid conjugate about 14:1 to about 7:1, between about 14:1 to about 8:1, thereof, is between about 9:1 to about 1:4, between about 9:1 between about 14:1 to about 9:1, between about 14:1 to to about 1:3, between about 9:1 to about 1:2, or between about 10:1, between about 14:1 to about 11:1, between about about 9:1 to about 1:1. In yet another embodiment, the ratio 13:1 to about 2:1, between about 13:1 to about 3:1, between of microcrystalline cellulose to obeticholic acid, or a phar about 13:1 to about 4:1, between about 13:1 to about 5:1, maceutically acceptable salt, ester, or amino acid conjugate between about 13:1 to about 6:1, between about 13:1 to thereof, is between about 8:1 to about 1:3, between about 8:1 about 7:1, between about 13:1 to about 8:1, between about to about 1:2, or between about 8:1 to about 1:1. In another 13:1 to about 9:1, between about 13:1 to about 10:1, between embodiment, the ratio of microcrystalline cellulose to obet about 13:1 to about 11:1, between about 12:1 to about 2:1, icholic acid, or a pharmaceutically acceptable salt, ester, or between about 12:1 to about 3:1, between about 12:1 to amino acid conjugate thereof, is between about 7:1 to about about 4:1, between about 12:1 to about 5:1, between about 1:2 or between about 7:1 to about 1:1. In yet another 12:1 to about 6:1, between about 12:1 to about 7:1, between embodiment, the ratio of microcrystalline cellulose to obet about 12:1 to about 8:1, between about 12:1 to about 9:1, icholic acid, or a pharmaceutically acceptable salt, ester, or between about 12:1 to about 10:1, between about 12:1 to amino acid conjugate thereof, is between about 6:1 to about about 11:1, between about 11:1 to about 2:1, between about 1:1. In other embodiments, the ratio of microcrystalline 11:1 to about 3:1, between about 11:1 to about 4:1, between cellulose to obeticholic acid, or a pharmaceutically accept about 11:1 to about 5:1, between about 11:1 to about 6:1, able salt, ester, or amino acid conjugate thereof, is between between about 11:1 to about 7:1, between about 11:1 to about 20:1 to about 1:1, between about 19:1 to about 1:1, about 8:1, or between about 11:1 to about 9:1, or between between about 18:1 to about 1:1, between about 17:1 to about 11:1 to about 10:1. Preferably, the ratio of microcrys about 1:1, between about 16:1 to about 1:1, between about talline cellulose to obeticholic acid, or a pharmaceutically 15:1 to about 1:1, between about 14:1 to about 1:1, between acceptable salt, ester, or amino acid conjugate thereof, may about 13:1 to about 1:1, between about 12:1 to about 1:1, or be between about 20:1 to about 5:1, between about 16:1 to between about 11:1 to about 1:1. In another embodiments, about 6:1, or between about 16:1 to about 11:1, or any of the the ratio of microcrystalline cellulose to obeticholic acid, or above-mentioned ratio ranges between about 20:1 to about a pharmaceutically acceptable salt, ester, or amino acid 5:1. In another embodiment, the ratio of microcrystalline US 2017/0035784 A1 Feb. 9, 2017 24 cellulose to obeticholic acid, or a pharmaceutically accept increased hardness. In particular, the tablets of the present able salt, ester, or amino acid conjugate thereof, is about disclosure comprising microcrystalline cellulose in both the 16:1. In yet another embodiment, the ratio of microcrystal intra-granular portion and extra-granular portion possess line cellulose to obeticholic acid, or a pharmaceutically increased hardness, for example, as compared with tablets acceptable salt, ester, or amino acid conjugate thereof, is comprising microcrystalline cellulose in only the intra about 11:1. In another embodiment, the ratio of microcrys granular portion. In one embodiment, the hardness is talline cellulose to obeticholic acid, or a pharmaceutically increased at least about 5%, at least about 10%, at least about acceptable salt, ester, or amino acid conjugate thereof, is 20%, at least about 30%, at least about 40%, at least about about 6:1. In yet another embodiment, the ratio of microc 50%, at least about 60%, or at least about 70%, for example, rystalline cellulose to obeticholic acid, or a pharmaceutically as compared with tablets comprising microcrystalline cel acceptable salt, ester, or amino acid conjugate thereof, is lulose in only the intra-granular portion. In one embodiment, between about 10:1 to about 1:1. In another embodiment, the the hardness is increased at least about 20%, at least about ratio of microcrystalline cellulose to obeticholic acid, or a 30%, at least about 40%, or at least about 50%, for example, pharmaceutically acceptable salt, ester, or amino acid con as compared with tablets comprising microcrystalline cel jugate thereof, is between about 5:1 to about 1:1. In yet lulose in only the intra-granular portion. In another embodi another embodiment, the ratio of microcrystalline cellulose ment, the hardness is increased between about 5% and about to obeticholic acid, or a pharmaceutically acceptable salt, 45%, between about 10% and about 40%, between about ester, or amino acid conjugate thereof, is between about 3:1 15% and about 35%, between about 20% and about 30%, to about 1:1. In another embodiment, the ratio of microc between about 25% and about 35%, between about 25% and rystalline cellulose to obeticholic acid, or a pharmaceutically about 40%, between about 25% and about 50%, or between acceptable salt, ester, or amino acid conjugate thereof, is about 30% and about 50%, for example, as compared with between about 2:1 to about 1:1. In another embodiment, the tablets comprising microcrystalline cellulose in only the ratio of microcrystalline cellulose to obeticholic acid, or a intra-granular portion. pharmaceutically acceptable salt, ester, or amino acid con 0251. In one embodiment, the tablets of the present jugate thereof, is between about 4:1 to about 2:1. In yet disclosure comprising obeticholic acid or a pharmaceuti another embodiment, the ratio of microcrystalline cellulose cally acceptable salt, ester, or amino acid conjugate thereof, to obeticholic acid, or a pharmaceutically acceptable salt, microcrystalline cellulose and optionally one or more addi ester, or amino acid conjugate thereof, is between about 3:1 tional pharmaceutical excipients in the intra-granular por to about 2:1. In another embodiment, the ratio of microc tion, and one or more pharmaceutical excipients in the rystalline cellulose to obeticholic acid, or a pharmaceutically extra-granular portion possess increased hardness. In acceptable salt, ester, or amino acid conjugate thereof, is another embodiment, the tablets of the present disclosure about 4:1. In another embodiment, the ratio of microcrys comprising obeticholic acid or a pharmaceutically accept talline cellulose to obeticholic acid, or a pharmaceutically able salt, ester, or amino acid conjugate thereof, microcrys acceptable salt, ester, or amino acid conjugate thereof, is talline cellulose, and optionally one or more additional about 3:1. In yet another embodiment, the ratio of microc pharmaceutical excipients in the intra-granular portion, and rystalline cellulose to obeticholic acid, or a pharmaceutically microcrystalline cellulose and optionally one or more addi acceptable salt, ester, or amino acid conjugate thereof, is tional pharmaceutical excipients in the extra-granular por about 2:1. In another embodiment, the ratio of microcrys tion possess improved dissolution of obeticholic acid or a talline cellulose to obeticholic acid, or a pharmaceutically pharmaceutically acceptable salt, ester, or amino acid con acceptable salt, ester, or amino acid conjugate thereof, is jugate thereof. In particular, the tablets of the present dis about 1:1. closure comprising microcrystalline cellulose in both the 0249. The tablet hardness of an obeticholic acid contain intra-granular portion and extra-granular portion possess ing tablet can be between about 6 kilopascals (kP) to about improved dissolution of obeticholic acid or a pharmaceuti 14 kP. In one embodiment, the tablet hardness is between cally acceptable salt, ester, or amino acid conjugate thereof, about 7 kP to about 12 kP. In another embodiment, the tablet for example, as compared with tablets comprising microc hardness is between about 8 kP to about 12 kP. In yet rystalline cellulose in only the intra-granular portion. For another, the tablet hardness is between about 8 kP to about example, obeticholic acid or a pharmaceutically acceptable 11 kP. In another embodiment, the tablet hardness is between salt, ester, or amino acid conjugate thereof in the tablets of about 9 kP to about 11 kP. In yet another embodiment, the the present disclosure dissolves (e.g., in a Disodium Hydro tablet hardness is between about 10 kP to about 11 kP. gen Phosphate Buffer) at a rate that is at least 2%. 3%, 4%, 0250 In one embodiment, the tablets of the present 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50%, disclosure comprising obeticholic acid or a pharmaceuti 80%, or 100% faster than, for example, as compared with cally acceptable salt, ester, or amino acid conjugate thereof, the dissolution rate tablets comprising microcrystalline cel microcrystalline cellulose and optionally one or more addi lulose in only the intra-granular portion. tional pharmaceutical excipients in the intra-granular por (0252 For example, about 55% to about 95% of obet tion, and one or more pharmaceutical excipients in the icholic acid or a pharmaceutically acceptable salt, ester, or extra-granular portion possess increased hardness. In one amino acid conjugate thereof in the tablet of the present embodiment, the tablets of the present disclosure comprising disclosure is dissolved within about 15 minutes, or about obeticholic acid or a pharmaceutically acceptable salt, ester, 65% to about 95% is dissolved within about 30 minutes, or or amino acid conjugate thereof, microcrystalline cellulose about 80% to about 95% is dissolved within about 45 and optionally one or more additional pharmaceutical minutes, or about 87% to about 97% is dissolved within excipients in the intra-granular portion, and microcrystalline about 60 minutes, or about 87% to about 99% is dissolved cellulose and optionally one or more additional pharmaceu within about 75 minutes. For example, about 60% to about tical excipients in the extra-granular portion possess 84% of obeticholic acid or a pharmaceutically acceptable US 2017/0035784 A1 Feb. 9, 2017 salt, ester, or amino acid conjugate thereof in the tablet of the magnesium Stearate) are added to provide a final blend present disclosure is dissolved within about 15 minutes, or which is further optionally blended. In one embodiment, about 75% to about 91% is dissolved within about 30 microcrystalline cellulose is added during the final blending. minutes, or about 85% to about 93% is dissolved within In one embodiment, the one or more pharmaceutical excipi about 45 minutes, or about 90% to about 96% is dissolved ents are added sequentially. In another embodiment, the one within about 60 minutes, or about 90% to about 97% is or more pharmaceutical excipients are added together. dissolved within about 75 minutes. For example, about 62% 0257 The final blend is then compressed to form the to about 83% of obeticholic acid or a pharmaceutically tablet. The compression parameters can be adjusted to acceptable salt, ester, or amino acid conjugate thereof in the produce tablets of the desired weight, hardness, thickness, tablet of the present disclosure is dissolved within about 15 and friability. The tablet press speed and feeder speed can minutes, or about 80% to about 90% is dissolved within also be adjusted to help reduce tablet weight variation. The about 30 minutes, or about 87% to about 94% is dissolved obeticholic acid tablets are then coated with a coating within about 45 minutes, or about 92% to about 96% is material (i.e., Opadry(R) II white, Opadry(R) II green, or dissolved within about 60 minutes, or about 91% to about Opadry(R II yellow) using a coating solution. 97% is dissolved within about 75 minutes. For example, 0258 Obeticholic acid compositions described herein about 60% to about 84% obeticholic acid or a pharmaceu can be administered in accordance with a dosing regimen. A tically acceptable salt, ester, or amino acid conjugate thereof dosing regimen refers to continual and intermittent admin in the tablet of the present disclosure is dissolved within istration of a obeticholic acid composition described herein about 15 minutes, or about 70% to about 90% is dissolved at one or more of the amounts described herein. Thus, in within about 30 minutes, or about 85% to about 92% is certain instances, a dosing regimen can include administra dissolved within about 45 minutes, or about 89% to about tion of a obeticholic acid composition described herein 96% is dissolved within about 60 minutes, or about 90% to continually for any number of days, weeks, months, or years about 96% is dissolved within about 75 minutes. For as set forth herein. In other instances, a dosing regimen can example, at least about 60% obeticholic acid or a pharma include administration of a obeticholic acid composition ceutically acceptable salt, ester, or amino acid conjugate described herein intermittently, where, for example, the thereof in the tablet of the present disclosure is dissolved composition is administered for one period of time followed within about 15 minutes, or at least about 90% is dissolved by a rest period or off period where the obeticholic acid within about 60 minutes. For example, obeticholic acid or a composition is not administered. pharmaceutically acceptable salt, ester, or amino acid con 0259 Obeticholic acid compositions useful in the meth jugate thereof in the tablet of the present disclosure has an ods of treating described herein include administration of in vitro dissolution profile of about 51% dissolved within Such compositions daily (QD), every other day (Q2D), once about 15 minutes, or about 66% dissolved within about 30 a week (QW), twice a week (BID), three times a week minutes, or about 79% dissolved within about 45 minutes, or (TIW), once a month (QM), or twice a month (Q2M). In one about 85% dissolved within about 60 minutes. embodiment, a obeticholic acid composition described 0253) Obeticholic acid tablets can be manufactured via a herein is administered QD. Thus, an effective amount of an manufacturing process comprising dry granulation by roller obeticholic acid composition described herein can be admin compaction followed by tablet compression and coating. istered QD to treat a disease or condition described herein. The process steps used to manufacture OCA tablets include: A starting dose described herein can be administered QD pre-blending, dry granulation, final blending, compression, during the course of a titration period described herein to coating, and packaging. treat a disease or condition described herein. An adjusted 0254 Obeticholic acid drug substance and one or more dose described herein can be administered QD to treat a pharmaceutical excipients (i.e., microcrystalline cellulose, disease or condition described herein. Sodium starch glycolate, and/or magnesium Stearate) are 0260. In another embodiment, an obeticholic acid com added and further optionally blended to produce a premix. In position described herein is administered Q2D. An effective one embodiment, OCA and microcrystalline cellulose is amount of an obeticholic acid composition described herein blended to produce a premix. In one embodiment, the can be administered Q2D to treat a disease or condition premix is blended, passed through a screen and then again described herein. A starting dose described herein can be blended. In another embodiment, the one or more pharma administered Q2D during the course of a titration period ceutical excipients are added in Small portions and blended described herein to treat a disease or condition described between each addition. In one embodiment, the one or more herein. An adjusted dose described herein can be adminis pharmaceutical excipients are added sequentially. In another tered Q2D to treat a disease or condition described herein. embodiment, the one or more pharmaceutical excipients are 0261. In another embodiment, an obeticholic acid com added together. position is described herein administered QW. An effective 0255. The premix is then granulated and optionally amount of an obeticholic acid composition described herein milled to reduce particle size. In one embodiment, the can be administered QW to treat a disease or condition premix is roller compacted. In another embodiment, the described herein. A starting dose described herein can be premix is further milled. The premix can be milled using administered QW during the course of a titration period various methods. In one embodiment, the premix is milled described herein to treat a disease or condition described using a comil. In another embodiment, the premix is milled herein. An adjusted dose described herein can be adminis using a comil followed by an oscillating bar screen mill. tered QW to treat a disease or condition described herein. 0256. Once the premix is granulated, a final blending of 0262. In another embodiment, an obeticholic acid com the obeticholic acid tablet formulation is performed. In the position is described herein administered BID. An effective final blending, one or more pharmaceutical excipients (i.e., amount of an obeticholic acid composition described herein microcrystalline cellulose, sodium starch glycolate, and/or can be administered BID to treat a disease or condition US 2017/0035784 A1 Feb. 9, 2017 26 described herein. A starting dose described herein can be includes a time of about: 2 months to about 4 months; 2 administered BID during the course of a titration period months to about 7 months; 2 months to about 8 months; 4 described herein to treat a disease or condition described months to about 8 months; 5 months to about 7 months; or herein. An adjusted dose described herein can be adminis 5 months to about 8 months. For example, a titration period tered BID to treat a disease or condition described herein. can be about 1 to about 6 months. In another example, a 0263. In another embodiment, an obeticholic acid com titration period can be about 3 to about 6 months. position is described herein administered TIW. An effective 0269. A titration period can include a time of about 1, 2, amount of an obeticholic acid composition described herein 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, can be administered TIW to treat a disease or condition 21, 22, 23, or 24 months. In certain embodiments, a titration described herein. A starting dose described herein can be period includes a time of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, administered TIW during the course of a titration period 11, or 12 months. In another embodiment, the titration described herein to treat a disease or condition described period includes a time of about 1, 2, 3, 4, 5, 6, 7, 8, or 9 herein. An adjusted dose described herein can be adminis months. In another embodiment, the titration period includes tered TIW to treat a disease or condition described herein. a time of about 1, 2, 3, 4, 5, or 6 months. In another 0264. In another embodiment, an obeticholic acid com embodiment, the titration period includes a time of about 1, position is described herein administered QM. An effective 2, or 3 months. For example, a titration period can be about amount of an obeticholic acid composition described herein 1 month. In another example a titration period can be about can be administered QM to treat a disease or condition 2 months. In another example a titration period can be about described herein. A starting dose described herein can be 3 months. In still another example a titration period can be administered QM during the course of a titration period about 4 months. In yet another example a titration period can described herein to treat a disease or condition described be about 5 months. In another example a titration period can herein. An adjusted dose described herein can be adminis be about 6 months. In one example a titration period is 3 tered QM to treat a disease or condition described herein. months or 6 months. In another example a titration period 0265. In another embodiment, an obeticholic acid com can be about 7 months. In another example a titration period position is described herein administered Q2M. An effective can be about 8 months. In another example a titration period amount of an obeticholic acid composition described herein can be about 9 months. can be administered Q2M to treat a disease or condition 0270. As provided above, the amounts of a obeticholic described herein. A starting dose described herein can be acid composition described herein, optionally administered administered Q2M during the course of a titration period in a titration period can be reduced compared to an adjusted described herein to treat a disease or condition described amount as described herein. Accordingly, provided herein herein. An adjusted dose described herein can be adminis are treatment regimens that include administering obet tered Q2M to treat a disease or condition described herein. icholic acid compositions described herein for the treatment 0266 The embodiments described above include admin of a disease or condition described herein (e.g., PBC) istration at an amount described above. For example, an wherein the starting dose administered during a titration obeticholic acid composition described herein can be admin period described above is lower than the amount of an istered in a frequency provided above in an amount of 5 mg. adjusted dose administered after a titration period. Still 10 mg, 25 mg, or 50 mg. further provided herein are treatment regimens that include 0267 Dosing regimens of the obeticholic acid composi administering obeticholic acid compositions described tions described herein useful for treating diseases and con herein for the treatment of a disease or condition described ditions described herein can include a titration period. A herein (e.g., PBC) where the starting dose administered titration period typically includes a lower dosage of an during a titration period described above is lower than the obeticholic acid composition described herein for a period of amount of an adjusted dose administered after a titration time. In certain instances, and without being bound by any period and where the frequency of administration (e.g., QD. particular theory, administration using a titration period Q2D, or QW) for the adjusted dose is greater than the described herein can decrease or eliminate the onset of frequency of administration of the starting dose. Still further adverse effects. In other instances, and without being bound provided herein are treatment regimens that include admin by any particular theory, administration using a titration istering obeticholic acid compositions described herein for period described herein can permit increased dosages of the treatment of a disease or condition described herein (e.g., obeticholic acid compositions described herein to an indi PBC) where the starting dose administered during a titration vidual over the course of a treatment. period described above is lower than the amount of an 0268 A titration period can be a period of time of about: adjusted dose administered after a titration period and where 1 month to about 24 months; 1 month to about 21 months; the frequency of administration (e.g., QD, Q2D, or QW) for 1 month to about 18 months; 1 month to about 15 months; the adjusted dose is less than the frequency of administration 1 month to about 12 months; 1 month to about 9 months; 1 of the starting dose. Increases in the adjusted dose (or any month to about 6 months; or 1 month to about 3 months. In re-adjusted dose) can be performed after the patient’s liver another embodiment, a titration period includes a time of function is assessed, monitored, or measured as described about: 3 months to about 24 months; 3 months to about 21 herein, where the liver function is considered not-impaired. months; 3 months to about 18 months; 3 months to about 15 0271 In embodiments, the adjusted dose can be months; 3 months to about 12 months; 3 or months to about increased compared to the starting dose when the level of 6 months. In still another embodiment, a titration period ALP is about equal to or is not reduced compared to a includes a time of about: 6 months to about 24 months: 6 control as described herein. In embodiments, the adjusted months to about 21 months; 6 months to about 18 months; can be increased compared to the starting dose when the 6 months to about 15 months; or 6 months to about 12 level of bilirubin is about equal to or is not reduced com months. In yet another embodiment, a titration period pared to a control as described herein. In embodiments, the US 2017/0035784 A1 Feb. 9, 2017 27 adjusted dose can be increased compared to the starting dose 0274 Further provided herein are treatment regimens when the level of ALP and bilirubin are about equal to or are that optionally include a starting dose and an adjusted dose not reduced compared to a control as described herein. In as provided in the regimens above, where the adjusted dose certain instances, the adjusted dose can be increased com is further reduced during the course of treatment. In certain pared to the starting dose where a patient described herein instances, the adjusted dose is reduced to a new re-adjusted tolerates the starting dose amount. In certain embodiments, dose having a decreased amount of an obeticholic acid the starting dose can be 5 mg. In certain embodiments, the composition described herein. In other instances the starting dose is 10 mg. In certain embodiments, the starting adjusted dose is reduced to a new re-adjusted dose having dose is 5 mg and the adjusted dose is greater than 5 mg (e.g., the same amount of an obeticholic acid composition about 6 mg to about 50 mg). In one embodiment, the starting described herein but a decreased frequency of administration dose is 5 mg and the adjusted dose is 10 mg. (e.g., from QD to Q2D or QW). In still other instances, the 0272. Also provided herein are treatment regimens that adjusted dose is modified such that the re-adjusted dose include administering obeticholic acid compositions includes a decreased amount of an obeticholic acid compo described herein for the treatment of a disease or condition sition described herein and is administered at a decreased described herein (e.g., PBC) where the starting dose admin frequency compared to the adjusted dose. istered during a titration period described above is equal to 0275. The obeticholic acid composition described herein the amount of an adjusted dose administered after a titration can be administered for any number of days, weeks, months, period. Further provided herein are treatment regimens that or years, including indefinitely, provided that the dosage include administering obeticholic acid compositions remains efficacious for the patient and the patient tolerates described herein for the treatment of a disease or condition the dosage (e.g., an adjusted or re-adjusted dose as described described herein (e.g., PBC) where the starting dose admin herein). In certain instances, an obeticholic acid composition istered during a titration period described above is equal to described herein is administered to a patient described the amount of an adjusted dose administered after a titration herein until loss of efficacy, or until development of unac period and where the frequency of administration (e.g., QD. ceptable toxicity or undesired adverse effects, such as, for Q2D, or QW) for the starting dose is the same as the adjusted example, those described herein. Daily dosing of an obet dose. Still further provided herein are treatment regimens icholic acid composition described herein can be dependent that include administering obeticholic acid compositions upon patient tolerance to the dosage, composition, or fre described herein for the treatment of a disease or condition quency of administration. For example, daily dosing can be described herein (e.g. PBC) where the starting dose admin administered to a patient described herein where the patient istered during a titration period described above is equal to tolerates a daily dosage amount (e.g., 5 mg, 10 mg, 25 mg. the amount of an adjusted dose administered after a titration or 50 mg). Alternatively or additionally, the daily dosing can period and where the frequency of administration (e.g., QD. be modified to increase or reduce the amount of an obet Q2D, or QW) for the adjusted dose is greater than the icholic acid composition described herein as provided above frequency of administration of the starting dose. Still further where the patient is tolerant or is intolerant to the dose, provided herein are treatment regimens that include admin respectively. In certain embodiments, modification of the istering obeticholic acid compositions described herein for adjusted dose (or any re-adjusted dose) can be performed the treatment of a disease or condition described herein (e.g., after the patient’s liver function is assessed, monitored, or PBC) where the starting dose administered during a titration measured as described herein. In certain instances, the period described above is equal to the amount of an adjusted adjusted dose (or re-adjusted dose) is increased or main dose administered after a titration period and where the tained (e.g., equivalent to a starting dose) where the liver frequency of administration (e.g., QD, Q2D, or QW) for the function is not-impaired. In other instances, the adjusted adjusted dose is less than the frequency of administration of dose (or re-adjusted dose) is decreased or maintained (e.g., the starting dose. The adjusted dose (or any re-adjusted equivalent to a starting dose) where the patient’s liver dose) can be equal to the starting dose where the patients function is impaired. liver function is assessed, monitored, or measured as 0276. The amount of an obeticholic acid described herein described herein, where the liver function is considered administered to a patient described herein can be modified as not-impaired. a result of intolerability or development of one or more 0273. In embodiments, the adjusted dose can be equal to adverse effects such as those described herein. For example, the starting dose when the level of ALP is reduced compared in one instance the amount of an obeticholic acid composi to a control as described herein. In embodiments, the tion described herein administered to a patient can be adjusted dose can be equal to the starting dose when the changed from a QD dosage to a Q2D dosage. In certain level of bilirubin is reduced compared to a control as embodiments, the dosage of an obeticholic acid described described herein. In embodiments, the adjusted dose can be herein is modified from a QD to Q2D dosage upon devel equal to the starting dose when the level of ALP and opment of an adverse effect described herein (e.g., severe bilirubin are reduced compared to a control as described pruritus). In one example, administration of an obeticholic herein. In certain instances, the adjusted dose can be equal acid composition described herein at 5 mg QD can be to the starting dose where a patient described herein tolerates modified to a 5 mg Q2D dosage. Such a modification can or poorly tolerates (e.g., has onset of adverse effects reduce or eliminate undesired adverse effects while main described herein) the starting dose amount. In certain taining the desired efficacy. In another example, administra embodiments, the starting dose can be 5 mg. In certain tion of an obeticholic acid composition described herein at embodiments, the starting dose is 10 mg. In certain embodi 10 mg QD can be reduced to 5 mg QD. It should be ments, the starting dose is 5 mg and the adjusted dose is 5 understood that exemplary dosing regimens described mg. In one embodiment, the starting dose is 10 mg and the herein can be combined. For example, a reduced dosage of adjusted dose is 10 mg. an obeticholic acid composition described herein from 10 US 2017/0035784 A1 Feb. 9, 2017 28 mg to 5 mg QD could be further reduced to a 5 mg Q2D 0283. In one example dosing regimen, a patient having dosage where undesired adverse effects remain. In still hepatic impairment is administered an obeticholic acid com another example, dosing of the obeticholic acid composition position described herein at an amount of about 1 mg to can be temporarily suspended (e.g., an off period) for about about 5 mg, where the composition is administered at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days, or 1, 2, 3, once weekly (QW). In one instance, the obeticholic acid or 4 weeks. composition described herein is administered at an amount 0277. In one exemplary dosing regimen, a PBC patient is of about 5 mg once weekly to a patient diagnosed with administered an obeticholic acid composition described hepatic impairment (e.g., Child-Pugh Class B or C). herein where: the starting dose of the obeticholic acid 0284. For example, the dosing regimen can include composition described herein is administered QD to a administering an obeticholic acid composition described patient described herein at an amount of 5 mg and the herein to a patient having hepatic impairment, where the obeticholic acid composition is administered QD to the obeticholic acid composition is administered at a starting patient in an adjusted dose of 5 mg. The exemplary dosing dose of 5 mg QW for a titration period of 3 or 6 months and regimen can include a titration period of about 1 to about 6 administered at an adjusted dose of 5 mg QW. The patients months. liver function can be assessed, monitored, or measured as 0278. In another exemplary dosing regimen, a PBC described herein. Where the patient’s liver function is not patient is administered an obeticholic acid composition impaired, the adjusted dose can be increased to a re-adjusted described herein where: the starting dose of the obeticholic dose of 5 mg administered BIW or 5 mg QD. acid composition described herein is administered QD to a 0285. In certain instances a patient can develop liver patient described herein at an amount of 5 mg in a titration impairment during the course of administration. It is under period of about 3 months or about 6 months and the stood, using the disclosure provided herein, that the adjusted obeticholic acid composition is administered QD to the dose can be decreased in amount or frequency to avoid patient in an adjusted dose of 5 mg. progression of liver impairment. 0279. In still another exemplary dosing regimen, a PBC 0286 Further provided herein is a method of treating patient is administered an obeticholic acid composition PBC in a patient in need thereof by administering an described herein where: the starting dose of the obeticholic effective amount of a obeticholic acid composition described acid composition described herein is administered QD to a herein QD, where the effective amount is either a 5 mg or 10 patient in a titration period of about 3 months or about 6 mg dose. In another aspect is a method of treating PBC in months and the obeticholic acid composition is administered a patient in need thereof by administering a starting dose of QD to the patient in an adjusted dose of 10 mg. 5 mg QD of an obeticholic acid composition described 0280. In another exemplary dosing regimen, a PBC herein for at least 3 months; evaluating the tolerance of the patient is administered an obeticholic acid composition patient, the patient’s liver function as described herein, described herein where: the starting dose of the obeticholic and/or the efficacy of treatment, where patient tolerance, acid composition described herein is administered QD to a liver function, and/or lowered efficacy indicate end of a patient in a titration period of about 3 months or about 6 titration period and administration of an adjusted dose of 10 months and the obeticholic acid composition is administered mg QD. In one embodiment, the patient tolerance, liver QD to the patient in an adjusted dose of 5 mg, where the function, and/or lowered efficacy indicate end of a titration adjusted dose is modified to a 5 mg Q2D re-adjusted dose period and administration of an adjusted dose of 5 mg QD. upon development of an adverse effect (e.g., pruritus or 0287. In embodiments described herein, an obeticholic severe pruritus). acid composition described herein can be metabolized to a 0281. In still another exemplary dosing regimen, a PBC obeticholic acid conjugate. Such as for example, a glycine, patient is administered a obeticholic acid composition taurine, or sarcosine conjugate of obeticholic acid. Such described herein, where the starting dose of the obeticholic metabolites can be useful in treating a disease or condition acid composition described herein is administered QD to a provided herein. In certain instances, production of conju patient in a titration period of about 3 months or about 6 gates can be assessed, monitored, measured, or detected, as months and the obeticholic acid composition is administered described herein during the course of a treatment. In some QD to the patient in an adjusted dose of 10 mg, where the embodiments, increased levels of obeticholic acid conju adjusted dose is Subsequently modified to a 5 mg QD gates can result in adjusted dosages of an obeticholic acid re-adjusted dose upon development of an adverse effect composition described herein. (e.g., pruritus or severe pruritus). 0288 Also provided herein are methods of treating a 0282. The amount of an obeticholic acid composition disease or condition described herein where the treatment described herein administered to a patient can be determined further includes administration of one or more active agents by the existence of any preexisting conditions in the patient. and combinations thereof. For example, urSodeoxycholic For example, where a patient described herein has or has had acid (UDCA) is commonly administered for treatment of hepatic impairment, the dosage of the obeticholic acid PBC, yet a majority of patients administered UDCA alone composition described herein can be modified. In certain have either an inadequate response or no response to the instances, the hepatic impairment is a Child-Pugh Class B or treatment. In Such instances, there is a need for new medi Class Chepatic impairment. In one embodiment, the hepatic caments or additional medicaments for the treatment of impairment is Child-Pugh Class C. In such instances, the PBC. The obeticholic acid compositions described herein amount of an obeticholic acid composition described herein can be administered as described herein (e.g., according to can be administered in a decreased amount during and after one or more dosing regimens provided above) in combina a titration period when compared to administration of the tion with UDCA. In some instances, the UDCA is admin same obeticholic acid composition to a patient who does not istered at an amount of about 10 to 15 mg/kg/day. In another have hepatic impairment. instance, the UDCA is administered at an amount of about US 2017/0035784 A1 Feb. 9, 2017 29 300, 600, 900, or 1200 mg/day. Administration of UDCA ride; carZelesin; castanospermine; cecropin B; cedefingol; can include a rest or off period of 1, 2, 3, or 4 weeks. In one celecoxib; cetrorelix; chlorins; chloroquinoxaline Sulfona example, an obeticholic acid composition described herein mide; cicaprost; chlorambucil; Chlorofusin; cirolemycin; is administered as described herein in combination with cisplatin: CI-1040; cis-porphyrin; cladribine; clomifene ana UDCA, where the UDCA is administered at an amount logues; clotrimazole; collismycin A; collismycin B; com provided above or in accordance with a package insert. The bretastatin A4, combretastatin analogue; conagenin, cramb term package insert refers to instructions customarily escidin 816; crisinatol; crisinatol mesylate; cryptophycin 8: included in commercial packages of medicaments approved cryptophycin A derivatives; curacin A; cyclopentanthraqui by the FDA or a similar regulatory agency of a country other nones; cycloplatam, cypemycin; cyclophosphamide; cytara than the USA, which contains information about, for bine; cytarabine ocfosfate; cytolytic factor; cytostatin; dac example, the usage, dosage, administration, contraindica arbazine; dactinomycin; daunorubicin; daunorubicin tions, and/or warnings concerning the use of Such medica hydrochloride; decarbazine; dacliximab; dasatinib. decit mentS. abine; dehydrodidemnin B; deslorelin; dexamethasone: 0289. In another example, the active agent is a peroxi dexifosfamide; dexraZOxane; dexVerapamil; dexormaplatin: some proliferator-activated receptor alpha (PPARC.) agonist, deZaguanine; deZaguanine mesylate; diaziquone; didemnin a peroxisome proliferator-activated receptor delta (PPARö) B; didox; diethylnorspermine; dihydro 5 azacytidine; dihy agonist, a dual PPARC/ö agonist, a dual PPARO/Yagonist, or drotaxol; 9-dioxamycin; diphenyl spiromustine; docosanol: pan-PPAR agonist, an HMG CoA reductase inhibitor, a dolasetron; docetaxel, doxorubicin; doxorubicin hydrochlo GLP1 agonist, insulin, insulin mimetic, metformin, a GTP4 ride: doxifluridine; droloxifene; droloxifene citrate; dromo agonist, an HST2 inhibitor, a DPP-IV inhibitor, an SGLT2 stanolone propionate; dronabinol; duaZomycin; duocarmy inhibitor or a hydroxysteroid dehydrogenase (HSD) inhibi cin SA; ebselen; ecomustine; edelfosine; edrecolomab, tor, such as an 113-HSD1 inhibitor, an ASK1 inhibitor, an edatrexate; eflornithine hydrochloride; eflornithine; ACC1 inhibitor, a NOX1 and/or NOX4 inhibitor, an inhibi elemene; emitefur; elsamitrucin; enloplatin; enpromate; epi tor or antagonist of one or more chemokine receptors, such propidine; epirubicin; epirubicin hydrochloride; epristeride; as, for example, CCR2 and CCR5. erbulozole; eribulin; esorubicin hydrochloride; estramus 0290. In instances where an obeticholic acid composition tine; estramustine phosphate Sodium; etanidazole; etopo described herein is useful for the treatment of a cancer side, etoposide phosphate: etoprine; exemestane; fadrozole; described herein, Such compositions can be co-administered fadrozole hydrochloride; fazarabine; fenretinide; filgrastim; With one or more cancer agents. finasteride; flavopiridol: flezelastine; fluasterone; floxuri 0291. The anti-cancer agent useful in methods of treating dine; fludarabine phosphate; fludarabine; fluorodaunorubi Solid-tumor cancers provided herein can include any known cin hydrochloride; forfenimex; formestane; fluorouracil; class of anti-cancer agents such as, for example, radiation floXouridine; flurocitabine; fosquidone; fostriecin Sodium; therapy, operations, alkylating agents, antimetabolites, fostriecin, fotemustine, gadolinium texaphyrin; gallium anthracyclines, campothecins, Vinca alkaloids, taxanes or nitrate; galocitabine; ganirelix; gelatinase inhibitors; gem platinums, as well as other antineoplastic agents known in citabine; geldanamycin; gossyphol; GDC-0973; the art. Such anti-cancer agent and antineoplastic agent GSK1120212/trametinib; herceptin; hydroxyurea; hepsul classifications are known in the art and used in accordance fam; heregulin; hexamethylene bisacetamide; hypericin; with their plain and ordinary meaning. ibandronic acid; ibrutinib. idarubicin; idarubicin hydrochlo 0292 Exemplary anti-cancer agents include but are not ride; ifosfamide; canfosfamide, ilmofosine, iproplatin; idox limited to: ABRAXANE; abiraterone; ace-11; aclarubicin; ifene; idramantone, ilmofosine; illomastat; imidazoacri acivicin; acodazole hydrochloride; acronine; actinomycin; dones; imatinib (e.g., GLEEVEC); imiquimod; iniparib (BSI acylfulvene; adecypenol; adoZelesin; adriamycin; aldesleu 201); iobenguane; iododoxorubicin; ipomeanol; irinotecan; kin; all trans-retinoic acid (ATRA); altretamine; ambamus irinotecan hydrochloride; irsogladine; isobengaZole; isoho tine; ambomycin; ametantrone acetate; amidox; amifostine; mohalicondrin B; itasetron; iimofosine; interleukin IL-2 aminoglutethimide; aminolevulinic acid; amrubicin; amsa (including recombinant interleukin II; or rlL. Sub.2); inter crine; anagrelide; anastroZole; andrographolide; antarelix; feron alfa-2a: interferon alfa-2b; interferon alfa-n1; inter anthramycin; aphidicolin glycinate; apurinic acid; ara-CDP feron alfa-n3; interferon beta-1a; interferon gamma-1b; jas DL-PTBA; arginine deaminase; ARRY-162: ARRY-300; plakinolide; kahalalide F: lamellarin N triacetate; lanreotide; ARRY-142266; AS703026; asparaginase; asperlin; asula leinamycin; lenograstim; lentinan Sulfate; leptolstatin; letro crine; atamestane; atrimustine; AVASTIN: axinastatin 1: Zole; leuprorelin; levamisole; lenalidomide; lenvatinib; axinastatin 2; axinastatin 3; aZasetron; azatoxin; azatyrosine; liarozole; lissoclinamide 7: lobaplatin: lombricine; lom azacitidine, AZD8330; azetepa; azotomycin; balanol; bati etrexol; lonidamine; losoxantrone; lovastatin; loxoribine; mastat; BAY 1 1-7082; BAY 43-9006; BAY 869766; benda lurtotecan; lutetium texaphyrin; lysofylline; lanreotide mustine; benzochlorins; benzodepa; benzoylstaurosporine; acetate; lapatinib, letrozole; leucovorin; leuprolide acetate; beta-alethine; betaclamycin B; betulinic acid; b-FGF inhibi liarozole hydrochloride; lometrexol sodium; lomustine: tor, bicalutamide; bisantrene; bisaziridinylspermine; bisna losoxantrone hydrochloride; pomalidomide: LY294.002: fide; bisnafide dimesylate; bistratene A. bisantrene hydro maitansine; mannostatin A; marimastat; masoprocol; mas chloride; bleomycin; bleomycin sulfate; busulfan; bizelesin: pin; matrilysin inhibitors; menogaril; merbarone; meterelin; breflate; bortezomib: brequinar sodium; bropirimine; budo methioninase; metoclopramide: MIF inhibitor; mifepris titane; buthionine Sulfoximine, bryostatin: cactinomycin; tone; miltefosine; mirimoStim, mitoguaZone; mitolactol; calusterone; calcipotriol; calphostin C; camptothecin deriva mitonafide; mitoxantrone; mofarotene; molgramoStim; tives; capecitabine; carboxamide-amino-triazole; car mopidamol; mycaperoxide B; myriaporone; maytansine; boxyamidotriazole; CaRest M3; CARN 700; caracemide: mechlorethamine hydrochloride; megestrol acetate; carbetimer, carboplatin; carmustine; carubicin hydrochlo melengestrol acetate; melphalan; mercaptopurine; metho US 2017/0035784 A1 Feb. 9, 2017 30 trexate; methotrexate sodium; metoprine; meturedepa; mit 0293. Other exemplary anti-cancer agents include Erbu indomide; mitocarcin, mitocromin, mitogillin, mitomalcin; lozole (e.g., R-55 104); Dolastatin 10 (e.g., DLS-10 and mitomycin; mitosper, mitotane; mitoxantrone hydrochlo NSC-376128); Mivobulin isethionate (e.g., CI-980); NSC ride, mycophenolic acid; nafarelin; nagreStip; napavin; 639829; Discodermolide (e.g., NVP-XX-A-296); ABT-751 naphterpin, nartograstim; nedaplatin; memorubicin; (Abbott; e.g., E-7010); Altorhyrtin A; Altorhyrtin C: Cema neridronic acid; nilutamide; nisamycin; nitric oxide modu dotin hydrochloride (e.g., LU-103793 and NSC-D-669356); lators; nitroxide antioxidant; nitrullyn; nocodazole; CEP 9722; Epothilone A: Epothilone B: Epothilone C: nogalamycin; oblimersen (GENASENSE); octreotide; oki Epothilone D: Epothilone E; Epothilone F: Epothilone B cenone: olaparib (LYNPARZA); oligonucleotides; onapris N-oxide: Epothilone AN-oxide; 16-aza-epothilone B: tone; ondansetron; oracin; oral cytokine inducer, ormapla 21-aminoepothilone B: 21-hydroxyepothilone D; 26-fluo tin, OXisuran, oxaloplatin: osaterone; oxaliplatin: roepothilone; Auristatin PE (e.g., NSC-654663); Soblidotin oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic (e.g., TZT-1027); LS-4559-P (Pharmacia: e.g., LS-4577): acid; panaxytriol; panomifene; parabactin: PARP (polyADP LS-4578 (Pharmacia: e.g., LS-477-P); LS-4477 (Pharma ribose polymerase) inhibitors; paZelliptine; pegaspargase; cia); LS-4559 (Pharmacia); RPR-112378 (Aventis); peldesine; pentosan polysulfate sodium; pentostatin: pentro DZ-3358 (Daiichi): FR-182877 (Fujisawa; e.g., Zole; perflubron; perfosfamide; perillyl alcohol; phenazino WS-9265B); GS-164 (Takeda); GS-198 (Takeda); KAR-2 mycin; phenylacetate; phosphatase inhibitors; picibanil; (Hungarian Academy of Sciences); BSF-223651 (BASF: pilocarpine hydrochloride; pirarubicin; piritrexim; placetin e.g., ILX-651 and LU-223651); SAH-49960 (Lilly/Novar A: placetin B; porfiromycin; prednisone; prostaglandin J2; tis); SDZ-268970 (Lilly/Novartis); AM-97 (Armad/Kyowa pyrazoloacridine: paclitaxel; PD035901; PD184352: Hakko); AM-132 (Armad); AM-138 (Armad/Kyowa PD318026: PD98059; peliomycin; pentamustine; peplomy Hakko); IDN-5005 (Indena); Cryptophycin 52 (e.g., cin Sulfate; PKC412; pipobroman; piposulfan; piroXantrone LY-355703); AC-7739 (Ajinomoto; e.g., AVE-8063A and hydrochloride; plicamycin; plomestane; podophyllotoxin; CS-39.HCl); AC-7700 (Ajinomoto; e.g., AVE-8062; AVE polyphenol E., porfimer Sodium; porfiromycin; predni 8062A; CS-39-L-SerHCl; and RPR-258062A); Vitilevu mustine; procarbazine; procarbazine hydrochloride; puro amide; Tubulysin A; Canadensol; CA-170 (Curis, Inc.); mycin; puromycin hydrochloride; pyrazofurin; raltitrexed: Centaureidin (e.g., NSC-106969); T-138067 (Tularik; e.g., ramosetron; retelliptine demethylated; rhizoxin: rituximab: T-67: TL-138067 and TI-138067); COBRA-1 (Parker Ru retinamide, rogletimide; rohitukine; romurtide; roqui Hughes Institute; e.g., DDE-261 and WHI-261); H10 (Kan nimex: rubiginone B1; ruboxyl riboprine; romidepsin; ruca sas State University); H16 (Kansas State University); Onco parib; Safingol: Safingol hydrochloride; Saintopin; sarcophy cidin A1 (e.g., BTO-956 and DIME); DDE-313 (Parker tol A; SargramoStim. Semustine; sizofiran; Sobuzoxane: Hughes Institute); Fijianolide B: Laulimalide: SPA-2 Sodium borocaptate; sodium phenylacetate; solverol; Soner (Parker Hughes Institute); SPA-1 (Parker Hughes Institute; min; Sorafenib, Sunitinib: sparfosic acid; spicamycin D; e.g., SPIKET-P): 3-IAABU (Cytoskeleton/Mt. Sinai School spiromustine; splenopentin; spongistatin 1: Spongistatin 2: of Medicine; e.g., MF-569): Narcosine (e.g., NSC-5366); Spongistatin 3: Spongistatin 4: Spongistatin 5: Spongistatin Nascapine: D-24851 (Asta Medica): A-105972 (Abbott): 6; Spongistatin 7: Spongistatin 8; and Spongistatin 9; Hemiasterlin: 3-BAABU (Cytoskeleton/Mt. Sinai School of squalamine; stipiamide; Stromelysin inhibitors; Sulfinosine; Medicine; e.g., MF-191); TMPN (Arizona State University): Suradista; Suramin; Swainsonine; SB239063; selumetinib/ Vanadocene acetylacetonate: T-138026 (Tularik); Monsa AZD6244; simtraZene; SP600 125; sparfosate sodium; spar trol; lnanocine (e.g., NSC-698666): 3-IAABE (Cytoskel Somycin; Spirogermanium hydrochloride; spiroplatin; Strep eton/Mt. Sinai School of Medicine); A-204197 (Abbott): tonigrin: Streptozocin, Sulofenur; tallimustine; tamoxifen T-607 (Tularik; e.g., T-900607); RPR-115781 (Aventis); methiodide; talazoparib (BMN 673); tauromustine; tazaro Eleutherobins (e.g., Desmethyleleutherobin: Desaet tene; tecogalan Sodium, tegafur, tellurapyrylium; yleleutherobin; lsoeleutherobin A; and Z-Eleutherobin); temoporfin; temozolomide; teniposide; tetrachlorodecaox Caribaeoside; Caribaeolin; Halichondrin B: D-64131 (Asta ide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin: Medica); D-68144 (Asta Medica); Diazonamide A: thymalfasin; thymopoietin receptor agonist; thymotrinan; A-293620 (Abbott): NPI-2350 (Nereus); Taccalonolide A: tirapazamine; titanocene bichloride; topsentin; toremifene; TUB-245 (Aventis); A-259754 (Abbott); DioZostatin: (-)- tretinoin; triacetyluridine; triciribine; trimetrexate; triptore Phenylahistin (e.g., NSCL-96F037); D-62638 (Asta lin; tropisetron; turosteride; tyrphostins; talisomycin; TAK Medica); D-62636 (Asta Medica); Myoseverin B: D-43411 733; taxotere; tegafur; teloxantrone hydrochloride; terox (Zentaris; e.g., D-81862): A-289099 (Abbott): A-318315 irone; testolactone; thiamiprine; thioguanine; thiotepa; (Abbott): HTI-286 (e.g., SPA-110; trifluoroacetate salt) tiazofurin; tirapazamine; toremifene citrate; trastuzumab; (Wyeth); D-82317 (Zentaris); D-82318 (Zentaris); trestolone acetate; triciribine phosphate; trimetrexate; trime SC-12983 (NCI); Resverastatin phosphate sodium; BPR trexate glucuronate; triptorelin; tubulozole hydrochloride; OY-007 (National Health Research Institutes); and SSR tumor necrosis factor-related apoptosis-inducing ligand 250411 (Sanofi)); goserelin; leuprolide; triptolide; homohar (TRAIL); UBC inhibitors: ubenimex: U0126; uracil mus ringtonine; topotecan; itraconazole; deoxyadenosine; tard; uredepa; vapreotide; variolin B; velaresol; veliparib Sertraline; pitavastatin: clofazimine; 5-nonyloxytryptamine; (ABT-888); Veramine; verteporfin; vinorelbine; vinxaltine; vemurafenib, dabrafenib; gefitinib (IRESSA); erlotinib vitaxin; vinblastine; vinblastine sulfate; Vincristine sulfate; (TARCEVA); cetuximab (ERBITUX); lapatinib (TYK vindesine; Vindesine Sulfate; Vinepidine Sulfate; Vinglycinate ERB); panitumumab (VECTIBIX): Vandetanib sulfate; Vinleurosine sulfate; Vinorelbine tartrate; Vinrosidine (CAPRELSA); afatinib/BIBW2992: CI-1033/canertinib; sulfate; Vinzolidine sulfate; Vorozole; wortmannin; XL518; neratinib/HKI-272; CP-7247 14: TAK-285; AST-1306; Zanoterone; Zeniplatin: Zilascorb; Zinostatin stimalamer, ARRY334543; ARRY-380; AG-1478; dacomitinib/ Zinostatin; and Zorubicin hydrochloride. PF299804: OSI-420/desmethyl erlotinib: AZD8931; US 2017/0035784 A1 Feb. 9, 2017 AEE726; pelitinib/EKB-569; CUDC-101; WZ8040; obeticholic acid composition described herein at least about WZ4002; WZ3146; AG-490; XL647: PD153035: 5-azathio 4 to 6 hours before or after the dosage of the obeticholic acid prine; 5-aza-2'-deoxycytidine, 17-N-Allylamino-17 composition. Demethoxygeldanamycin (17-AAG); 20-epi-1.25 dihy 0303. In one embodiment, the compositions described droxyvitamin D3; 5 ethynyluracil; and BMS-599626. herein reduce adverse effects associated with other formu 0294. In one aspect is a method for treating patients with lations (e.g., larger particle sized obeticholic acid). For colorectal cancer (optionally refractory) by administering an example, an obeticholic acid composition described herein obeticholic acid composition described herein in combina when administered to a patient described herein for a tion with capecitabine and/or PLX4032 (Plexxikon). condition or disease described herein can reduce one or 0295. In another aspect is a method for treating colorectal more adverse effects selected from Hepatic encephalopathy, cancer (optionally refractory) by administering an obet ascites, variceal bleeding, skin eruptions, prurigo, pruritus icholic acid composition described herein in combination (including generalized, eye, anal, Vulvovaginal and rash), with capecitabine, Xeloda, and/or CPT-11. fatigue, asthenia, abdominal pain (including upper and lower pain and tenderness), abdominal discomfort, gastrointestinal 0296. In another aspect is a method for treating colorectal pain, dizziness, urticaria (including cholinergic), rashes (in cancer (optionally refractory) by administering an obet cluding macular, popular, maculo-papular, and heat rashes), icholic acid composition described herein in combination arthralgia, oropharyngeal pain, cough, constipation, edemal with capecitabine, Xeloda, and/or CPT-11. peripheral, palpitations, pyrexia, eczema, and procedural 0297. In another aspect is a method for treating patients pain. In certain instances, the one or more adverse effects with colorectal cancer (optionally refractory) or patients that are reduced include pruritus. It was discovered, inter with unresectable or metastatic colorectal carcinoma by alia, that titration of an obeticholic acid composition administering an obeticholic acid composition described described herein can reduce the incidence of or mean time herein in combination with capecitabine and irinotecan. until onset of severe pruritus. 0298. In another aspect is a method for treating patients 0304. In another embodiment, the obeticholic acid com with unresectable or metastatic hepatocellular carcinoma by positions described herein include reduced levels of impu administering an obeticholic acid composition described rities commonly found in the synthesis of obeticholic acid. herein in combination with interferon alpha or capecitabin. 6O-ethylursodeoxycholic acid (6-EUDCA), 3C-hydroxy 0299. In another aspect is a method for treating patients 6O-ethyl-7-keto-5 B-cholan-24-oic acid, 6.3-ethylchenode with pancreatic cancer by administering an obeticholic acid oxycholic acid; 3C.7C.-dihydroxy-6(3-ethyl-5f-cholan-24 composition described herein in combination with gemcit oic acid, 3C,7C.-dihydroxy-6-ethyliden-5B-cholan-24-oic abine. acid, Chenodeoxycholic acid (CDCA); 3C.7C.-dihydroxy 0300 Patients described herein include a patients having 5 B-cholan-24-oic acid, Dimer of OCA, 3C-(3C.7C.-dihy a disease or condition described herein. A patient can be droxy-6C.-ethyl-5B-cholan-24-oyloxy)-7C.-hydroxy-6C.- described or referred to by the condition treated. For ethyl-5 f-cholan-24-oic acid, or 3C-O-Acetyl-6C.- example, a patient having PBC can be referred to herein as ethylchenodeoxycholic acid; 3C-O-acetyl-7C.-hydroxy-6C.- a PBC patient. A patient described herein can have a ethyl-5 f-cholan-24-oic acid. preexisting condition (e.g., a condition other than the disease 0305 All publications and patent documents cited herein or condition treated by the obeticholic acid composition are incorporated herein by reference as if each such publi described herein that existed at the time of first administra cation or document was specifically and individually indi tion). In one instance a patient described herein has hepatic cated to be incorporated herein by reference. Citation of impairment. In another instance a patient described herein publications and patent documents is not intended as an has renal impairment. In yet another instance the patient is admission that any is pertinent prior art, nor does it consti an elderly/geriatric patient or a pregnant patient. In another tute any admission as to the contents or date of the same. The instance the patient is an pediatric patient. disclosure having now been described by way of written 0301 In some embodiments, administration of an obet description, those of skill in the art will recognize that the icholic acid composition described herein together with disclosure can be practiced in a variety of embodiments and certain contra-active agents can result in (1) decreased that the foregoing description and examples below are for efficacy of the obeticholic acid composition and/or (2) purposes of illustration and not limitation of the claims that development of toxicity or adverse effects described herein. follow. For example, administration of an obeticholic acid compo Selected Embodiments sition described herein with blood clotting and anti-coagul lation agents can result in decreased International Normal Embodiment 1 ized Ratio (INR). In certain instances, coagulation and 0306 A method of treating primary biliary cirrhosis anti-coagulation agents can be administered in combination (PBC) in a patient in need thereof, the method comprising with an obeticholic acid composition described herein by administering a composition comprising obeticholic acid, or monitoring fluctuations of the INR of the patient and adjust a pharmaceutically acceptable salt, ester, or amino acid ing dosages as understood in the art to maintain proper INR. conjugate thereof, wherein obeticholic acid or a pharmaceu 0302) In another example, administration of an obet tically acceptable salt, ester, or amino acid conjugate thereof icholic acid composition described herein in combination is in the form of particles, and wherein at least 50% of the with a bile acid binding resin (e.g., cholestyramine, coles particles have a diameter of 200 um or less. tipol, or colesevelam) can result in decreased efficacy of the obeticholic acid composition at a lower dosage of the Embodiment 2 composition (e.g., 1 to 5 mg). In certain embodiments, a bile 0307. A method of treating primary sclerosing cholangi acid binding resin is administered in combination with an tis (PSC), chronic liver disease, nonalcoholic fatty liver US 2017/0035784 A1 Feb. 9, 2017 32 disease (NAFLD), nonalcoholic steatohepatitis (NASH). Embodiment 11 hepatitis C infection, alcoholic liver disease, liver damage due to progressive fibrosis, or liver fibrosis in a patient in 0316. The method of embodiment 7 or 8, wherein the need thereof, the method comprising administering a com autoimmune disease is selected from the group consisting position comprising obeticholic acid, or a pharmaceutically of PBC, multiple sclerosis, rheumatoid arthritis, and type-I acceptable salt, ester, or amino acid conjugate thereof, diabetes. wherein obeticholic acid or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof is in the form of Embodiment 12 particles, and wherein at least 50% of the particles have a 0317. The method of any one of embodiments 1-2, 6 or diameter of 200 um or less. 9, wherein the titration period comprises 1 to 6 months. Embodiment 3 Embodiment 13 0308. The method of embodiment 2, wherein the method 0318. The method of embodiment 11, wherein the titra comprises treating NASH. tion period is 3 months. Embodiment 14 Embodiment 4 0319. The method of embodiment 11, wherein the titra 0309. A method of treating a solid-tumor cancer in a tion period is 6 months. patient in need thereof, the method comprising administer ing an effective amount of a composition comprising obet Embodiment 15 icholic acid, or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof, wherein obeticholic acid or a 0320. The method of any one of embodiments 12 to 15, pharmaceutically acceptable salt, ester, or amino acid con wherein the starting dose is administered to the patient once jugate thereof is in the form of particles, and wherein at least daily. 50% of the particles have a diameter of 200 um or less. Embodiment 16 Embodiment 5 0321. The method of any one of embodiments 11 to 14, wherein the starting dose is administered to the patient once 0310. The method of embodiment 1, 2 or 4, wherein the daily. effective amount comprises a starting dose. Embodiment 17 Embodiment 6 0322 The method of any one of embodiments 11 to 14, 0311. The method of embodiment 5, wherein the starting wherein the starting dose is administered to the patient once dose is administered in a titration period. weekly. Embodiment 7 Embodiment 18 0323. The method of any one of embodiments 11 to 14, 0312 The method of any one of embodiments 4 to 6, wherein the starting dose is administered to the patient once wherein the cancer comprises hepatocellular carcinoma every other day. (HCC), colorectal cancer, gastric cancer, liver cancer, kidney cancer, or pancreatic cancer. Embodiment 19 Embodiment 8 0324. The method of any one of embodiments 11 to 17, wherein the starting dose comprises about 1 mg to 50 mg. 0313 A method of treating an autoimmune disease in a patient in need thereof, the method comprising administer Embodiment 20 ing an effective amount of a composition comprising obet 0325 The method of any one of embodiments 11 to 17, icholic acid, or a pharmaceutically acceptable salt, ester, or wherein the starting dose comprises about 1 mg to 25 mg. amino acid conjugate thereof, wherein obeticholic acid or a pharmaceutically acceptable salt, ester, or amino acid con Embodiment 21 jugate thereof is in the form of particles, and wherein at least 50% of the particles have a diameter of 200 um or less. 0326. The method of any one of embodiments 11 to 17, wherein the starting dose comprises about 1 mg to 10 mg. Embodiment 9 Embodiment 22 0314. The method of embodiment 7, wherein the effec 0327. The method of any one of embodiments 11 to 17, tive amount comprises a starting dose. wherein the starting dose comprises about 1 mg to 5 mg. Embodiment 10 Embodiment 23 0315. The method of embodiment 8, wherein the starting 0328. The method of any one of embodiments 11 to 17, dose is administered in a titration period. wherein the starting dose comprises about 5 mg. US 2017/0035784 A1 Feb. 9, 2017 Embodiment 24 Embodiment 36 0329. The method of any one of embodiments 11 to 17, 0341 The method of embodiment 33, wherein the wherein the starting dose comprises about 10 mg. adjusted dose is greater than the titrated dose. Embodiment 25 Embodiment 37 0342. The method of any one of embodiments 33 to 36, 0330. The method of any one of embodiments 11 to 17, wherein the adjusted dose is administered more frequently wherein the starting dose comprises about 25 mg. than the titrated dose. Embodiment 26 Embodiment 38 0331. The method of any one of embodiments 11 to 17, 0343. The method of any one of embodiments 33 to 36, wherein the starting dose comprises about 50 mg. wherein the adjusted dose is administered less frequently than the titrated dose. Embodiment 27 0332 The method of any one of embodiments 1 to 26, Embodiment 39 further comprising assessing or monitoring liver function 0344) The method of any one of embodiments 33 to 38, before, during, or after the titration period. wherein the adjusted dose of the obeticholic acid composi tion is administered to the patient once daily. Embodiment 28 Embodiment 40 0333. The method of embodiment 27, wherein the assess ing or monitoring comprises measuring a level of one or (0345. The method of any one of embodiments 33 to 38, more liver biomarkers compared to a control. wherein the adjusted dose of the obeticholic acid composi tion is administered to the patient once daily. Embodiment 29 Embodiment 41 0334. The method of embodiment 28, wherein the liver 0346. The method of any one of embodiments 33 to 38, biomarker is selected from the group consisting of AST. wherein the adjusted dose of the obeticholic acid composi ALT, alkaline phosphatase (ALP), bilirubin, glycine conju tion is administered to the patient once daily. gated obeticholic acid, taurine conjugated obeticholic acid, a bile acid, a bile acid glycine conjugate, or a bile acid Embodiment 42 taurine conjugate. (0347 The method of any one of embodiments 33 to 38, Embodiment 30 wherein the adjusted dose of the obeticholic acid composi tion is administered to the patient once weekly. 0335 The method of embodiment 29, comprising detect ing a level of ALP in the patient. Embodiment 43 0348. The method of any one of embodiments 33 to 38, Embodiment 31 wherein the adjusted dose of the obeticholic acid composi 0336. The method of embodiment 29 or 30, comprising tion is administered to the patient once every other day. detecting a level of bilirubin in the patient. Embodiment 44 Embodiment 32 (0349 The method of any one of embodiments 33 to 38, 0337 The method of any one of embodiments 27 to 31, wherein the adjusted dose of the obeticholic acid composi further comprising calculatinga AST to platelet ratio (APRI) tion is administered to the patient twice a week. for the patient. Embodiment 45 Embodiment 33 0350. The method of any one of embodiments 33 to 44, wherein the adjusted dose comprises about 1 mg to 50 mg. 0338. The method of any one of embodiments 12 to 32, wherein the obeticholic acid composition is administered to Embodiment 46 the patient as an adjusted dose after the titration period. 0351. The method of any one of embodiments 33 to 44, Embodiment 34 wherein the adjusted dose comprises about 1 mg to 25 mg. 0339. The method of embodiment 33, wherein the Embodiment 47 adjusted dose is equal to the titrated dose. 0352. The method of any one of embodiments 33 to 44, wherein the adjusted dose comprises about 1 mg to 10 mg. Embodiment 35 Embodiment 48 0340. The method of embodiment 33, wherein the adjusted dose is equal to the starting dose when the level of 0353. The method of any one of embodiments 33 to 44, ALP is reduced compared to a control. wherein the adjusted dose comprises about 1 mg to 5 mg. US 2017/0035784 A1 Feb. 9, 2017 34 Embodiment 49 assessing liver function of the patient before, during, and after the titration period by: calculating an AST to platelet 0354. The method of any one of embodiments 33 to 44, ratio (APRI) score for the patient; or measuring the level of wherein the adjusted dose comprises about 5 mg. one or more liver biomarker selected from ALP. bilirubin, AST, ALT, glycine conjugated obeticholic acid, taurine Embodiment 50 conjugated obeticholic acid, a bile acid, a bile acid glycine 0355 The method of any one of embodiments 33 to 44, conjugate, or a bile acid taurine conjugate; wherein the adjusted dose comprises about 10 mg. wherein a reduced APRI score compared to a control or a reduced level of the one or more liver biomarkers compared Embodiment 51 to a control indicates non-impaired liver function; 0356. The method of any one of embodiments 33 to 44, assessing tolerance of the patient to the starting dose by wherein the adjusted dose comprises about 25 mg. grading the severity of one or more adverse effects, if present; and Embodiment 52 administering an adjusted dose of the obeticholic acid com 0357 The method of any one of embodiments 33 to 44, position, wherein the adjusted dose comprises an amount wherein the adjusted dose comprises about 50 mg. equal to or greater than an amount of the starting dose. Embodiment 53 Embodiment 59 0358. The method of any one of embodiments 1 to 52, 0365. The method of embodiment 58, wherein the wherein the method further comprises administering one or adjusted dose is administered at an amount equal to an more active agents, or combinations thereof. amount of the starting dose. Embodiment 54 Embodiment 60 0359. The method of embodiment 53, wherein the active 0366. The method of embodiment 58, wherein the agent is ursodeoxycholic acid (UDCA). adjusted dose is administered at an amount greater than an Embodiment 55 amount of the starting dose. 0360. The method of embodiment 53, wherein the active Embodiment 61 agent is a peroxisome proliferator-activated receptor alpha (PPARC) agonist, a peroxisome proliferator-activated recep 0367 The method of embodiment 58, wherein the tor delta (PPARö) agonist, a dual PPARC/ö agonist, a dual adjusted dose of the obeticholic acid composition is admin PPARO/Y agonist, or pan-PPAR agonist, an HMG CoA istered at the same frequency as the starting dose. reductase inhibitor, a GLP1 agonist, insulin, insulin mimetic, metformin, a GTP4 agonist, an HST2 inhibitor, a Embodiment 62 DPP-IV inhibitor, an SGLT2 inhibitor or a hydroxysteroid dehydrogenase (HSD) inhibitor, such as an 113-HSD1 0368. The method of embodiment 58, wherein the inhibitor, an ASK1 inhibitor, an ACC1 inhibitor, a NOX1 adjusted dose of the obeticholic acid composition is admin and/or NOX4 inhibitor, an inhibitor or antagonist of one or istered at a decreased frequency than the starting dose. more chemokine receptors, such as, for example, CCR2 and CCR5. Embodiment 63 0369. The method of embodiment 58, wherein the effec Embodiment 56 tive amount of the obeticholic acid composition is admin 0361. The method of any one of embodiments 1 to 55, istered at an increased frequency than the starting dose. wherein the obeticholic acid composition is administered as a first line therapy for the treatment of PBC. Embodiment 64 Embodiment 57 0370. The method of any one of embodiments 58 to 63, wherein the starting dose is 5 mg. 0362. The method of any one of embodiments 1 to 56, wherein the patient is has renal impairment or hepatic Embodiment 65 impairment. 0371. The method of any one of embodiments 58 to 64, Embodiment 58 wherein the starting dose is administered QD. 0363 A method for treating primary biliary cirrhosis (PBC) in a patient in need thereof, the method comprising: Embodiment 66 0364 administering a starting dose of a composition 0372. The method of any one of embodiments 58 to 64, comprising obeticholic acid, or a pharmaceutically accept wherein the adjusted dose is 5 mg. able salt, ester, or amino acid conjugate thereof, in a titration period, wherein obeticholic acid or a pharmaceutically Embodiment 67 acceptable salt, ester, or amino acid conjugate thereof is in the form of particles, and wherein at least 50% of the 0373 The method of any one of embodiments 58 to 64, particles have a diameter of 200 um or less; wherein the adjusted dose is 10 mg. US 2017/0035784 A1 Feb. 9, 2017 Embodiment 68 Embodiment 78 0374. The method of any one of embodiments 58 to 67, 0385. A composition comprising obeticholic acid, or a wherein the adjusted dose is administered QD or Q2D. pharmaceutically acceptable salt, ester, or amino acid con jugate thereof, wherein obeticholic acid or a pharmaceuti Embodiment 69 cally acceptable salt, ester, or amino acid conjugate thereof is in the form of particles, and wherein at least 50% of the 0375. The method of any one of embodiments 58 to 68, particles have a diameter of 200 um or less, for use in further comprising assessing the patient for tolerance to the treating primary biliary cirrhosis (PBC) in a patient in need adjusted dose. thereof. Embodiment 70 Embodiment 79 0376. The method of embodiment 69, wherein the 0386 A composition comprising obeticholic acid, or a adjusted dose is modified to a re-adjusted dose when the pharmaceutically acceptable salt, ester, or amino acid con patient. jugate thereof, wherein obeticholic acid or a pharmaceuti cally acceptable salt, ester, or amino acid conjugate thereof Embodiment 71 is in the form of particles, and wherein at least 50% of the particles have a diameter of 200 um or less, for use in 0377 The method of embodiment 70, wherein the re treating primary Sclerosing cholangitis (PSC), chronic liver adjusted dose comprises an equal amount compared to the disease, nonalcoholic fatty liver disease (NAFLD), nonal adjusted dose and administration at a reduced frequency. coholic steatohepatitis (NASH), hepatitis C infection, alco holic liver disease, liver damage due to progressive fibrosis, Embodiment 72 or liver fibrosis in a patient in need thereof in a patient in need thereof. 0378. The method of embodiment 71, wherein the re adjusted dose comprises a reduced amount compared to the Embodiment 80 adjusted dose and administration at an equal frequency. 0387. The composition of embodiment 79, for use in Embodiment 73 treating NASH. 0379 The method of embodiment 58, wherein the patient Embodiment 81 has hepatic impairment. 0388 A composition comprising obeticholic acid, or a pharmaceutically acceptable salt, ester, or amino acid con Embodiment 74 jugate thereof, wherein obeticholic acid or a pharmaceuti cally acceptable salt, ester, or amino acid conjugate thereof 0380. The method of embodiment 73, wherein the start is in the form of particles, and wherein at least 50% of the ing dose is administered QW. particles have a diameter of 200 um or less, for use in treating a solid-tumor cancer in a patient in need thereof. Embodiment 75 Embodiment 82 0381. The method of embodiment 74, wherein the start ing dose is 5 mg. (0389. The composition of embodiments 77, 79 or 81, wherein said composition further comprises said obeticholic Embodiment 75 acid composition as a starting dose. 0382. The method of any one of embodiments 58 to 75, Embodiment 83 wherein the adjusted dose is equivalent to the starting dose 0390 The composition of embodiment 82, wherein said when the level of ALP is reduced compared to a control. starting dose is prepared to be administered in a titration Embodiment 76 period. 0383. The method of any one of embodiments 58 to 75, Embodiment 84 wherein the adjusted dose comprises an amount equal to the 0391 The composition of any one of embodiments 81 to starting dose and wherein the adjusted dose is administered 83, for use in treating hepatocellular carcinoma (HCC), at a greater frequency than the starting dose. colorectal cancer, gastric cancer, liver cancer, kidney cancer, or pancreatic cancer. Embodiment 77 0384. A composition comprising obeticholic acid, or a Embodiment 85 pharmaceutically acceptable salt, ester, or amino acid con 0392 A composition comprising obeticholic acid, or a jugate thereof, wherein obeticholic acid or a pharmaceuti pharmaceutically acceptable salt, ester, or amino acid con cally acceptable salt, ester, or amino acid conjugate thereof jugate thereof, wherein obeticholic acid or a pharmaceuti is in the form of particles, and wherein at least 50% of the cally acceptable salt, ester, or amino acid conjugate thereof particles have a diameter of 200 um or less, for use in is in the form of particles, and wherein at least 50% of the treating primary biliary cirrhosis (PBC) in a patient in need particles have a diameter of 200 um or less, for use in thereof. treating an autoimmune disease in a patient in need thereof. US 2017/0035784 A1 Feb. 9, 2017 36 Embodiment 86 Embodiment 98 0393. The composition of embodiment 85, wherein said 04.05 The composition of any one of embodiments 89 to composition further comprises said obeticholic acid com 95, wherein said starting dose comprises about 1 mg to 10 position as a starting dose. ng. Embodiment 87 Embodiment 99 0394 The composition of embodiment 86, wherein said 0406. The composition of any one of embodiments 89 to starting dose is prepared to be administered in a titration period. 95, wherein said starting dose comprises about 1 mg to 5 mg. Embodiment 100 Embodiment 88 0395. The composition of embodiment 85 or 86, for use 0407. The composition of any one of embodiments 89 to in treating multiple Sclerosis, rheumatoid arthritis, or type-I 95, wherein said starting dose comprises about 5 mg. diabetes. Embodiment 101 Embodiment 89 0408. The composition of any one of embodiments 89 to 0396 The composition of any one of embodiments 95, wherein said starting dose comprises about 10 mg. 78-79, 83 or 87, wherein said titration period comprises 1 to 6 months. Embodiment 102 04.09. The composition of any one of embodiments 89 to Embodiment 90 95, wherein said starting dose comprises about 25 mg. 0397. The composition of embodiment 89, wherein said titration period is 3 months. Embodiment 103 Embodiment 91 0410 The composition of any one of embodiments 89 to 95, wherein said starting dose comprises about 50 mg. 0398. The composition of embodiment 89, wherein said titration period is 6 months. Embodiment 104 Embodiment 92 0411. The composition of any one of embodiments 78 to 103, wherein said patient liver function assessed or moni 0399. The composition of any one of embodiments 89 to tored before, during, or after said titration period. 91, wherein said starting dose is prepared to be administered to said patient once daily. Embodiment 105 Embodiment 93 0412. The composition of embodiment 104, wherein said 0400. The composition of any one of embodiments 89 to assessing or monitoring comprises measuring a level of one 92, wherein said starting dose is prepared to be administered or more liver biomarkers compared to a control. to said patient once daily. Embodiment 106 Embodiment 94 0413. The composition of embodiment 105, wherein said 04.01 The composition of any one of embodiments 89 to liver biomarker is selected from the group consisting of 92, wherein said starting dose is prepared to be administered AST, ALT, alkaline phosphatase (ALP), bilirubin, glycine to said patient once weekly. conjugated obeticholic acid, taurine conjugated obeticholic acid, a bile acid, a bile acid glycine conjugate, or a bile acid Embodiment 95 taurine conjugate. 0402. The composition of any one of embodiments 89 to Embodiment 107 92, wherein said starting dose is prepared to be administered to said patient once every other day. 0414. The composition of embodiment 106, wherein said liver biomarker is ALP. Embodiment 96 Embodiment 108 0403. The composition of any one of embodiments 89 to 95, wherein said starting dose comprises about 1 mg to 50 0415. The composition of embodiment 106 or 107, ng. wherein said liver biomarker is bilirubin. Embodiment 97 Embodiment 109 04.04 The composition of any one of embodiments 89 to 0416) The composition of any one of embodiments 104 to 95, wherein said starting dose comprises about 1 mg to 25 108, further comprising calculating an AST to platelet ratio ng. (APRI) for said patient. US 2017/0035784 A1 Feb. 9, 2017 37 Embodiment 110 Embodiment 121 0417. The composition of any one of embodiments 89 to 0428 The composition of any one of embodiments 110 to 109, wherein said obeticholic acid composition is prepared 115, wherein said adjusted dose of said obeticholic acid to be administered to said patient as an adjusted dose after composition is prepared to be administered to said patient said titration period. twice a week. Embodiment 111 Embodiment 122 0418. The composition of embodiment 110, wherein said 0429. The composition of any one of embodiments 110 to adjusted dose is equal to said titrated dose. 121, wherein said adjusted dose comprises about 1 mg to 50 ng. Embodiment 112 Embodiment 123 0419. The composition of embodiment 110, wherein said 0430. The composition of any one of embodiments 110 to adjusted dose is equal to said starting dose when a level of 121, wherein said adjusted dose comprises about 1 mg to 25 ALP is reduced compared to a control. ng. Embodiment 113 Embodiment 124 0420. The composition of embodiment 110, wherein said 0431. The composition of any one of embodiments 110 to adjusted dose is greater than said titrated dose. 121, wherein said adjusted dose comprises about 1 mg to 10 ng. Embodiment 114 0421. The composition of any one of embodiments 110 to Embodiment 125 113, wherein said adjusted dose is prepared to be adminis 0432. The composition of any one of embodiments 110 to tered more frequently than said titrated dose. 121, wherein said adjusted dose comprises about 1 mg to 5 ng. Embodiment 115 0422 The composition of any one of embodiments 110 to Embodiment 126 113, wherein said adjusted dose is prepared to be adminis 0433. The composition of any one of embodiments 110 to tered less frequently than said titrated dose. 121, wherein said adjusted dose comprises about 5 mg. Embodiment 116 Embodiment 127 0423. The composition of any one of embodiments 110 to 0434. The composition of any one of embodiments 110 to 115, wherein said adjusted dose of said obeticholic acid 121, wherein said adjusted dose comprises about 10 mg. composition is prepared to be administered to said patient once daily. Embodiment 128 0435 The composition of any one of embodiments 110 to Embodiment 117 121, wherein said adjusted dose comprises about 25 mg. 0424 The composition of any one of embodiments 110 to 115, wherein said adjusted dose of said obeticholic acid Embodiment 129 composition is prepared to be administered to said patient 0436 The composition of any one of embodiments 110 to once daily. 121, wherein said adjusted dose comprises about 50 mg. Embodiment 118 Embodiment 130 0425 The composition of any one of embodiments 110 to 0437. The composition of any one of embodiments 78 to 115, wherein said adjusted dose of said obeticholic acid 129, wherein said obeticholic acid composition is prepared composition is prepared to be administered to said patient to be co-administered one or more active agents, or combi once daily. nations thereof. Embodiment 119 Embodiment 131 0426. The composition of any one of embodiments 110 to 0438. The composition of embodiment 130, wherein said 115, wherein said adjusted dose of said obeticholic acid active agent is ursodeoxycholic acid (UDCA). composition is prepared to be administered to said patient once weekly. Embodiment 132 0439. The composition of embodiment 130, wherein the Embodiment 120 active agent is a peroxisome proliferator-activated receptor 0427. The composition of any one of embodiments 110 to alpha (PPARC.) agonist, a peroxisome proliferator-activated 115, wherein said adjusted dose of said obeticholic acid receptor delta (PPAR8) agonist, a dual PPARC/ö agonist, a composition is prepared to be administered to said patient dual PPARO/Y agonist, or pan-PPAR agonist, an HMG CoA once every other day. reductase inhibitor, a GLP1 agonist, insulin, insulin US 2017/0035784 A1 Feb. 9, 2017 mimetic, metformin, a GTP4 agonist, an HST2 inhibitor, a Embodiment 139 DPP-IV inhibitor, an SGLT2 inhibitor or a hydroxysteroid dehydrogenase (HSD) inhibitor, such as an 113-HSD1 0448. The composition of embodiment 135, wherein said inhibitor, an ASK1 inhibitor, an ACC1 inhibitor, a NOX1 adjusted dose of said obeticholic acid composition is pre and/or NOX4 inhibitor, an inhibitor or antagonist of one or pared to be administered at a decreased frequency than said more chemokine receptors, such as, for example, CCR2 and starting dose. CCR5. Embodiment 140 Embodiment 133 0449 The composition of embodiment 135, wherein said 0440 The composition of any one of embodiments 78 to effective amount of said obeticholic acid composition is 132, wherein said obeticholic acid composition is prepared prepared to be administered at an increased frequency than to be administered as a first line therapy for the treatment of said starting dose. PBC. Embodiment 141 Embodiment 134 0450. The composition of any one of embodiments 135 to 0441 The composition of any one of embodiments 78 to 140, wherein said starting dose is 5 mg. 133, wherein said patient is has renal impairment or hepatic impairment. Embodiment 142 0451. The composition of any one of embodiments 135 to Embodiment 135 141, wherein said starting dose is prepared to be adminis 0442. A composition comprising a starting dose of obet tered QD. icholic acid, or a pharmaceutically acceptable salt, ester, or Embodiment 143 amino acid conjugate thereof, wherein obeticholic acid or a pharmaceutically acceptable salt, ester, or amino acid con 0452. The composition of any one of embodiments 135 to jugate thereof is in the form of particles, and wherein at least 141, wherein said adjusted dose is 5 mg. 50% of the particles have a diameter of 200 um or less for use in treating primary biliary cirrhosis (PBC) in a patient in Embodiment 144 need thereof wherein the composition is prepared to be 0453 The composition of any one of embodiments 135 to administered in a titration period wherein 141, wherein said adjusted dose is 10 mg. 0443 the liver function of the patient is assessed before, during, and after said titration period by calculating an AST Embodiment 145 to platelet ratio (APRI) score for said patient or by measur ing the level of one or more liver biomarker selected from 0454. The composition of any one of embodiments 135 to ALP. bilirubin, AST, ALT, glycine conjugated obeticholic 144, wherein said adjusted dose is prepared to be adminis acid, taurine conjugated obeticholic acid, a bile acid, a bile tered QD or Q2D. acid glycine conjugate, or a bile acid taurine conjugate, wherein a reduced APRI score compared to a control or a Embodiment 146 reduced level of said one or more liver biomarkers compared 0455 The composition of any one of embodiments 135 to to a control indicates non-impaired liver function; and 145, wherein said patient is assessed for tolerance to said 0444 the tolerance of the patient to said starting dose is adjusted dose. assessed by grading the severity of one or more adverse effects, if present; and the obeticholic acid composition is Embodiment 147 prepared to be administered as an adjusted dose, wherein said adjusted dose comprises an amount equal to or greater 0456. The composition of embodiment 146, wherein said than an amount of said starting dose. adjusted dose is modified to a re-adjusted dose. Embodiment 136 Embodiment 148 0445. The composition of embodiment 135, wherein said 0457. The composition of embodiment 147, wherein said adjusted dose is prepared to be administered at an amount re-adjusted dose comprises an equal amount compared to equal to an amount of said starting dose. said adjusted dose and is prepared to be administrated at a reduced frequency. Embodiment 137 Embodiment 149 0446. The composition of embodiment 135, wherein said adjusted dose is prepared to be administered at an amount 0458. The composition of embodiment 148, wherein said greater than an amount of said starting dose. re-adjusted dose comprises a reduced amount compared to said adjusted dose and is prepared to be administrated at an Embodiment 138 equal frequency. 0447 The composition of embodiment 135, wherein said adjusted dose of said obeticholic acid composition is pre Embodiment 150 pared to be administered at the same frequency as said 0459. The composition of embodiment 135, wherein said starting dose. patient has hepatic impairment. US 2017/0035784 A1 Feb. 9, 2017 39 Embodiment 151 Embodiment 159 0460. The composition of embodiment 150, wherein said 0468. The use of embodiments 155, 156 or 158, wherein starting dose is prepared to be administered QW. said composition further comprises said obeticholic acid composition as a starting dose. Embodiment 152 Embodiment 160 0461 The composition of embodiment 151, wherein said starting dose is 5 mg. 0469. The use of embodiment 159, wherein said starting dose is prepared to be administered in a titration period. Embodiment 153 Embodiment 161 0462. The composition of any one of embodiments 135 to 152, wherein said adjusted dose is equivalent to said starting 0470 The use of any one of embodiments 158 to 160, dose when said level of ALP is reduced compared to a wherein said cancer is hepatocellular carcinoma (HCC), control. colorectal cancer, gastric cancer, liver cancer, kidney cancer, or pancreatic cancer. Embodiment 154 Embodiment 162 0463. The composition of any one of embodiments 135 to 152, wherein said adjusted dose comprises an amount equal 0471 Use of a composition comprising obeticholic acid, to said starting dose and wherein said adjusted dose is or a pharmaceutically acceptable salt, ester, or amino acid prepared to be administered at a greater frequency than said conjugate thereof, wherein obeticholic acid or a pharmaceu starting dose. tically acceptable salt, ester, or amino acid conjugate thereof is in the form of particles, and wherein at least 50% of the Embodiment 155 particles have a diameter of 200 um or less, for the manu facture of a medicament for use in treating an autoimmune 0464 Use of a composition comprising obeticholic acid, disease in a patient in need thereof. or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof, wherein obeticholic acid or a pharmaceu Embodiment 163 tically acceptable salt, ester, or amino acid conjugate thereof is in the form of particles, and wherein at least 50% of the 0472. The use of embodiment 162, wherein said obet particles have a diameter of 200 um or less, for the manu icholic acid composition is prepared to be administered as a facture of a medicament for use in treating primary biliary starting dose. cirrhosis (PBC) in a patient in need thereof. Embodiment 164 Embodiment 156 0473. The use of embodiment 163, wherein said starting 0465. Use of a composition comprising obeticholic acid, dose is prepared to be administered in a titration period. or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof, wherein obeticholic acid or a pharmaceu Embodiment 165 tically acceptable salt, ester, or amino acid conjugate thereof is in the form of particles, and wherein at least 50% of the 0474. The use of embodiment 162 or 163, wherein said particles have a diameter of 200 um or less, for the manu autoimmune disease is multiple Sclerosis, rheumatoid arthri facture of a medicament for use in treating primary Scleros tis, or type-I diabetes. ing cholangitis (PSC), chronic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis Embodiment 166 (NASH), hepatitis C infection, alcoholic liver disease, liver 0475. The use of any one of embodiments 155-156, 160 damage due to progressive fibrosis, or liver fibrosis in a or 164, wherein said titration period comprises 1 to 6 patient in need thereof in a patient in need thereof. months. Embodiment 157 Embodiment 167 0466. The use of embodiment 156, for use in treating 0476. The use of embodiment 166, wherein said titration NASH. period is 3 months. Embodiment 158 Embodiment 168 0467 Use of a composition comprising obeticholic acid, 0477. The use of embodiment 166, wherein said titration or a pharmaceutically acceptable salt, ester, or amino acid period is 6 months. conjugate thereof, wherein obeticholic acid or a pharmaceu tically acceptable salt, ester, or amino acid conjugate thereof Embodiment 169 is in the form of particles, and wherein at least 50% of the particles have a diameter of 200 um or less, for the manu 0478. The use of any one of embodiments 166 to 168, facture of a medicament for use in treating a solid-tumor wherein said starting dose is prepared to be administered to cancer in a patient in need thereof. said patient once daily. US 2017/0035784 A1 Feb. 9, 2017 40 Embodiment 170 Embodiment 183 0479. The use of any one of embodiments 166 to 169, 0492. The use of embodiment 182, wherein said liver wherein said starting dose is prepared to be administered to biomarker is selected from the group consisting of AST. said patient once daily. ALT, alkaline phosphatase (ALP), bilirubin, glycine conju gated obeticholic acid, taurine conjugated obeticholic acid, Embodiment 171 a bile acid, a bile acid glycine conjugate, or a bile acid 0480. The use of any one of embodiments 166 to 169, taurine conjugate. wherein said starting dose is prepared to be administered to said patient once weekly. Embodiment 184 0493. The use of embodiment 183, wherein said liver Embodiment 172 biomarker is ALP. 0481. The use of any one of embodiments 166 to 169, wherein said starting dose is prepared to be administered to Embodiment 185 said patient once every other day. 0494. The use of embodiment 183 or 184, wherein said Embodiment 173 liver biomarker is bilirubin. 0482. The use of any one of embodiments 166 to 172, Embodiment 186 wherein said starting dose comprises about 1 mg to 50 mg. 0495. The use of any one of embodiments 181 to 185, Embodiment 174 further comprising calculating an AST to platelet ratio (APRI) for said patient. 0483 The use of any one of embodiments 166 to 172, wherein said starting dose comprises about 1 mg to 25 mg. Embodiment 187 Embodiment 175 0496 The use of any one of embodiments 166 to 186, wherein said obeticholic acid composition is prepared to be 0484 The use of any one of embodiments 166 to 172, administered to said patient as an adjusted dose after said wherein said starting dose comprises about 1 mg to 10 mg. titration period. Embodiment 176 Embodiment 188 0485 The use of any one of embodiments 166 to 172, wherein said starting dose comprises about 1 mg to 5 mg. 0497. The use of embodiment 187, wherein said adjusted dose is equal to said titrated dose. Embodiment 177 Embodiment 189 0486 The use of any one of embodiments 166 to 172, wherein said starting dose comprises about 5 mg. 0498. The use of embodiment 187, wherein said adjusted dose is equal to said starting dose when a level of ALP is Embodiment 178 reduced compared to a control. 0487. The use of any one of embodiments 166 to 172, Embodiment 190 wherein said starting dose comprises about 10 mg. 0499. The use of embodiment 187, wherein said adjusted Embodiment 179 dose is greater than said titrated dose. 0488. The use of any one of embodiments 166 to 172, wherein said starting dose comprises about 25 mg. Embodiment 191 (0500. The use of any one of embodiments 187 to 190, Embodiment 180 wherein said adjusted dose is prepared to be administered 0489. The use of any one of embodiments 166 to 172, more frequently than said titrated dose. wherein said starting dose comprises about 50 mg. Embodiment 192 Embodiment 181 (0501) The use of any one of embodiments 187 to 190, 0490 The use of any one of embodiments 155 to 180, wherein said adjusted dose is prepared to be administered wherein liver function of said patient is assessed or moni less frequently than said titrated dose. tored before, during, or after said titration period. Embodiment 193 Embodiment 182 (0502. The use of any one of embodiments 187 to 192, 0491. The use of embodiment 181, wherein said assess wherein said adjusted dose of said obeticholic acid compo ing or monitoring comprises measuring a level of one or sition is prepared to be administered to said patient once more liver biomarkers compared to a control. daily. US 2017/0035784 A1 Feb. 9, 2017 Embodiment 194 Embodiment 206 0503. The use of any one of embodiments 187 to 192, 0515. The use of any one of embodiments 187 to 198, wherein said adjusted dose of said obeticholic acid compo wherein said adjusted dose comprises about 50 mg. sition is prepared to be administered to said patient once daily. Embodiment 207 0516. The use of any one of embodiments 155 to 206, Embodiment 195 wherein said obeticholic acid composition is prepared to be 0504. The use of any one of embodiments 187 to 192, administered in combination with one or more active agents, wherein said adjusted dose of said obeticholic acid compo or combinations thereof. sition is prepared to be administered to said patient once daily. Embodiment 208 0517. The use of embodiment 207, wherein said active Embodiment 196 agent is ursodeoxycholic acid (UDCA). 0505. The use of any one of embodiments 187 to 192, wherein said adjusted dose of said obeticholic acid compo Embodiment 209 sition is prepared to be administered to said patient once 0518. The use of embodiment 207, wherein the active weekly. agent is a peroxisome proliferator-activated receptor alpha (PPARC) agonist, a peroxisome proliferator-activated recep Embodiment 197 tor delta (PPARö) agonist, a dual PPARC/ö agonist, a dual 0506. The use of any one of embodiments 187 to 192, PPARO/Y agonist, or pan-PPAR agonist, an HMG CoA wherein said adjusted dose of said obeticholic acid compo reductase inhibitor, a GLP1 agonist, insulin, insulin sition is prepared to be administered to said patient once mimetic, metformin, a GTP4 agonist, an HST2 inhibitor, a every other day. DPP-IV inhibitor, an SGLT2 inhibitor or a hydroxysteroid dehydrogenase (HSD) inhibitor, such as an 113-HSD1 Embodiment 198 inhibitor, an ASK1 inhibitor, an ACC1 inhibitor, a NOX1 and/or NOX4 inhibitor, an inhibitor or antagonist of one or 0507. The use of any one of embodiments 187 to 192, more chemokine receptors, such as, for example, CCR2 and wherein said adjusted dose of said obeticholic acid compo CCR5. sition is prepared to be administered to said patient twice a week. Embodiment 210 0519. The use of any one of embodiments 155 to 209, Embodiment 199 wherein said obeticholic acid composition is prepared to be 0508. The use of any one of embodiments 187 to 198, administered as a first line therapy for the treatment of PBC. wherein said adjusted dose comprises about 1 mg to 50 mg. Embodiment 211 Embodiment 200 0520. The use of any one of embodiments 155 to 210, 0509. The use of any one of embodiments 187 to 198, wherein said patient is has renal impairment or hepatic wherein said adjusted dose comprises about 1 mg to 25 mg. impairment. Embodiment 201 Embodiment 212 0510. The use of any one of embodiments 187 to 198, 0521. The use of a composition comprising a starting wherein said adjusted dose comprises about 1 mg to 10 mg. dose of obeticholic acid, or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof, wherein obet Embodiment 202 icholic acid or a pharmaceutically acceptable salt, ester, or amino acid conjugate thereof is in the form of particles, and 0511. The use of any one of embodiments 187 to 198, wherein at least 50% of the particles have a diameter of 200 wherein said adjusted dose comprises about 1 mg to 5 mg. um or less for use in treating primary biliary cirrhosis (PBC) in a patient in need thereof wherein the composition is Embodiment 203 prepared to be administered in a titration period wherein: the liver function of the patient is assessed before, during, 0512. The use of any one of embodiments 187 to 198, and after said titration period by calculating an AST to wherein said adjusted dose comprises about 5 mg. platelet ratio (APRI) score for said patient or by measuring the level of one or more liver biomarker selected from ALP, Embodiment 204 bilirubin, AST, ALT, glycine conjugated obeticholic acid, 0513. The use of any one of embodiments 187 to 198, taurine conjugated obeticholic acid, a bile acid, a bile acid wherein said adjusted dose comprises about 10 mg. glycine conjugate, or a bile acid taurine conjugate, wherein a reduced APRI score compared to a control or a reduced Embodiment 205 level of said one or more liver biomarkers compared to a control indicates non-impaired liver function; and 0514. The use of any one of embodiments 187 to 198, the tolerance of the patient to said starting dose is assessed wherein said adjusted dose comprises about 25 mg. by grading the severity of one or more adverse effects, if US 2017/0035784 A1 Feb. 9, 2017 42 present; and the obeticholic acid composition is prepared to Embodiment 224 be administered as an adjusted dose, wherein said adjusted dose comprises an amount equal to or greater than an 0533. The use of embodiment 223, wherein said adjusted amount of said starting dose. dose is modified to a re-adjusted dose. Embodiment 225 Embodiment 213 0534. The use of embodiment 224, wherein said re 0522 The use of embodiment 212, wherein said adjusted adjusted dose comprises an equal amount compared to said dose is prepared to be administered at an amount equal to an adjusted dose and is prepared to be administrated at a amount of said starting dose. reduced frequency. Embodiment 214 Embodiment 226 0523 The use of embodiment 212, wherein said adjusted 0535. The use of embodiment 225, wherein said re dose is prepared to be administered at an amount greater adjusted dose comprises a reduced amount compared to said than an amount of said starting dose. adjusted dose and is prepared to be administrated at an equal frequency. Embodiment 215 Embodiment 227 0524. The use of embodiment 212, wherein said adjusted dose of said obeticholic acid composition is prepared to be 0536 The use of embodiment 212, wherein said patient administered at the same frequency as said starting dose. has hepatic impairment. Embodiment 216 Embodiment 228 0525. The use of embodiment 212, wherein said adjusted 0537. The use of embodiment 227, wherein said starting dose of said obeticholic acid composition is prepared to be dose is prepared to be administered QW. administered at a decreased frequency than said starting dose. Embodiment 229 0538. The use of embodiment 228, wherein said starting Embodiment 217 dose is 5 mg. 0526. The use of embodiment 212, wherein said effective amount of said obeticholic acid composition is prepared to Embodiment 230 be administered at an increased frequency than said starting 0539. The use of any one of embodiments 212 to 229, dose. wherein said adjusted dose is equivalent to said starting dose when said level of ALP is reduced compared to a control. Embodiment 218 0527. The use of any one of embodiments 212 to 217, Embodiment 231 wherein said starting dose is 5 mg. 0540. The use of any one of embodiments 212 to 229, wherein said adjusted dose comprises an amount equal to Embodiment 219 said starting dose and wherein said adjusted dose is prepared 0528. The use of any one of embodiments 212 to 218, to be administered at a greater frequency than said starting wherein said starting dose is prepared to be administered dose. QD. EXAMPLES Embodiment 220 (0541. The disclosure is further illustrated by the follow ing examples, which are not to be construed as limiting this 0529. The use of any one of embodiments 212 to 218, disclosure in scope or spirit to the specific procedures herein wherein said adjusted dose is 5 mg. described. It is to be understood that the examples are provided to illustrate certain embodiments and that no Embodiment 221 limitation to the scope of the disclosure is intended. It is to 0530. The use of any one of embodiments 212 to 218, be further understood that resort may be had to various other wherein said adjusted dose is 10 mg. embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without Embodiment 222 departing from the spirit of the present disclosure and/or Scope of the appended claims. 0531. The use of any one of embodiments 212 to 221, wherein said adjusted dose is prepared to be administered Example 1 QD or Q2D. Particle Size Analysis Embodiment 223 0542 5 mg tablet and 10 mg tablet formulations of 0532. The use of any one of embodiments 212 to 222, obeticholic acid (OCA or INT-747) demonstrated a slow wherein said patient is assessed for tolerance to said adjusted dissolution release profile. Particle size of agglomeration dose. was identified as playing a primary role in the release rate US 2017/0035784 A1 Feb. 9, 2017 and dissolution and variability in the blend uniformity and determine the optimum set of jet mill parameters. The jet content uniformity of the tablet formulations. In order to mill parameters used in the Hosokawa AFG 100 jet mill are obtain an appropriate particle size distribution (PSD), mill provided below: ing of obeticholic acid was investigated. The particle size of 0557 Hosokawa AFG 100 jet mill parameters: the formulations was reduced using comilling and jet milling 0558 Pressure in the mill: -0.2-0.3 mm Aq. to improve its dissolution release profile. Particle size analy 0559 Nozzle diameter/number: 1.9 dmmx 3 sis was performed using a dry dispersion method and 0560 Consumption of compressed air: 0.7 Nm3/min analyzed by laser diffraction using Sympatec equipment. 0561 Classification Parameters 0543 Particle size distribution was assessed using a dry 0562 Rotor rotation speed: 4000 rpm dispersion method analyzed by laser diffraction using a 0563 Current rating of motor: 4.2 Amp Sympatec Laser Helos/KF-Magic F71000 with Rodos Dis 0564 Current operating: 2.4 Amp persing Unit. The OCA sample (0.5 g sample) was tested as 0565 Rotor seal pressure: 0.1 MPa (1 bar) a dry powder. The parameters for the validated particle size 0566 Bearing seal pressure: 0.1 MPa (1 bar) analysis method are described below: 0567 Rotor type: SUS 0544. Apparatus: Sympatec Laser Helos/KF-Magic 0568 Powder Collector F71000 with Rodos Dispersing Unit, Vibri sampling unit 0569. Filter material/length/number: Gore/2 ft/4 with Sniffer rotation, Nilfisk exhaustion or equivalent. 0570. The particle size distribution of unmilled and jet 0545 Deionization apparatus: Sartorius or equivalent. milled OCA (API) is shown below in Table 2. (0546 Measuring range: R3: 0.5/0.9 to 175 um. 0547 Dispersing principle: Dry. TABLE 2 0548 Pressure: 1.0 bar. 0549. Feed rate: 80%. Particle size distribution of unmilled 0550 Feed height: 2 mm. and iet milled obeticholic acid. 0551 Sniffer rotation: 20%. Sample Description Dio D16 Dso D84 Doo Dog 0552. Trigger conditions: Time base: 100 ms: Start: Unmilled API 4.8 218.6 — 427.6 — Ka.28>1%; Stop: 1 s c.opts 1%. Jet mill, classifier speed 1.7 2.3 10.9 S7.2. 69.3 97.9 0553 Comilling. The use of a comil with different screen 2000 rpm sizes was evaluated. Three comil screens were utilized: 1.14 Jet mill, classifier speed 1.3 1.7 4.2 15.2 18.9 S5.8 mm, 0.61 mm, and 0.46 mm. The milled active pharmaceu 5000 rpm Jet mill, classifier speed 1.1 1.4 2.7 4.7 5.6 9.0 tical ingredient (API) was evaluated for appearance, particle 10000 rpm size distribution as well as process yield. The process yield Jet mill, classifier speed 1.3 1.6 3.8 17.0 21.7 36.O was difficult to determine accurately, but as expected, a 4000 rpm larger amount of milled drug product was recovered from the larger screen sizes. The particle size distribution of 0571. The results above show that jet milling at high unmilled and comilled obeticholic acid is shown below in classifier speeds (i.e., 4000 rpm, 5000 rpm and 10,000 rpm) Table 1. showed a significant reduction in the PSD. 0572 Jet milling using spiral jet mill. Jet milling studies TABLE 1. were performed using a spiral jet mill. The results showed a Particle size distribution of unmilled and comilled obeticholic acid. significant reduction in the particle size distribution (PSD). Jet milling was carried out with various a range of param Sample Description Dio D25 Dso D75 Doo Dos eters to determine the optimal settings. The jet mill param Unmilled API (no comil) 4.8 105.1 218.6 335.7 427.6 472.6 eters used in the spiral jet mill are provided below: Unmilled API (no comil) 3.3 36.4 167.7 273.7 355.6 398.2 (0573 Spiral jet mill parameters controlling the final PSD Comilled with 0.46 mm 5.7 122.9 217.5 283.0 335.1 360.3 a. SCCEl Comilled with 0.61 mm 4.1 102.2 263.1 351.O 410.9 447.9 0574 Feed rate: Product amount fed into the milling SCCEl chamber per unit time Comilled with 0.61 mm S.S 106.6 223.2 320.8 393.8 429.8 0575 Pressure: Fluid pressure through the nozzle section SCCEl Comilled with 1.14 mm 7.9 73.9 239.3 340.8 412.O 452.7 which influences the speed at which the particles collide SCCEl TABLE 3 0554. After the comil, the material visually appeared to Milling Parameters Used During Development at JetPharma have a lower particle size and be more uniform in size when compared to unmilled (API). However, the measured par Lot Batch Nitrogen ticle size distribution of the material by dry dispersion Number Size Feed Rate Pressure PSD described above did not show a difference between the JP1307001 10.0 kg Evaluated Evaluated Xo: 1 In comilled and the unmilled OCA. The PSD data demonstrate range: range: Xso: 5 Lim 200-400 g/30" 2.0-4.0 bar Xoo: 20 m a more robust milling technique is required to significantly Target range: Target range: reduce the particle size of the material. 300 + 10 g/30" 3.0 + 0.2 bar 0555 Jet milling using Hosokawa AFG 100 jet mill JP1408001 5.6 kg Evaluated Evaluated Xo: 1 In range: range: Xso: 5 Lim 0556. Jet milling studies were performed using a 200-400 g/30" 2.0-4.0 bar Xoo: 19 lim Hosokawa AFG 100 jet mill. The results showed a signifi Target range: Target range: cant reduction in the particle size distribution (PSD). Jet 290 + 10 g/30" 3.2 + 0.2 bar milling was carried out with various classifier speeds to US 2017/0035784 A1 Feb. 9, 2017 44 TABLE 3-continued compaction followed by tablet compression and coating. The process steps used to manufacture OCA tablets include: Milling Parameters Used During Development at JetPharma pre-blending: dry granulation, final blending, compression, Lot Batch Nitrogen coating, and packaging. The equipment used to manufacture Number Size Feed Rate Pressure PSD OCA tablets are shown in Table 5. JP14080O2 4.8 kg Evaluated Evaluated Xo: 1 In range: range: Xso: 4 In TABLE 5 200-400 g/30" 2.0-4.0 bar Xoo: 14 lim Target range: Target range: Equipment Used to Manufacture OCA Tablets 290 + 10 g/30" 3.2 + 0.2 bar JP1408003 6.3 kg Evaluated Evaluated Xo: 1 In Process Step Equipment range: range: Xso: 4 In 200-400 g/30" 2.0-4.0 bar Xoo: 15 m Sieving 0.5 mm and 1.0 mm aperture sieve Target range: Target range: Pre-blending Drum and Bin blender, appropriately sized drum 290 + 10 g/30" 3.2 + 0.2 bar and bin Roller Roller compactor, Alexanderwerk PP150 (or WP120) compaction or equivalent fitted with upper and lower mill SCCES 0576. The impact of jet-milling on API particle size and Final Bin blender, appropriately sized bin surface area is detailed in Table 4-1 and Table 4-2, respec blending tively. Surface area was tested per a BET (Brunauer, Compression Rotary tablet press, Kilian T300 or equivalent Emmett, and Teller theory). The BET method for analyzing Coating Perforated pan coater, Manesty Accelacota 150 or Surface area is based on adsorption of gas on a surface. The equivalent 48-inch coating pan amount of gas adsorbed at a given pressure allows a deter mination of the Surface area. 0577 As can be observed from Table 2, the API particle 0579 Microcrystalline cellulose was added to the intra size distribution after jet-milling undergoes a dramatic shift granular portion of the tablet mixture which produced tablets towards much smaller, more uniformly-sized particles of moderate hardness. Modification to the manufacturing within a tighter distribution, while Surface area increases approximately 3-fold. FIG. 1 and FIG. 2 illustrate the typical process to add microcrystalline cellulose to both the intra particle size distribution of unmilled and jet-milled API, granular and extra-granular portions of the tablet for both the respectively. 5 mg and 10 mg tablet generated more robust tablets (harder tablets). The compression challenges observed were over TABLE 4-1 come by redistributing a portion of microcrystalline cellu lose in the 5 mg and 10 mg OCA formulation blends. This Impact of jet-milling (micronization) on particle change in the manufacturing process impacted the quality size distribution of OCA drug substance Particle Size Distribution of Unmicronized attributes, specifically the dissolution profile, of the OCA and Micronized OCA Drug Substance tablets. OCA Example # 0580 OCA drug substance and excipients were added in specific quantities and order during pre- and final blending. 1 2 3 Prior to manufacture, the materials were dispensed in the Before After Before After Before After appropriate portions as shown in Table 6. Microcrystalline cellulose (MCC) and sodium starch glycolate (SSG) were D, (10) 2.6 0.7 1.8 O6 5.3 0.7 sieved with a 1.0 mm aperture sieve before use. Magnesium D. (50) 26 6.1 19 4.4 39 4.9 D (90) 162 18.8 231 17.8 221 14.1 Stearate was sieved using a 0.5 mm aperture sieve immedi D., (99) 419 30.8 509 34-6 S13 25.9 ately before use. TABLE 6 TABLE 4-2 Material Dispensing Summary for OCA Tablets Impact of jet-milling (micronization) Quantity for Quantity for Quantity for on Surface area of OCA drug Substance 5 mg OCA 10 mg OCA 25 mg OCA Surface Area of Unmicronized and Micronized OCA Drug Substance Tablet Tablet Tablet Formulation Formulation Formulation OCA Example # Component (kg) (kg) (kg) 1 2 3 Intra-granular (Pre Blending) Before After Before After Before After OCA drug Substance 2.5g 5.0° 12.5 MCC-for-Premix 7.5 1O.O 2SO Surface Area 1557 31.78 1854 3848 809 3412 MCC-for-Rinse 7.5 1O.O 12.5 (m/kg) MCC-1 25.5 33.0 41.0° SSG-1 4.0 4.0 4.0 Silicon dioxide-1 1.O Magnesium Stearate-1 O.S O.S O.S Example 2 Extra-granular (Final Blending) Improved Manufacturing Process of Obeticholic MCC-2 50.0 35.0° Acid (OCA) Tablets SSG-2 2.0 2.0 2.0 0578. The manufacturing process of 5 mg and 10 mg Silicon dioxide-2 1.0 obeticholic acid (OCA) tablets uses dry granulation by roller US 2017/0035784 A1 Feb. 9, 2017 TABLE 6-continued revolutions for the various preblending steps provide homo geneity of the pre-blend formulation. Material Dispensing Summary for OCA Tablets 0584) Dry granulation. The pre-blend was transferred Quantity for Quantity for Quantity for from the bin blender to the roller compactor hopper. The 5 mg OCA 10 mg OCA 25 mg OCA pre-blend was roller compacted to provide flakes which Tablet Tablet Tablet were milled into granules through an in-line dual screen Formulation Formulation Formulation milling system. The granules were then collected in a Component (kg) (kg) (kg) Suitable container. Roller compaction parameters used in the Magnesium Stearate-2 0.5 O.5. 0.58 commercial production are shown in Table 7. This process Coating provided the roller compacted active granules (intra-granu Opadry (R) II Yellow 6.0 6.0 6.0 lar portion) for use in the final blending step. Roll pressure 85F32351 (compaction force), roll gap, and Screen size (lower mill) are Purified water 24.O 24.0 24.0 meaningful process parameters in the roller compaction Total 104.O 104.O 104.O process. The roll pressure, roll gap, and screen size provided MCC = Microcrystalline cellulose; granules with consistent physical characteristics and par SSG = Sodium starch glycolate; ticle-size distribution. OCA drug substance amount assumes the drug substance content is 100%; actual amount added is adjusted for based on the potency of the drug substance lot used; the amount of microcrystalline cellulose is correspondingly decreased. TABLE 7 The amounts of extra-granular excipients are adjusted based on the yield of the process through roller compaction. The dispensing summary presented assumes a 100% yield through roller compaction, Roller Compactor Settings Used for Commercial Production The amount of coating material prepared during the process is 150% of target, Excess coating material is discarded. Attribute Setting ater is removed during processing, Roll pressure (bar) 40 to 48 0581 Preblending Process. To an appropriately sized Roll gap (mm) 2.5 to 4.0 blender drum was added OCA and a microcrystalline cel Upper mill screen size (mm) 2.0 lulose (MCC) for premix (MCC-for-Premix: a portion of the Lower mill screen size (mm) O.8 total MCC added to the tablet formulation) to produce OCA premix. The resulting mixture was blended 90 to 120 0585 Final Blending. The final blending of the OCA revolutions (approximately for 3 minutes at a blender speed tablet formulation was performed in 2 steps. First, an of about 30 rpm) and discharged. For the 5 mg tablets, OCA appropriately sized bin was charged with the roller-com was pre-mixed with approximately 3 parts MCC (to 1 part pacted active granules (intra-granular portion), extra-granu OCA). For the 10 mg tablets, OCA was pre-mixed with lar sodium starch glycolate-2 (SSG-2) and extra-granular approximately 2 parts MCC (to 1 part OCA). MCC-2, and the resulting mixture was blended for 450 to 540 revolutions. For the 25 mg tablet, silicon dioxide was 0582. After unloading the API/MCC premix (OCA pre added via a 0.5 aperture sieve together with SSG-2 and mix) from the drum, the drum was rinsed with a further extra-granular MCC-2. Magnesium Stearate-2 was then portion of MCC (MCC-for-Rinse: same amount as used for added to the bin and the mixture was blended for 70 to 90 the premix), to recover any API retained on the drum revolutions. Blender revolution is a meaningful process surfaces to provide the MCC-rinse portion. A blend time of parameter in the final blending process providing a final 3 minutes (i.e., about 90 to 120 revolutions) was used for this blend with acceptable homogeneity. rinse process, i.e., MCC-rinse process. The API/MCC pre 0586 Compression Process. The final blend prepared in mix and MCC drum rinse (MCC-rinse portion) were passed the blending process was used to supply the rotary tablet through a 1.0 mm aperture sieve on addition to the larger press fitted with the appropriate OCA tablet tooling. OCA drum used for the Pre-RC (roller compaction) blending tablet tooling is specific to the tablet strength. During process (i.e., 150 liter drum for 5 mg tablets and 70 liter equipment start-up, the tablet press was set up by adjusting drum for 10 mg tablets). The sieve removed any soft compression parameters to produce tablets that meet the agglomerates of OCA, and ensured good blend uniformity in-process control targets for tablet weight, hardness, thick was achieved before roller compaction. ness, and friability. Tablet press speed (about 70 rpm) and 0583. An appropriately sized bin was then charged with feeder speed (about 30 rpm to about 40 rpm) were set to the following components: approximately /4 (one-fourth) of achieve satisfactory tablet weight variation. The tablet press MCC-1, /2 (half) of OCA Premix, MCC drum rinse (MCC depth of fill was set to achieve the target tablet weight. The Rinse), /2 of OCA Premix, and 4 of MCC-1 in the order main compression pressure (rollers) was set to achieve the specified. The resulting mixture was then blended for 300 to target hardness and thickness (compression force of about 8 360 revolutions (about 20 minutes for 5 mg tablets, about 10 kN). A small amount of pre-compression force (about 0.5 minutes for 10 mg tablets) in a Pharmatech MB400 drum kN) was applied before the main compression to expel air blender or a Tumblemix drum blender or V-blender. The from the blend to ensure satisfactory tablet friability. Adjust SSG-1 and the remaining /2 of MCC-1 was added to the bin ments were made throughout the compression operation to and the mixture was then blended for 300 to 360 revolutions continuously meet the in-process control targets. After the (about 10 to 20 minutes). Magnesium stearate-1 was then tablets were ejected from the press, they were passed added to the bin via a 0.5 mm aperture sieve and the mixture through a tablet deduster and metal detector prior to collec was blended for 70 to 90 revolutions (about 3 minutes). For tion in tablet containers. the 25 mg tablet, silicon dioxide was added via a 0.5 mm 0587. In-process control testing for appearance, tablet aperture sieve together with SSG-1 and the remaining /2 of weight, hardness, thickness, friability, and disintegration MCC-1 to the bin and the mixture was then blended for 300 time is conducted at specific internals throughout the tablet to 360 revolutions (about 10 to 20 minutes). The blender compression process and are provided in Table 8. Press US 2017/0035784 A1 Feb. 9, 2017 46 speed and compression are meaningful process parameters was achieved, the pan speed and Supply air temperature were in the tablet compression process. The specified press speed reduced (to about 4 rpm and 45° C.) to ensure dry tablets. provided tablets with the target tablet weight. Compression, The heater was then turned off and tablets were further including both pre- and main compression, provided tablets cooled while jogging the pan. Tablet weight gain (target 4% that met the tablet hardness, thickness and firability limits. In gain) and appearance were checked periodically during the addition, the provided tablets showed fast disintegration tablet coating process as in-process controls. The in-process time. tests conducted during the coating process are shown below in Table 9. TABLE 8 In-Process Tests for Compression Step TABLE 9 5 mg OCA 10 mg OCA 25 mg OCA In-Process Tests for Coating Process In-process Tablets Tablet Tablet Test Acceptance Criteria 5 mg OCA 10 mg OCA 25 mg OCA In-process Tablets Tablets Tablets Appearance White, round White, White, oval Test Acceptance Criteria tablets with triangular tablets with 5 debossed on tablets with 25 debossed on Appearance Off-white to Off-white to Off-white to one side and 10 debossed on one side and yellow, round yellow, yellow, oval INT on the one side and INT on the tablets with triangular tablets with other side INT on the other side 5 debossed on tablets with 25 debossed on other side one side and 10 debossed on one side and Weight of 20 3.92 g to 4.08 g (Target 4.00 g) INT on the one side and INT on the tablets other side INT on the other side Individual 200 mg, NMT 2 individual tablets deviate from mean other side weight of by more than 7.5% and none by more than 15% Tablet 3.0% to S.O% 3.0% to 5.0% 3.0% to 5.0% 20 tablets weight Hardness 7 kP to 13 kP 8 kP to 14 kP 9 kP to 15 kP gain (mean) (target 10 kP) (target 11 kP) (target 12 kP) Thickness 3.5 mm to 4.0 mm to 4.3 mm to (mean) 4.1 mm 4.6 mm 4.9 mm (target: 3.8 mm) (target: 4.3 mm) (target: 4.6 mm) 0591 Packaging. Tablets were packaged in the commer Friability NMT 0.5% cial primary packaging configuration using a standard auto (6.5 g/100 mated bottling operation. The primary packaging configu rotations) Disintegra- NMT2 min ration utilized a white high-density polyethylene bottle (40 tion time cc) and child resistant cap with an induction seal. The (6 tablets) commercial bottle will contain 30 OCA tablets. Tablet quantity, induction seal, cap torque, print quality, and NMT = not more than appearance control testing was conducted at specific inter 0588 Tablet Coating. The 5 mg and 10 mg OCA tablets vals throughout the packaging process. Induction sealing is were coated with a non-functional immediate release coating a meaningful process parameter in the packaging process material. Tablet cores were coated with Opadry(R) II coating providing a completely sealed bottle. The in-process testing material using a perforated pan coater and a 48-inch pan. A parameters for the packaging process is provided in Table 10 20% w/w coating solution was prepared by mixing Opadry(R) below. II with purified water. An excess of coating solution was prepared to ensure Sufficient coating material is available for TABLE 10 the coating process. 0589. The tablet cores were loaded into the pan of the In-Process Tests for Packaging Process perforated pan coater (i.e., O'Hara Labcoat MX coating In-process Test Acceptance Criteria machine and 1XSchlick Model 93.077-1 S35 with 1.2 mm noZZle spray gun) and the coating process was initiated. The Tablet quantity Correct tablet fill quantity (30 count) pan rotation speed (about 12 rpm) was monitored and Induction seal integrity Totally sealed bottle maintained in the appropriate range to ensure the tablet cores Cap torque test 15 lb/in2 to 25 lb/in2 flowed consistently throughout the coating process. Pan Print quality Print is present and correct speed is a meaningful process parameter, as this can affect Appearance (AQL inspection) Satisfactory tablet appearance (too high a pan speed can damage the tablets). Tablet bed temperature is a meaningful process AQL = Acceptable quality limit parameter, as this can affect tablet water content and protects the tablets from over-wetting (which causes tablet appear Example 3 ance defects). Exhaust air temperature is linked to tablet bed temperature and is a meaningful process parameter if tablet bed temperature is not recorded. Dissolution Testing of Obeticholic Acid 0590 The supply air temperature of about 60 to 72° C. Film-Coated Tablets and an exhaust air temperature of about 45 to 55° C. was used to maintain tablet bed temperature at about 45 to 48°C. 0592 Unmilled 5 mg tablet and 10 mg tablet formula Supply and exhaust air temperatures were monitored tions of OCA were observed to release the drug slowly. The throughout the coating step to maintain the bed temperature formulation of the 5 mg and 10 mg tablets are shown below range of about 45 to 48°C. After the desired 4% weight gain in Table 11. US 2017/0035784 A1 Feb. 9, 2017 47 TABLE 11 TABLE 12-continued 5 mg. 10 mg, and 25 mg film-coated tablets formulations Parameters for the obeticholic acid 5 Ing and 10 mg tablet dissolution method. Parameter Value Material 5 mg 10 mg 25 mg Dissolution Volume 900 mL. Intragranular Rotation Speed 75 rpm Temperature 37° C. O.S. C. OCA Drug Substance S.O 1O.O 2SO Sample Volume 10 mL with medium replacement Microcrystalline Cellulose 81.0 106.0 157.0 Sample Pull Times 10, 15, 30, 45, 60 minutes Sodium Starch Glycolate 8.0 8.0 8.0 Sample Analysis HPLC,Corona CAD Colloidal Silicon Dioxide 2.0 Magnesium Stearate 1.O 1.O 1.O Abbreviations: HPLC = high performance liquid chromatography; Granule Mass 95.0 12SO 1930 rpm = revolutions per minute; Ratio of Microcrystalline about about about USP = United States Pharmacopeia; Cellulose to OCA 16:1 11:1 6:1 CAD = charged aerosol detector Extragranular Microcrystalline Cellulose 1OOO 7O.O 0596. Obeticholic acid was comilled with a 0.61 mm Sodium Starch Glycolate 4.0 4.0 4.0 screen or jet-milled as described above to reduce the particle Colloidal Silicon Dioxide 2.0 size of the material. Jet-milling (i.e., micronization) resulted Magnesium Stearate 1.O 1.O 1.O in material that had a smaller, more uniform particle size and Final BlendTablet Core 2OO.O 2OO.O 2OO.O increased surface area, leading to faster drug release from Tablet Coating tablets containing jet-milled OCA. The dissolution release rate of tablets containing comilled and jet-milled OCA is Opadry II Coating Material 8.0 8.0 8.0 shown below in Table 13. Coated Tablet 208.O 208.O 208.O TABLE 13 OCA quantity presented assumes drug substance is anhydrous and 100% pure; actual amount is adjusted based on potency of the drug substance lot used, and amount of Dissolution release rates of comilled and iet-milled OCA microcrystalline cellulose is correspondingly decreased. 5 mg tablets 10 mg tablets 5 mg tablets 0593. Upon testing, the tablets containing unmilled OCA containing containing containing demonstrated a slow dissolution release profile. For the Dissolution comilled OCA comilled OCA Jet-milled OCA dissolution method, both RI and Corona detectors were time Dissolution Dissolution Dissolution initially evaluated for analysis of the dissolution media. (min) rate (%) rate (%) rate (%) Considering the need to quantify OCA (INT-747) at levels as 15 42 51 83 low as 10% of a 5 mg strength tablet dissolved in the 30 57 66 89 dissolution media (1 g/mL), the Corona CAD detector was 45 68 79 91 chosen for the dissolution tests because it has a better 60 77 85 94 sensitivity to OCA than the RI detector. 75 89 92 95 0594 Tablet dissolution for both the 5 mg and 10 mg tablets was conducted in 900 mL of 50 mM Disodium 0597 Table 13 shows that reduction in particle size of the Hydrogen Phosphate Buffer (NaHPO), pH 6.8 at 37° C. OCA drug product improves elution properties. using USP II paddle apparatus at a paddle speed of 75 rpm. Samples were assayed undiluted by filtering through a 0.2 0598. As shown in FIG. 3 and FIG. 4, the particle size um PVDF syringe filter using a gradient RP-HPLC method distribution of the OCA impacted the drug dissolution rate, with CAD detection. This method utilized an Agilent Zorbax even in media where OCA is freely soluble (pH 6.8). It is SB-C18 4.6 mmx150 mm, 3.5 um HPLC column. A 50 uL therefore possible that differences in particle size could sample was separated by a 20 minute gradient program, at impact OCA bioavailability if dissolution becomes rate a temperature of 40°C. and a flow rate of 1.5 mL per minute. limiting for absorption. For this reason, the particle size Two mobile phases were used in the program; one consisted distribution of the active is considered a critical process of a degassed Acidified Water pH 3.0/Acetonitrile (45:55) parameter. mixture and the other degassed Acetonitrile. The OCA drug 0599. The dissolution profiles of 10 mg tablets containing substance eluted with an approximate retention time of 10 either unmilled (a batch of unmilled OCA with smaller minutes. particle size; Dso about 100 LM), unmilled/agglomerated, 0595. The dissolution methodology is summarized below or jet-milled OCA is compared in FIG. 3. in Table 12. 0600 Drug release was compared for 5 mg tablets con taining unmilled (agglomerated) and jet-milled OCA. The TABLE 12 difference in release profiles was more dramatic for the 5 mg Parameters for the obeticholic acid 5 tablets than the 10 mg tablets. This is likely due to coning ng and 10 mg tablet dissolution method. effects in the smaller dissolution volume of 500 mL which may have contributed to the slower/incomplete dissolution Parameter Value due to the non-favorable hydrodynamics in the test vessel. Apparatus USP Apparatus II (paddles) The dissolution profiles of 5 mg tablets containing either Dissolution Media 50 mM sodium phosphate dibasic buffer, pH 6.8 unmilled/agglomerated, or jet-milled OCA is compared in FIG. 4. US 2017/0035784 A1 Feb. 9, 2017 48 Example 4 Content Uniformity Testing of Obeticholic Acid Tablets 0601 The content uniformity of 5 mg and 10 mg tablets containing comilled OCA and jet-milled OCA was evaluated by RP-HPLC. The results are shown below in Table 14. TABLE 1.4 1. Content uniformity of 5 mg and 10 mg tablets of unmilled, comilled and jet-milled OCA OCA 12. O 5 mg tablets 10 mg tablets 5 mg tablets containing containing containing comilled OCA comilled OCA jet-milled OCA o-r Content 104 (AV = 18, 104 (AV = 14, 105.2 (AV = 8, Uniformity 89.0%-110.6%) 97.4%-111.5%) 101.4%-109.2%) (%) How 1“o 0602. The results in Table 14 show the content uniformity 1. data for tablets containing comilled and jet-milled OCA. ethyl ester impurity Tablets containing comilled OCA showed a higher variabil ity in content uniformity. The smaller particle size of the jet-milled material provides better content uniformity of the 0606 An analysis was conducted with LC/HRMS using OCA tablets. LTQ-Orbitrap Discovery. The LC/HRMS Test conditions used are outlined in Table 15 below: Example 5 TABLE 1.5 Stability Studies of 5 mg and 25 mg Obeticholic LC/HRMS conditions for identifying impurities Acid Tablets found in OCA after stability testing Equipment: HPLC Shimadzu prominence (LC-20A series) MS) Thermo Fisher Scientific LTQ Orbitrap 0603 The stability of 5 mg and 25 mg tablets were tested Discovery in accelerated stability studies. The stability test was con Ionization ESI (negative and positive mode) ducted at 40°C. and 75 relative humidity (RH) for 6 months. method: The formulation of the 5 mg and 25 mg tablets are shown HPLC Column Phenomenex, Kinetex C-18, 2.6 m, conditions: 4.6 mm I.D. x 100 mm above in Table 11. Mobile A: AcOH aqueous solution' containing 0604 5 mg and 25 mg OCA tablets were placed on phase 15% MeOH stability at the 40°C./75% RH storage conditions. Samples B: MeCN containing 15% MeOH stored at the accelerated condition were pulled from Storage Gradient conditions. at 1, 2, 3, and 6 months for assessment of stability. The tests performed for stability evaluations include appearance, Time (min.) B (%). assay for OCA by HPLC, and related substances by HPLC O.O - 25.0 40 - 65 Corona. 25.0 - 35.0 65 -e 95 35.0 -e SO.O 95 0605. Obeticholic acid and formulations of obeticholic SO.O -e SO.1 95 - 40 SO.1 - 60.0 40 acid were tested for stability. An unknown impurity at 60.1 stop relative retention time (RRT) 1.75 was observed during stability studies of the tablets containing different batches of Measurement 60 min time the 5 mg and 25 mg tablet formulation. The stability test Detection Total Ion Current Chromatogram using uncoated tablets showed an increase of a new impurity (TICC) at about 0.05% with the test conducted at 25°C., 60% RH Flow rate 1.0 mL/min. Column Approximately 40° C. for 4 weeks, and about 0.2% with the test conducted at 40° temperature C., 75% RH for 4 weeks. A study was conducted to identify Sample drug Mobile phase B the structure of the impurity, clarify the origin for the product solvent generation of the impurity, and adopt measures to ensure that Injection 5 ul quality was not compromised during storage of the tablet. Sample? OCA drug product (product stored for 4 weeks at The structure of OCA and the identified structure of the 60° C.) solution (OCA concentration 500 g/mL) * impurity are respectively shown below: US 2017/0035784 A1 Feb. 9, 2017 49 TABLE 15-continued observed as early as three months into the stability study. This data indicates that the ethanol content of the sodium LCHRMS conditions for identifying impurities starch glycolate is critical to the stability of the OCA found in OCA after stability testing formulation. Drug product placebo Solution (prepared in the same way as (1)) 0612 Stability Testing of Film Coated Tablets. Further Impurity 1-5 and OCA mixed solution more, in the film coated tablet stability test an increase in a (5 g/mL each) OCA powder (5000 rpm) specific impurity was confirmed at a rate of approximately OCA unground product 0.09% with the test conducted at 40° C., 75% RH for 4 OCA drug product (stored at 50° C., 85% RH for weeks. Given that the generation of this impurity only 4 weeks) solution occurred in film coated tablets, it was surmised that the impurity was a reactant with a film coating component. Also, 0607 Based on the results, it was determined that the based on the structure of ethyl ester impurity it is known that impurity is an ethyl ester of obeticholic acid (OCA). Sub the carboxylic acid of OCA reacted easily with alcohol. Of sequently, an authentic sample of the ethyl ester was Syn the film coating components, it was possible that 2 compo thesized by dissolving obeticholic acid in ethanol, adding nents, polyvinyl alcohol (PVA) and polyethylene glycol concentrated Sulfuric acid and heating the mixture. The (PEG) 4000 could be the cause of the impurity. retention time and mass spectrometry of the authentic sample matched those of the impurity and thus the structure 0613 Subsequently, when a blending combination of the impurity was confirmed as an ethyl ester of obet change test was conducted the specific impurity was gener icholic acid (FIG. 7A and FIG. 7B). Comparison of the ated and it was discovered that PEG4000 was the cause. retention time and the mass spectrum of the ethy ester Therefore, it was estimated that the structure of this impurity impurity and authentic sample is shown in FIG. 7A and FIG. was an ester produced by a reaction between a PEG4000 TB. hydroxyl group and the OCA carboxylic acid. The structure 0608. Bottom row: TICC of ethyl ester (positive mode) of OCA and PEG ester impurity are shown below: 0609. The structure of the ethyl ester impurity (shown above) was determined through mass spectrometry analysis combined with analysis of OCA fragmentation, and was confirmed by mass spectrometry analysis of synthesized OCA ethyl ester (the above authentic sample having the same retention time as the ethyl ester impurity). 0610 Since the ethyl ester impurity can be formed in the presence of ethanol, the formulation was examined to deter mine if any excipient could be a possible source of the ethanol. It was found that sodium starch glycolate from two different manufacturers, sodium starch glycolate (Glyco lys(R) from Roquette Pharma containing no more than 6% ethanol and sodium starch glycolate (Explotab(R) from JRS Pharma containing no more than 3% ethanol, were used to make the tablet formulations. A comparison of accelerated stability data at 40° C./75% RH of batches are shown below in Table 16. TABLE 16 OCA Ethyl Ester Impurity (RRT 1.75) Content in Accelerated (40 C./75% RH) Stability Studies Lot Number (Manufacturer) Time O 1 Month 3 Months 6 Months DNSY, 5 mg ND ND ND ND PEG ester impurity Patheon (Explotab (R) DNSZ, 25 mg ND ND ND ND Patheon (Explotab (R) PDSOO48-03, 5 mg ND NT O.35% O.44% 0614 High resolution mass spectrometry (HRMS) was Piramal (Glycolys (R) PDSOO48-10, 25 mg ND NT O.17% O.25% conducted to confirm the structure. The mean molecular Piramal (Glycolys (R) weight of PEG ester impurity was expected to exceed 4000. ND = Not detected; microTOF-QII (Bruker Daltonics) was used to measure NT = Not tested high molecular weight compounds. When measured with the APCI technique in positive mode, an m/z was obtained that 0611. The results in Table 16 show that the ethyl ester impurity is not observed after 6 months in samples contain supported the structure of PEG ester impurity shown above. ing low ethanol Sodium starch glycolate (i.e., ExplotabR). (FIGS. 8A, 8B, and 8C). Enlargement of the mass spectrum However, the ethyl ester impurity in Samples containing of a sample containing the specific impurity showed peak high ethanol Sodium starch glycolate (i.e., GlycolySR) was spacing characteristic of PEG (FIG. 9). US 2017/0035784 A1 Feb. 9, 2017 50 0615. The LC/HRMS Test conditions used are outlined in TABLE 1.8 Table 17 below: Equilibrium solubility and recovery for OCA at TABLE 17 37 C. in various buffers from pH 1.2 to 10.0 Solubility % USP Solubility LC/HRMS test conditions for the identification of the impurity pH, Media (Buffer) (mg/mL) Recovery Rating found in film coated OCA tablets after stability testing. pH 1.2 Hydrochloric acid NA <1 Practically Equipment: (HPLC Agilent 1200 insoluble pH 2.0 Hydrochloric acid NA <1 Practically MS) microTOF-QII (Bruker Daltonics) insoluble Ionization APCI positive mode bH 3.0 Acid Phthalate NA <1 Practically method: insoluble HPLC Column Phenomenex, Kinetex C-18, 2.6 m, bH 4.1. Acetate O.OO3 <1 Slightly soluble conditions: 4.6 mm I.D. x 100 mm pH 5.1 Acetate O.O23 5 Sparingly soluble Mobile A: AcOH aqueous solution? pH 6.0 Phosphate O.OSO 10 Soluble phase containing 15% MeOH pH 6.8 Phosphate O.220 94 Freely soluble B: MeCN containing 15% MeOH pH 7.0 Phosphate O462 92 Freely soluble pH 8.0 Phosphate O486 97 Freely soluble pH 9.0 Alkaline Borate O462 92 Freely soluble Gradient conditions. pH 10.0 Alkaline Borate O.OS6 11 Soluble Time (min.) B (%). Dissolution media (50 mM sodium phosphate dibasic buffer, pH 6.8) Basic decomposition of drug substance suspected, O.O - 25.0 40 - 65 25.0 - 35.0 6S -e 95 0618 OCA is a weak acid (pK 4.82) and exhibits a 35.0 -e SO.O 95 pH-solubility profile consistent with that of a weak acid. As SO.O -e SO.1 95 - 40 expected, the solubility of the free acid form is highest when SO.1 - 60.0 40 deprotonated and lowest when protonated. 60.1 stop. 0619 OCA drug substance was observed to precipitate out of solution in those acidic buffers in the pH range 1.2 to Measurement 60 min 3.0. Solutions at pH 4.1 to 6.0 also had some precipitation time resulting in a cloudy solution. Solutions at pH 6.8 to 10 Detection Total Ion Current Chromatogram produced clear solutions. The recovery of OCA steadily (TICC) diminishes at pH higher than 8.0, indicating basic decom Flow rate 1.0 mL/min. position of the drug Substance. Column Approximately 40° C. 0620. The nominal concentration for dissolved 5 mg and temperature 10 mg tablets in the typical dissolution volume of 900 mL Sample drug Mobile phase B is approximately 0.006 & 0.01 mg/mL, respectively. Above product pH 6.8 the solubility is well above 0.01 mg/mL, the mini solvent mum concentration required to dissolve a 5 mg or 10 mg Injection 5 ul tablet in 900 mL of dissolution medium (i.e., sink condi Sample OCA film coated tablet (product stored for tions). 4 weeks at 60° C.) extract solution* 0621. As demonstrated in FIG. 5, solubility of OCA increases as a function of increasing pH, plateauing just *pH 3.0 above approximately pH 7. The dramatic increase in solu *The 500 ul sample prepared was concentrated to dryness under a stream of nitrogen, dissolved in 50 ul of mobile phase B and used as the sample (OCA concentration: 5 bility observed between approximately pH 4 and pH 7 mg/mL), indicates that this pH region is less-than-ideal for use in the dissolution media. However, given that OCA is freely 0616) The extract from the film coated tablets was mea soluble at pH 6.8 and that this pH is physiologically relevant Sured using the APCI technique in positive mode. Analysis to the site of absorption, it was selected for use in diligent of the retention time, the mass spectra, and the m/z value pursuit of a discriminating and relevant dissolution method. confirmed the structure of PEG ester impurity (shown above 0622 Solubility Studies of OCA in Biological Media. A and in FIGS. 8A, 8B, and 8C). solubility study was performed in physiologically relevant dissolution media at 37° C. and pH of 1.2, 4.5, and 6.8 along Example 6 with fasted state simulated gastric fluid (FaSSGF. pH 1.2). fed state simulated intestinal fluid (FeSSIF. pH 5.0) and fasted state simulated intestinal fluid (FaSSIF. pH 6.5). The Solubility Studies of OCA in Various Buffers and solubility results for OCA in physiologically relevant buffers Biological Media are presented in Table 19. 0617 Solubility Studies of OCA in Various Buffers. A TABLE 19 study was performed to screen different media of various pH over the pH range 1.2-10.0, incorporating the physiological Solubility of OCA in biologically relevant media at 37° C. pH range (1.2-6.8) for immediate release tablets. The solu Solubility bility of OCA was measured at 37° C. in various buffers pH (Medium) (mg/mL) USP Solubility Rating from pH 1.2 to 10.0. The equilibrium solubility results for 1.2 (0.1N HCI) TABLE 19-continued cholangitis, alcoholic liver disease, definite autoim mune liver disease or biopsy proven nonalcoholic ste Solubility of OCA in biologically relevant media at 37 C. atohepatitis (NASH). Solubility 0638. The percent change (%) in serum ALP from Base pH (Medium) (mg/mL) USP Solubility Rating line to End of Study (EOS) was monitored. The baseline value was the mean of the pretreatment screening and day 0 4.5 TABLE 22 ALP (U/L) at Baseline to Day 85/ET: ITT Population (N = 165) and Completer Population (N = 136). Placebo OCA 10 mg OCA 25 mg OCA 50 mg ITT Population (n = 38) (n = 38) (n = 48) (n = 41) Baseline Mean (SD) 275.2 (102.7) 294.4 (149.4) 290.0 (123.6) 289.5 (106.2) Median 249.5 234.8 255.8 262.5 Day 85/ET Mean (SD) 270.7 (118.7) 219.0 (113.5) 225.0 (169.1) 227.9 (115.9) Median 234.5 177.5 187.5 1970 Mean (SD) Change -4.6 (34.9) -75.4 (81.5) -65.0 (91.3) –62.9 (101.9) Median Change -6.3 -47.5 -69.3 -S6.5 Mean (SD) Percent -2.6 (12.4) -23.3 (17.1) -24.0 (18.8) –20.0 (27.4) Change Median Percent -3.2 -21.0 -27.8 -22.7 Change P-value NA Example 9 0670. History of elevated ALP levels for at least 6 months 0664. This example describes a randomized, double 0671 Positive anti-mitochondrial antibody (AMA) blind, placebo-controlled, parallel-group, 12-month trial titer or if AMA negative or in low titer (<1:80) PBC evaluating OCA in patients with PBC as a monotherapy. The specific antibodies (anti-GP210 and/or anti-SP100 study was performed using a randomized, double-blind, and/or antibodies against the major M2 components placebo-controlled, parallel-group, in patients with PBC PDC-E2, 2-oxo-glutaric acid dehydrogenase com who either: (1) were on ursodeoxycholic acid (UDCA) for at plex) least 12 months (and on stable dose for >3 months), or (2) were unable to tolerate UDCA, and did not receive UDCA 0672 Liver biopsy consistent with PBC for 3 months prior to Day 0. 0673. At least 1 of the following qualifying biochem 0665. Where all eligibility criteria (see below) were met, istry values: participants were stratified into one of four groups, i.e., two 0674 ALP 1.67xULN or factors each with two Sub-categories (specified in parenthe 0675 Total bilirubind-ULN but<2xULN ses): 0676 Ages 18 years 0.666 pre-treatment ALPa3.0xULN and/or aspartate 0677 Taking UDCA for at least 12 months (stable dose aminotransferase (AST)>2.0xULN and/or TB ULN; for >3 months) prior to Day 0, or unable to tolerate (no for all three conditions, yes to at least one of the UDCA (no UDCA for >3 months) prior to Day 0. three conditions) 0678 Contraception: Female patients had to be post 0667 intolerance to UDCA: ('no' hence UDCA usage menopausal, Surgically sterile, or if premenopausal, for at least 12 months, with a stable dose for at least 3 had to use > 1 effective (s.1% failure rate) method of months, prior to study start with the assumption of contraception during the trial and for 30 days after the continued stable usage of UDCA throughout the study: EOT Visit. 'yes' hence no UDCA usage for at least 3 months prior 0679 Kevy exclusion criteria to study start with the assumption of continued non 0680 Any hepatic decompensation usage of UDCA throughout the study). 0681 Portal hypertension, cirrhosis and complica 0668 Key Inclusion Criteria tions of cirrhosis/portal hypertension 0669 Definite or probable PBC diagnosis as demon 0682. History of liver transplantation, current place strated by the presence of 2 of the following 3 diag ment on a liver transplant list or current Model for nostic factors: End Stage Liver Disease (MELD) scores 15 US 2017/0035784 A1 Feb. 9, 2017 54 0683 Cirrhosis with complications, including his (0704) Normal bilirubin (values ULN) and/or normal tory or presence of spontaneous bacterial peritonitis, albumin (values lower limit of normal LLN; (Kuiper hepatocellular carcinoma, bilirubin-2xULN 2009) Rotterdam criterial) 0684 Hepatorenal syndrome (type I or II) or Screen 0705 The absolute change from Baseline for enhanced ing serum creatinine2 mg/dL (178 umol/L) liver fibrosis (ELF) and hepatic stiffness (at select sites) as 0685 Competing etiology for liver disease (e.g., hepa assessments of end stage liver failure. The absolute and titis C, active hepatitis B, nonalcoholic steatohepatitis percent change from Baseline on: C-reactive protein (CRP), (NASH), alcoholic liver disease (ALD), autoimmune tumor necrosis factor-alpha (TNF-C.), tumor necrosis factor hepatitis, primary Sclerosing cholangitis, Gilbert's Syn beta (TGF-B), fibroblast growth factor-19 (FGF-19) levels, drome) interleukin-6 (IL-6), and CK-18 was measured. The absolute 0686. Severe pruritus (Intense or widespread and inter and percent change from Baseline on PBC-40 domains was fering with activities of daily living) or pruritus requir measured. ing treatment with bile acid sequestrants, rifampicin 0706. Absolute and percent change from Baseline on within 2 months of day 0 PBC autoantibodies (IgA, IgG, IgM) and interleukins (IL-12 0687. On prohibited medications (such as fenofibrates, p40, IL-23) were measured. budesonide, corticosteroids, Valproate, isoniazid etc.); 0707 Measuring the plasma OCA concentrations includ please see the list of prohibited medications in protocol ing OCA (unconjugated), conjugates (glyco-OCA and tauro review. OCA), and total OCA (the sum of OCA unconjugated, 0688 Patients who had previously participated in a glyco-OCA, and tauro-OCA). clinical trial of OCA were not allowed to participate 0708 Measuring the absolute change from Baseline for total bile acids, endogenous bile acids, and individual total 0689 Prolonged QT interval, pregnancy or lactation. and unconjugated bile acids (UDCA, deoxycholic acid, 0690. If female: known pregnancy, or had a positive cholic acid and lithocholic acid), glyco-conjugate, and tauro urine pregnancy test (confirmed by a positive serum conjugate; proportion of each of the individual bile acids to pregnancy test), or lactating total bile acids 0691 Known history of human immunodeficiency 0709 Bile acid sequestrant (BAS) concomitant exposure. virus infection The primary analysis set used for all efficacy analyses, along 0692 Presence of any other disease or condition that with the Summarization of disposition along with demo was interfering with the absorption, distribution, graphics and baseline characteristics, was the Intent-to metabolism, or excretion of drugs including bile salt Treat' (ITT) analysis set. This analysis set included all metabolism in the intestine. Patients with inflammatory randomized patients who received at least one dose of bowel disease or who had undergone gastric bypass blinded study drug. When utilizing this analysis set, patients procedures were excluded (gastric lap band was accept were analyzed according to the treatment group that they able). were randomized to regardless of the actual treatment 0693 Medical conditions that could cause non-hepatic received. It should be noted that all but one randomized increases in ALP (e.g., Paget’s disease) patient received at least one dose of blinded study drug. 0694 One goal of the study was to demonstrate the 0710 For sensitivity analysis purposes, all efficacy analy efficacy of OCA, relative to placebo, based on its effects on ses were repeated utilizing a Completer analysis set. This ALP and TB. Other objectives included assessing safety, analysis set was comprised of all ITT patients who partici histological, bile acid, and biomarker (i.e., not including pated through the end of the double-blind period (i.e., ALP and TB) parameters. through the Month 12 visit). When utilizing this analysis set, 0695 ALP and TB composite response criteria were patients were analyzed according to the treatment group that measured; a patient was designated as a responder if all three they were randomized to, regardless of the actual treatment of the following conditions were met: received. 0696. A value of ALP<1.67xULN 0711 For additional sensitivity analysis purposes, all 0697 ALP reduction from baselined 15% efficacy analyses were again repeated utilizing an Efficacy Evaluable (EE) analysis set. This analysis set was com 0698. A value of TB-ULN prised of all Completer patients who did not have any 0699 The absolute and percent change from Baseline in major protocol deviations that would potentially affect the ALP gamma-glutamyl transferase (GGT), alanine amino efficacy of the study drug. This analysis set definition was transferase (ALT), AST, total bilirubin, conjugated (direct) finalized in a blinded manner prior to database lock. bilirubin, albumin, prothrombin time and international nor 0712 For population pharmacokinetic (PK) analysis pur malized ratio (INR) at all-time points was measured. The poses, the PK analysis set was utilized, which consisted of percentage of patients with a decrease in ALP of >10%. all patients who had at least 1 confirmed fasted analyzable >15%, c20%, and >40% from Baseline or sULN at month sample at and who did not have any major protocol devia 12 was measured. The percentage of patients achieving the tions that could potentially affect exposure levels. following biochemical response criteria was also measured: 0713 To control the overall study-wise type I error rate, (0700 ALPs3xULN and ASTs2xULN and bilirubi a step-down/closed sequential testing procedure was pre nsULN (Corpechot 2008); Paris I) specified to adjust for the multiple comparisons of the two 0701 ALPs 1.5xULN and ASTs 1.5xULN and biliru OCA dose groups individually to placebo on the primary bin ULN (Corpechots2011), Paris II) study endpoint alone. Starting with the 10 mg OCA com (0702 ALPs 1.67xULN and bilirubinsULN ((Momah parison to placebo on the primary endpoint, the step-down 2012), Mayo II) could only be carried to the OCA Titration comparison to (0703 ALPs 1.76xULN ((Kumagi 2010b), Toronto II) placebo (on the primary endpoint), if and only if the 10 mg US 2017/0035784 A1 Feb. 9, 2017 OCA comparison to placebo was found to be statistically ing procedure as previously described, formal hypothesis significant (i.e. p-value less than 0.05). If the 10 mg OCA testing is stopped at this point. Any Subsequent inferential comparison to placebo was not statistically significant (i.e., statistic reported below should be considered exploratory p-value greater than or equal to 0.05), then the hypothesis test for the OCA Titration comparison to placebo on the TABLE 23 primary endpoint would be deemed as exploratory. 0714. This pre-specified multiplicity adjustment proce Proportion of Patients who Achieved Response dure was narrow in scope in that it only pertained to the individual OCA dose comparisons with placebo on the primary endpoint alone. Hence even if both OCA dose 10 mg OCA OCA Titration Placebo comparisons were found to be statistically significant, then Statistics (N = 73) (N = 70) (N = 73) any other hypothesis test would still be deemed as explor atory in nature. Response at Month 6 - 37 (50.7%) 24 (34.3%) 5 (6.9%) 0715. A Cochran-Mantel-Haenszel (CMH) test which n (1%) 1 adjusted for both randomization stratification variables as Corresponding 95% 39.2%, 62.2%. 23.2%, 45.4% 1.1%, 12.6% described above, was used for pre-specified analysis. In Wald CI tandem with the CMH test, a Breslow-Day test was also Response at Month 12 - 34 (46.6%) 32 (45.7%) 7 (9.6%) conducted, to test for the homogeneity of the treatment effect n (%) 1 across the different randomization strata. Corresponding 95% 36.5%, 59.4%. 34.0%, 57.4% 2.8%, 16.3% 0716. The PK population was used to summarize OCA Wald CI and bile acid concentrations. The change from Baseline CMH Test p-value 2 concentrations within each treatment group was compared Corresponding using a paired t-test. Descriptive statistics of OCA plasma Breslow-Day concentrations and the extent of BAS concomitant exposure Test p-value were provided by treatment group. Initial evaluation of the effects of BAS on OCA, total bile acid concentrations, and ALP was performed using a correlation analysis. 0718. It can be observed from Table 24 that both OCA 0717. It can be observed from Table 23 that both OCA treatment arms reduced ALP relative to placebo. It should be treatment groups showed a Superior difference in the pro noted that the continuous descriptive statistics pertaining to portion/percentage of patients achieving response at Month the baseline absolute change from baseline 12 and percent 12 when individually compared to placebo using the CMH age change from baseline utilized only the available data at test. The corresponding Breslow-Day test result shows that those time points (i.e., no missing data were imputed). The the treatment effects were homogeneous across the different categorical descriptive statistics (i.e., frequencies and cor randomization strata. This analysis was repeated utilizing responding proportions) utilized the worse-case (i.e., non the Completer and EE analysis sets and the conclusions were response) imputation Strategy. consistent. The ultra-worse-case imputation strategy, imple mented by the FDA statistical reviewer as described above, 0719 Patients from the OCA Titration and OCA 10 mg did not impact the study conclusions. In regards to ALP or groups, respectively, achieved an ALP reduction from Base TB values at Month 12, there were no patients who were line-40% compared with 1 (1%) placebo patient. The num designated as outliers (i.e., by having studentized residual bers of patients normalizing ALP values i.e., 118 U/L in values greater than three), and there was no impact on study females and 124 U/L males are as follows: 1 (1%) patient conclusions between corrected 30 laboratory values (as from OCA titration group, 5 (7%) patients from the OCA 10 presented) and original (i.e., uncorrected) laboratory values. mg group, and Zero placebo-treated patients. All of the previously presented analyses were re-conducted utilizing a baseline value that was the median of all pre-first 0720. It can be seen that ALP concentration levels are dose measurements, and, separately, a traditional baseline reduced in both OCA treatment groups, and during the first definition (both approaches as described above); there was three months; these reduced levels remain stable during the no impact on study conclusions with either approach. Con long-term safety and efficacy (LTSE) period, signifying sidering the pre-specified step-down/closed sequential test durability of response. TABLE 24 Total Bilirubin (TB) Summary. 10 mg OCA OCA Titration Placebo Time Point Statistics (N = 73) (N = 70) (N = 73) Baseline ALP Concentration (UIL) N 73 70 73 Mean (SD) 316.3 (103.88) 325.9 (116.24) 327.5 (115.01) Median 271.3 281.3 311.9 Min, Max 207, 620 187, 811 144, 746 Month 12 ALP Concentration (UIL) N 63 64 70 Mean (SD) 191.2 (61.38) 219.5 (99.76) 321.3 (142.88) US 2017/0035784 A1 Feb. 9, 2017 56 TABLE 24-continued Total Bilirubin (TB) Summary. 10 mg OCA OCA Titration Placebo Time Point Statistics (N = 73) (N = 70) (N = 73) Median 181.7 1966 270.5 Min, Max 95, 444 116,690 149, 733 Absolute Change from Baseline to Month 12 (UIL) N 63 64 70 Mean (SD) -1117.1 (72.84) -103.5 (87.03) -7.7 (87.96) Median -99.O -85.5 -15.8 Min, Max -346, 0.3 -402, 127 –208,308 Percentage Change from Baseline to Month 12 (%) N 63 64 70 Mean (SD) -36.4 (14.88) –30.5 (18.97) –2.5 (23.82) Median -383 -31.5 -4.7 Min, Max -72, 0.1 -74, 23 –45, 80 Decrease in ALP & 10% at 61 (83.6%) 55 (78.6%) 29 (39.7%) Month 12 - n (%) Decrease in ALP & 15% at 57 (78.1%) 54 (77.1%) 21 (28.8%) Month 12 - n (%) Decrease in ALP & 20% at 54 (74.0%) 49 (70.0%) 17 (23.3%) Month 12 - n (%) Decrease in ALP is 40% at 25 (34.3%) 21 (30.0%) 1 (1.4%) Month 12 - n (%) Baseline ALP Concentration (xULN) N 73 70 73 Mean (SD) 2.658 (0.878) 2.747 (0.9851) 2.760 (0.9732) Median 2.293 2.378 2.607 Min, Max 1.68, 5.23 1.58, 6.86 1.22, 6.31 Month 12 ALP Concentration (xULN) N 63 64 70 Mean (SD) 1.606 (0.5161) 1.851 (0.8449) 2.705 (1.1987) Median 1527 1661 2.286 Min, Max 0.80, 3.75 0.98, 5.84 1.26, 6.19 ALP < 1.0 x ULN at 5 (6.9%) 1 (1.4%) O Month 12 - n (%) ALP < 1.67 x ULN at 48 (54.8%) 33 (47.1%) 12 (16.4%) Month 12 - n (%) 0721. After completing the treatment period, 193 out of 36 (52%) remained at 5 mg for the duration of the treatment the 216 ITT patients (64 on 10 mg OCA, 63 on OCA period and 33 (48%) who did not meet the primary com Titration, and 66 Placebo patients) continued on open-label posite endpoint at Month 6, but, because they tolerated the OCA treatment during the LTSE period (note: that all investigational product, were titrated to 10 mg. Thirteen placebo patients were switched to OCA 5 mg and then all (39%) of the patients who up-titrated met the composite patients were switched to OCA 10 mg). FIG. 11 presents endpoint Suggesting that a benefit can be gained with ALP concentrations over time, organized by originally ran titration of OCA from 5 mg to 10 mg in those patients who domized treatment group. did not respond to the 5 mg dose. 0722. It can be observed from Table above that reductions 0724. Because for some patients, a response can be from baseline in TB were greater in both OCA treatment achieved with OCA 5 mg, initiating treatment on OCA 5 mg groups than in the placebo group. It should be noted that the and titrating Subsequently to 10 mg if needed and if tolerated continuous descriptive statistics pertaining to the baseline, appears to be a reasonable dosing strategy. For patients who absolute change from baseline and percentage change from do not achieve an optimal response within 6 months of baseline values utilized only the available data at those time treatment with OCA 5 mg, additional benefit may be gained points (i.e., no missing data was imputed). The categorical by titrating to OCA 10 mg. descriptive statistics (i.e., frequencies and corresponding 0725. Effect of Bile Acid Sequestrants (BAS) Exposure proportions) utilized the worse-case imputation strategy. on Efficacy. For patients receiving BAS, OCA 5 mg and 10 FIG. 12 illustrates TB concentrations over time, organized mg trough concentrations were slightly lower compared to by originally randomized treatment group for the 193 ITT those patients who did not receive BAS. The decreased patients continuing on open-label OCA treatment during the trough concentrations resulted in a modest attenuation in LTSE period. efficacy in patients receiving OCA 5 mg (despite instruction 0723 Dose Titration: A total of 69 of 70 ITT patients to dose BS at least 4 hours apart from OCA), but did not from the OCA titration group completed month 6. Of these, appear to affect efficacy in patients receiving OCA 10 mg. US 2017/0035784 A1 Feb. 9, 2017 57 0726 ALP and total bilirubin, were evaluated in relation follows: 1 (1%) patient from OCA titration group, 5 (7%) to age at baseline, age at time of diagnosis, and years since patients from the OCA 10 mg group, and Zero placebo diagnosis. The effect of OCA was consistent independent of treated patients. age at diagnosis, duration of PBC, or years since diagnosis. In general, the Subgroups were consistent with the observed Example 10 effect in the overall ITT population. Greater improvements were observed in OCA-treated subjects, compared with 0730. This example describes clinical pharmacology and placebo Subjects. dosing of obeticholic acid (OCA including obeticholic 0727. It can be observed from Table 25 that both OCA acid compositions described herein). The starting dosage of treatment groups showed a difference in the proportion/ OCA is 5 mg orally once daily in adult patients who have percentage of patients achieving response when individually failed to achieve an adequate reduction in alkaline phos compared to placebo. This analysis was repeated utilizing phatase on a stable dose of UDCA for an adequate duration the Completer and EE analysis sets and the conclusions were or who were intolerant to UDCA. OCA can be supplied as consistent. The ultra-worse-case imputation strategy, imple an oral tablet containing obeticholic acid in a formulation as mented by the FDA statistical reviewer as described above, described herein. did not impact the results. All of the previously presented 0731. If an adequate reduction in alkaline phosphatase analyses were re-conducted utilizing a baseline value that has not been achieved after 3 months of OCA 5 mg once was the median of all pre-first dose measurements, and, daily, and the patient is tolerating the drug, the dose of OCA separately, a traditional baseline definition (both approaches can be increased to 10 mg once daily. as described above); there was no impact on the results with 0732 For patients experiencing intolerability due to pru either approach. ritus, one of the following modifications was considered: TABLE 25 Proportion of Patients who Achieved Response 10 mg OCA OCA Titration Placebo Statistics (N = 60) (N = 60) (N = 61) Response at Month 6 - n (%) 1 25 (41.7%) 21 (35.0%) 1 (1.6%) Corresponding 95% Wald CI 29.2%, 54.1% 22.9%, 47.1% 0.0%, 4.8% Baseline ALP is 2.0 x ULN - n (%) 42 (70.0%) 47 (78.3%) 46 (75.4%) ALP < 2.0 x ULN at Month 6 - n (%)2 30 (71.4%) 24 (51.1%) 8 (17.4%) Decrease in ALP is 40% at Month 6 - n (%) 2 O (23.8%) 3 (27.7%) O ALP < 2.0 x ULN and Decrease is 40% at Month 6 - n (%) 2 9 (21.4%) 1 (23.4%) O Baseline ALP - 1.67 x ULN but < 2.0 x ULN - n (%) 8 (30.0%) 3 (21.7%) 15 (24.6%) ALP < 1.67 x ULN at Month 6 - n (%) [3] 7 (94.4%) O (76.9%) 3 (20.0%) Decrease in ALP is 15% at Month 6 - n (%) 3 6 (88.9%) 1 (84.6%) 1 (6.7%) ALP < 1.67 x ULN and Decrease is 15% at Month 6 - n (%) 3 6 (88.9%) O (76.9%) 1 (6.7%) Response at Month 12 - n (%) 1 26 (43.3%) 23 (38.3%) 3 (4.9%) Corresponding 95% Wald CI 30.8%, 55.9% 26.0%, 50.6% 0.0%, 10.3% Baseline ALP is 2.0 x ULN - n (%) 42 (70.0%) 47 (78.3%) 46 (75.4%) ALP < 2.0 x ULN at Month 12 - n (%) [2] 29 (69.1%) 28 (59.6%) 9 (19.6%) Decrease in ALP is 40% at Month 12 - n (%) 2 3 (31.0%) 6 (34.0%) 1 (2.2%) ALP < 2.0 x ULN and Decrease is 40% at Month 12 - n (%)2 2 (28.6%) 3 (27.7%) 1 (2.2%) Baseline ALP - 1.67 x ULN but < 2.0 x ULN - n (%) 8 (30.0%) 3 (21.7%) 15 (24.6%) ALP < 1.67 x ULN at Month 12 - n (%) 3) 6 (88.9%) 1 (84.6%) 6 (40.0%) Decrease in ALP is 15% at Month 12 - n (%) 3 4 (77.8%) O (76.9%) 2 (13.3%) ALP < 1.67 x ULN and Decrease is 15% at Month 12 - n (%) 3 4 (77.8%) O (76.9%) 2 (13.3%) 0728 Treatment with OCA (10 mg) in a cohort of sub- (0733 Reduce the dosage to: jects with early stage PBC who were enrolled with incom 0734) 5 mg every other day, for patients intolerant to plete biochemical response to UDCA resulted in statistically 5 mg once daily or significant improvement from baseline in alkaline phos 0735. 5 mg once daily, for patients intolerant to 10 phatase for the pre-specified endpoint of reduction of ALP to mg once daily 0736. Alternative dosing schedules, such as dosing <1.67xULN and 15%, relative to placebo. The percentage of every other day, every third day or every seventh day. patients achieving response was statistically significantly 0737 Interruption of dosing for up to 2 weeks fol different than placebo 34 of 73 (46.6%) in the OCA 10 mg lowed by restarting at a reduced dose or on an alter arm, 32 of 70 (45.7%) in the titration arm and 7 of 73 (9.6%) native dosing schedule. in the placebo arm. The effect of OCA on achieving a 0738 hepatic decompensation. reduction in ALP was independent of age at diagnosis, 0739. Addition of an antihistamine or a bile acid duration of PBC, and baseline ALP. sequestrants. 0729 Secondary analysis showed that patients from the 0740 OCA may be taken with or without food. Food does OCA Titration and OCA 10 mg groups achieved an ALP not have a clinically relevant effect on the PK of 10 mg reduction from Baseline-40% compared with 1 (1%) pla OCA cebo patient. The numbers of patients normalizing ALP 0741 Bile acid binding resins may be taken at least 4 values i.e., 118 U/L in females and 124 U/L males are as hours before or 4 hours after (or at as great an interval as US 2017/0035784 A1 Feb. 9, 2017 possible) OCA. Bile acid binding resins such as 0752. The effective half-life of OCA is about 24 hours. cholestyramine, colestipol, or colesevelam affect bile acid 0753 Gender, age, and race had no impact on the phar absorption and may reduce the absorption, Systemic expo macokinetics of OCA based on the population-PK analysis. sure, and efficacy of OCA. Population PK analysis dataset consisted of 301 female and 0742 No dose adjustment is believed to beneeded when 505 male Subjects, age ranging from 18 to 71 years and had OCA is used in patients with serum creatinine clearance>50 10 Asian, 233 Black, 554 White and 9 Other subjects. mL/min/1.73 m. No data are available as to how severe 0754. In vitro studies: Obeticholic acid is not an inhibitor impairment would impact the systemic exposure to OCA of CYP2C8 and did not cause a significant change in the and its conjugates. expression of CYP2B6, CYP2C8, CYP2D6, MRP2, MRP3, 0743 Dose adjustment may be needed in patients with MRP4, MATE1, and OATP2B1. Obeticholic acid showed hepatic impairment. Dose adjustment may not be needed in either no or weak effects on these metabolizing enzymes and patients with mild hepatic impairment (Child-Pugh Class A). transporters. In some examples, the starting dosage is 5 mg once weekly 0755 Concomitant administration of 20 mg omeprazole for patients with moderate or severe hepatic impairment once daily with obeticholic acid 10 mg once daily resulted (Child-Pugh Class B or C). If an adequate reduction in in a less than 1.2-fold increase in obeticholic acid exposure. alkaline phosphatase has not been achieved after 3 months 0756 Treatment with obeticholic acid 10 mg or obet of OCA 5 mg once weekly, and the patient is tolerating the icholic acid titration (5 mg to 10 mg) resulted in clinically drug, the OCA dose should be increased to 5 mg twice meaningful and statistically significant increases (p<0.0001) weekly and then to 5 mg every day depending on response relative to placebo, in the number of patients achieving the and tolerability. primary composite endpoint at all study time points (see 0744 Obeticholic acid is absorbed with peak plasma Table 26). Responses occurred as early as 2 weeks and were concentrations (Cmax) occurring at a median time (timax) of dose dependent (obeticholic acid 5 mg compared with approximately 2 hours. Co-administration with food does obeticholic acid 10 mg at 6 months, p=0.04). not alter the extent of absorption of obeticholic acid. Fol lowing multiple-dose administration of 5, 10, and 25 mg TABLE 26 once daily for 14 days, systemic exposures of obeticholic acid increase dose proportionally. Exposures to glyco-obet Percentage of Patients Achieving Response. icholic acid and tauro-obeticholic acid, and total obeticholic Obeticholic acid it UDCA acid increase more than proportionally with dose. 0745. Following multiple oral doses of OCA 10 mg once Obeticholic acid Obeticholic acid daily, peak plasma concentrations (Cmax) of OCA occurring Titration 10 mg Placebo + UDCA at a median time (Tmax) of approximately 1.5 hours. (N = 70) (N = 73) (N = 73) Median T for glyco-OCA and tauro-OCA is 10 hours. Month 6 0746 Distribution. Human plasma protein binding of Dose 5 mg 10 mg obeticholic acid and its conjugates is greater than 99%. The Responders, 24 (34) 37 (51) 5 (7) volume of distribution of OCA is 613 L. The volume of n (%) distributions of glycol- and tauro-obeticholic acid has not p-value P 0763 There was no apparent association of change of endogenous agonist of FXR and differs from CDCA by the unbound free fraction percentage (% Fu) of OCA and addition of an ethyl group at the 6 carbon position. The tauro-OCA with the increased degree of hepatic impairment. addition of this ethyl group to CDCA confers approximately Mean 96 Fu of glyco-OCA increased in patients with severe 100-fold greater potency compared to CDCA. hepatic impairment. 0768 PBC is a rare chronic autoimmune disease charac Example 11 terized by T-cell mediated destruction of the intrahepatic bile ducts, decreased bile secretion, bile acid retention in the 0764 Obeticholic acid (OCA) is a farnesoid X receptor liver, inflammation, fibrosis, cirrhosis, and liver failure, (FXR) agonist and as shown, inter alia, useful for the followed by either liver transplantation or death. NASH is a treatment of primary biliary cholangitis/cirrhosis (PBC), chronic liver disease often associated with type 2 diabetes or nonalcoholic steatohepatitis (NASH), and other liver dis metabolic syndrome which is defined by presence of hepatic eases. OCA is the 6O-ethyl derivative of chenodeoxycholic Steatosis, inflammation, and cytological ballooning with acid (CDCA). Patients with cirrhosis have systemic bile acid eventual varying degrees of fibrosis and possible cirrhosis exposure higher than those in healthy subjects (x18) while leading to liver transplantation, hepatocellular carcinoma or hepatic bile acid exposure is only ~2x higher. Thus systemic death. In general, chronic injury to the liver can lead to the OCA exposure may not be reflective of OCA concentrations formation of regenerative nodules and fibrous bands in the in the liver or intestine, the primary sites of action. liver that form after an extended process of fibrosis. Cirrho 0765 Plasma levels of OCA and its conjugates were sis causes the interface between the sinusoids and the measured in healthy Subjects and cirrhotic patients with hepatocytes to fill with fibrotic tissue leading to increased US 2017/0035784 A1 Feb. 9, 2017 60 resistance to hepatic blood flow causing portal hypertension with each space possessing a compartment of either CDCA, and its associated complications. Previous reports have glycine-conjugated CDCA (glyco-CDCA), or taurine-con shown that patients with cirrhosis have systemic bile acid jugated CDCA (tauro-CDCA). The model included transfer exposure markedly higher than those in healthy Subjects coefficients describing fluid flow, biotransformation of (18-fold higher) while hepatic bile acid exposure was only chemical entities, and transport across membranes. ~2-fold higher. 0773 Without being bound by any particular theory, due 0769 There are 4 primary mechanisms of hepatic impair to the similar structure of CDCA, OCA was considered to ment that are related to the pharmacokinetics of endogenous have comparable pharmacokinetic properties when com bile acids and OCA: reduced hepatic uptake (caused in part pared to CDCA. This examples describes development of a by capillarization of the sinusoids), portal systemic shunting physiologic PK model to quantitatively describe the absorp (both hepatic and extrahepatic), decreased functional liver tion, distribution, metabolism, and excretion of OCA. In Volume, and increased taurine conjugation. Mild liver dis addition, the model was used to define the effects of hepatic ease may be associated with little or no change in the hepatic impairment to predict the systemic and liver exposure to uptake of bile acids but severe cirrhosis and/or jaundice OCA in subjects with various degrees of liver impairment causes large decreases in the extraction ratio that affects all relative to healthy subjects with normal liver function. The bile acids similarly. Healthy control subjects have hepatic model was developed based on 3 studies in healthy volun uptakes of bile acids of at least 70%. In contrast, values in teers and 2 studies in patients with varying degrees of cirrhotic patients were reduced over a wide range of values hepatic impairment (N-399). with some less than 10%. 0774 All participants in each of the studies were over 18 0770 Portosystemic shunting appears to occur secondary years of age and provided informed consent for willing to the development of portal hypertension. With ongoing participation. The studies were conducted in accordance liver injury, resultant fibrogenesis and the occurrence of with the Declaration of Helsinki (Seoul 2008 Revision) and nodular regeneration, intrahepatic resistance increases. adhered to guidelines for Good Clinical Practices and were When coupled with increased splanchnic blood flow into the approved by all relevant ethics committees. liver that occurs as a result of splanchnic vasodilation in 0775 Data from was used to develop the model in cirrhotics, portal pressures can become elevated and blood is healthy subjects (n=160) and then adjust for hepatic impair shunted through collateral vessels, away from the liver. ment (n=32) using the data from the above Examples. After Portosystemic shunting can occur via either diversion of development, the model was validated with data sourced blood through newly developed veins or via anastomoses from healthy subjects and cirrhotic patients. (“shunts”) formed between existing portal and hepatic veins 0776 The data used in model development included and is associated with higher systemic bile acid concentra Subject identifiers, time of dosing and sample collection, tions. Relative to normal controls, the portal blood flow was plasma drug concentrations (OCA, glyco-OCA, and tauro 91%, 64%, and 55%, for Child-Pugh scores -A, -B, and -C, OCA), dose amount, disease status (e.g., Child-Pugh score), respectively. In response to the decreased portal blood flow and meal consumption information. Study participants to the liver, the hepatic arterial blood flow increased by 41%, received standardized meals at specified times during inpa 63%, and 92% for Child Pugh-A, -B, and -C, relative to tient observation. Gallbladder contraction was assumed to normal controls. This increase in arterial blood flow in last 90 minutes after the start of a meal. Drug concentrations response to decreased portal blood flow is termed hepatic below the limit of quantification (BLO) were imputed to half arterial buffer response and allows for relatively constant of the lower limit of quantification (LLOQ). Observed and blood flow to the liver regardless of portosystemic shunting. BLO concentrations of OCA, glyco-OCA, and tauro-OCA The SimCYP library for cirrhotic subjects uses a decrease of associated with samples drawn prior to the first dose were 89%, 71%, and 61% in functional liver size relative to excluded from the analyses. As the glyco- and tauro-conju control subjects in subjects with Child-Pugh Score-A, -B, gates are nearly equipotent relative to OCA on FXR, total and -C, respectively, based on meta-analyses (SimCYP OCA concentrations were calculated as the sum of OCA, simulator Version 11; Simcyp Limited, Sheffield, UK). glyco-OCA, and tauro-OCA. 0771 Bile acids are metabolized in the liver, primarily by (0777 Concentrations of OCA (420.6 g/mol), glyco-OCA conjugation (N-acylamidation) to the amino acids glycine or (477.7 g/mol), and tauro-OCA (527.8 g/mol) were measured taurine. In healthy humans, a normal adult ratio of glycine from human plasma samples using high performance liquid to taurine bile acid conjugation (“G/T ratio) is 3:1 with a chromatography tandem mass spectrometry (LC-MS/MS) range of 1:1 to 5:1. Dietary intake of taurine increases the (Shimadzu 10AVP HPLC System, Kyoto, Japan; AB MDX proportion of bile acids conjugated with taurine. In contrast, Sciex API-4000 LC-MS/MS System, Framingham, Mass.). oral ingestion of glycine does not change the G/T ratio. The The LLOQ for OCA, glyco-OCA, and tauro-OCA was 0.594 G/T ratio in healthy and disease states appears to be gov nM, 0.523 nM, and 0.474 nM, respectively. erned by the liver as opposed to intestinal control via (0778 The PK model developed for CDCA used 27 preferential deconjugation of glycine conjugated bile acids compartments consisting of 9 spaces with anatomical and by bacteria or preferential conjugate uptake into the entero physiological considerations, each requiring three compart cytes. It has been reported in the literature that the G/T ratio ments to accommodate CDCA, glyco-CDCA, and tauro is decreased in patients with cirrhosis. CDCA. Division of each space into 3 compartments was 0772 A physiologic pharmacokinetic model exists necessary because while flow rates (e.g., blood flow) were describing the metabolism and enterohepatic circulation of independent of chemical structure, biotransformation rates CDCA. The CDCA model included 9 spaces based on (e.g., conjugation and deconjugation) and transport rates anatomical and physiological considerations (systemic cir (e.g., hepatic uptake) differed based on chemical structure. culation, portal circulation, sinusoidal circulation, liver, bile Values for the physiologic compartment Volumes and trans duct, gallbladder, duodenum-jejunum, ileum, and colon) ferrates used in the model were obtained from the literature. US 2017/0035784 A1 Feb. 9, 2017 To construct the PK model for OCA, the physiologic PK TABLE 28 model for CDCA was structurally modified to accurately Model Parameters and Coding Modification associated reflect the interaction of human physiology and OCA. with mechanism of Hepatic Impairment. 0779. A number of structural modifications were made to Anatomical the base CDCA model in order to adapt it for use with OCA. Physiological For simplification, a single space was used to represent the Change Equations gut (Small and large intestines). Since OCA is an exogenous Decreased to = to exp(Effect in Mild hepatic impairment molecule, it was assumed that there was no endogenous hepatic in hepatic uptake of OCA and conjugates) synthesis and an absorption compartment with a first-order uptake to a = to exp(Effect in Moderate hepatic impairment in hepatic uptake of OCA and conjugates) transfer coefficient (K) was included to represent the to see = to exp(Effect in Severe hepatic administration and absorption kinetics of an oral OCA dose. impairment in hepatic uptake of OCA and conjugates) Portal- f = f1.408 for mild hepatic impairment Based on steric hindrance by the 6-ethyl group of OCA, no systemic fate = f*1.625 for moderate hepatic impairment bacterial 7-alpha dehydroxylation biotransformation activity shunting fs = f1.915 for severe hepatic impairment Arterial f = f0.91 for mild hepatic impairment (i.e., CDCA to lithocholic acid) was included in the model. buffer fs are = f&* 0.635 for moderate hepatic impairment Compartment volumes in the model were fixed to physi response fs = f0.554 for severe hepatic impairment Decreased Vive-fit = Vie-eat.0.891 for mild hepatic ological values from the base CDCA model. The OCA functional impairmen model used the physiological flow values for blood, bile and anatomical Viver Moderate = Vierheatriy'O.71 for moderate hepatic gastrointestinal transit from the original physiologic PK liver impairmen volume Vive-severe = Vie-eat. O.61 for severe hepatic model for CDCA, with the exception of flows from bile duct impairmen to gallbladder and from bile duct to gut. The physiological Changes in bi = b exp(Effect of Mild hepatic metabolism impairment on OCA tauro-conjugation) for mild values from the base model led to poor predictions and may conjugation hepatic impairment not be applicable due to the simplification of the enteral b16 are = b 16' exp(Effect of Moderate hepatic impairment on OCA tauro-conjugation) for moderate system into a unified gut compartment. The biotransforma hepatic impairment tion and transport rates in the model, being dependent on base = the exp(Effect of Severe hepatic chemical entity structure, were estimated by fitting the impairment on OCA tauro-conjugation) for severe model to the plasma concentration time profiles of OCA, hepatic impairment glyco-OCA, and tauro-OCA. 0782. For the portal systemic shunting mechanism, the 0780. The PK model was first developed using the OCA, coefficient for portal to sinusoidal flow was progressively glyco-OCA, and tauro-OCA plasma concentration time pro decreased as hepatic impairment worsened and was matched files from healthy volunteers with normal hepatic function. by a progressive increase in flow from the portal to systemic Model parameter estimates related to healthy physiology circulation of equal magnitude. The latter flow does not were then held constant while the PK model was further occur in healthy individuals. To compensate for reduced developed using OCA, glyco-OCA, and tauro-OCA plasma blood flow to the liver, the coefficient for hepatic arterial flow from the systemic circulation to the sinusoids was concentration time profiles from patients with hepatic progressively increased with worsening hepatic impairment impairment (Child-Pugh scores A, B, and C). Only param (i.e., hepatic arterial buffer response). eters specific to hepatic impairment were estimated during 0783 The biotransformation coefficient for conjugation this process. of taurine to OCA was allowed to change for mild, moderate, 0781 Four mechanisms of hepatic impairment were and severe hepatic impairment relative to the coefficient in incorporated into the OCA PK model and included (1) healthy subjects while the coefficient for conjugation to reduction of hepatic uptake, (2) portal systemic shunting, (3) glycine was fixed at the value for healthy individuals. 0784 The OCA physiologic PK model used a population decreased functional Volume, and (4) preferential conjuga PK approach and consisted of a description of the relation tion to taurine. These parameters were incorporated in the ships between plasma drug concentrations and time as well model in a manner allowing the parameter estimates in as components for between Subject and residual variability. Subjects with mild, moderate, and severe hepatic impairment Between subject variability (BSV) was modeled assuming a to progressively deviate relative to the parameter values log-normal distribution as follows: estimated in healthy volunteers. These deviations for the 6-01-,exp(n) portal systemic shunting and decreased functional liver Volume mechanisms used physiological values from the (f... m)-MVN(0,92) Simcyp library for cirrhotic subjects (SimCYP simulator 0785. Where 0 is the population typical value for the Version 11; Simcyp Limited. Sheffield, UK). The deviations n" PK parameter (e.g., clearance) and m, (ETA) is the for the reduced hepatic uptake and change in OCA conju random BSV on the n" parameter for subject i that jointly follow a multivariate normal distribution (MVN) with a gation mechanisms were estimated based on fitting of the mean of Zero and variance of S2. The BSV model assumes plasma drug concentration time profiles from Subjects with that PK parameters are log-normally distributed. Due to the hepatic impairment. Table 28 lists the model parameters and high level of model complexity, BSV was only incorporated coding modifications associated with the four mechanisms on K, and the flow rate from gallbladder to gut, both of hepatic impairment. parameters that analysis showed had substantial impact on US 2017/0035784 A1 Feb. 9, 2017 62 the plasma concentration time profiles. Residual variability the proportional portion ranged from 72% to 88% (30-70% was assumed to have additive and proportional components: CV) for OCA and its conjugates. The pcVPC results shown in FIG. 25A, FIG. 25B, FIG. 25C, and FIG. 25D and the goodness of fit plots shown in FIG. 18 and FIG. 19 indicate 10786) Where y, and y, represent the i" observed and acceptable model performance. predicted plasma drug concentration for the i' subject and e is the random residual variability. Each e is normally dis TABLE 29 tributed with a mean of zero and a variance of of. Distinct residual variability components were estimated for OCA, Model Parameters in Normal Hepatic Function glyco-OCA, and tauro-OCA. BSV 0787 Model development was guided by feedback from Parameter Parameter Description Estimate CV 9% (RSE '%) various diagnostic plots including: observed OCA, glyco (L/h) Hepatic arterial flow 14.4 Fixed NA OCA, and tauro-OCA versus population prediction (PRED) (L/h) Hepatic portal flow 39.6 Fixed or individual prediction (IPRED) with a line of unity and o (h) OCA transport rate from 1698 1.O trend line, conditional weighted residuals (CWRES) of iver to sinusoidal space OCA, glyco-OCA, and tauro-OCA versus PRED or time, o (h) Glyco-OCA transport rate 1210 2.0 rom sinusoidal space to and prediction-corrected visual predictive checks (pcVPC; iver 200 iterations). 11 (h) Tauro-OCA transport rate 1615 1.9 0788. A simulation with 200 replicates was performed rom sinusoidal space to iver based on Subjects in the phase 1 hepatic impairment study 1s (h) OCA transport rate from 1.62 Fixed using the OCA physiologic PK model. Dosing and meal sinusoidal space to liver consumption history were used to simulate rich 0 to 216 2 (h) Glyco-OCA and tauro-OCA 1.62 Fixed hour concentration-time profiles of OCA, glyco-OCA, and ransport rate from liver tauro-OCA. Total OCA was calculated for each observation o sinusoidal space 24 (L/h) Flow from bile duct to gut 7.29 4.5 by Summing the molar-based concentrations for OCA, 22 (L/h) Flow from bile duct to O.856 4.4 78.1% glyco-OCA, and tauro-OCA. Total OCA concentrations gallbladder (19.3) from the systemic circulation and liver were subjected to 23 (h') Rate of output from 1.2 Fixed NA gallbladder to gut non-compartmental analysis to calculate C, and AUCo. k (L/h) Rate of fecal elimination O612 5.5 2167). of OCA 0789 Phoenix(R) NLMETM software version 1.3 (Certara bis(h) OCA rate of conjugation 1.44 4.5 with glycine Inc., Princeton, N.J.) was used for the physiologic popula big (h) OCA rate of conjugation O.312 1.9 tion PK analysis and simulations with Lindstrom-Bates with taurine First-order Conditional Estimation (FOCE-LB). Analysis bag (h) Glyco-OCA rate of O.0431 4.5 datasets, visualizations, and exploratory analyses were cre deconjugation to OCA bs, (h) Tauro-OCA rate of O.O2OO 1.8 ated using R software version 3.1 (The R Foundation) and deconjugation to OCA SAS version 9.4 (SAS Institute Inc., Cary, N.C.). GraphPad (h) OCA rate of absorption 0.857 3.4 Prism software version 6.07 (Graphpad Software Inc., La from gut to portal space Jolla, Calif.) was used for the generation of Some graphical (h) Glyco-OCA rate of O904 1.1 analyses. absorption from gut to portal space 0790. The OCA physiologic PK model was initially s (h) Tauro-OCA rate of 1.62 2.2 developed using 8248 plasma sample concentrations of absorption from gut to OCA, glyco-OCA, and tauro-OCA from 160 healthy vol portal space K. (h) OCA first order rate 5.32 1.O 195% unteers administered 10 mg OCA in a cross-over design. constant of oral (2.21) Each subject contributed PK samples from both study peri absorption ods. The healthy volunteer pool had normal hepatic func 19 (h) Glyco-OCA transport rate 7:44 0.7 NA tion, was primarily male (59%), mean (SD) age was 37.0 from liver to bile duct 2 (h) Tauro-OCA transport rate 9.28 1.O (9.8) years, and mean (SD) weight was 76.4 (11.8) kg. from liver to bile duct Volunteers were 65.6% white, 32.5% black, 0.6% Asian, and Proportional Error OCA (%) 88.0 33.9 NA 1.3% other. The percentage of BLO samples with imputed Proportional Error Glyco-OCA (%) 62.6 32.7 concentrations was 38.2%, 9.4%, and 24.4% for OCA, Proportional Error Tauro-OCA (%) 71.6 704 Additive Error OCA (nM) OS46 16.5 glyco-OCA, and tauro-OCA, respectively. Additive Error Glyco-OCA (nM) 0.675 21.8 0791. The healthy PK model contained a total of 22 Additive Error Tauro-OCA (nM) O469 S.O.3 parameters: 7 flow parameters, 4 biotransformation param eters, and 11 transport parameters (Table 29). Many of these were expected to have values specific to exogenous OCA 0792 Development of the PK model for the physiologi (e.g., hepatic uptake) or did not exist in the base model (e.g., cal changes associated with hepatic impairment used 928 K or K) and thus required estimation. Most of the flow plasma sample concentrations of OCA, glyco-OCA, and parameters were fixed to physiological values from the tauro-OCA from 32 subjects-8 subjects each with mild, literature with the exception of bile duct to gallbladder and moderate, severe hepatic impairment and normal hepatic from bile duct to gut. All structural parameters (Table 29) function. Subjects were administered a single 10 mg dose of were well estimated (<5.5% CV). The BSV for flow from OCA. The study subjects were primarily male (72%), had a bile duct to gallbladder was 78.1% (19.3% CV) and for the mean (SD) age of 55.0 (5.6) years, and mean (SD) body oral absorption of OCA was 195% (2.21% CV). The additive weight was 81.7 (16.9) kg. Participants were 90.6% white, portion of residual variability was s1 nM (15-50% CV) and 3.1% black, 3.1% Asian, and 3.1% other. Mean Child-Pugh