US010376507B2 (12 ) United States Patent (10 ) Patent No. : US 10 , 376 , 507 B2 Srinivasan et al. (45 ) Date of Patent: Aug. 13 , 2019

CRESEMBA® ( isavuconazonium sulfate) , Highlights of Prescrib (54 ) METHOD OF TREATING A PATIENT WITH ing Information , Label ; Patient Information approved by the U . S . A CYP3A4 SUBSTRATE DRUG Food and Drug Administration ; Astellas Pharma US , Inc. ( Licensed from Basilea Pharmaceutics International Ltd . ) , Illinois, USA , Ini (71 ) Applicant: Bow River LLC , Corona Del Mar , CA tial U . S . Approval: 2015 , Revised Mar. 2015 , Reference ID : 3712237, ( US ) 28 pages . DIFLUCAN® ( fluconazole ), Label ; Patient Information , Reference ( 72 ) Inventors : Sundar Srinivasan , Corona Del Mar, ID : 3650838 , Roerig , Division of Pfizer Inc ., New York , NY, Revised Mar. 2013 , 35 pages. CA (US ) ; Christina Chow , Seattle , WA NIZORAL® (ketoconazole )Label ; Patient Information approved by (US ) the U . S . Food and Drug Administration , Reference ID : 3458324 , Copyright 2014 Janssen Pharmaceuticals, Inc . , New Jersey, USA , ( 73 ) Assignee : BOW RIVER LLC , Corona del Mar , Revised Feb . 2014 , 23 pages . NOXAFIL® (posaconazole ) , Highlights of Prescribing Informa CA (US ) tion , Label; Patient Information approved by the U . S . Food and Drug Administration ; Copyright © 2006 , 2010 , 2013 , 2014 Merck ( * ) Notice : Subject to any disclaimer, the term of this Sharp & Dohme Corp . , a subsidiary of Merck & Co ., Inc ., New patent is extended or adjusted under 35 Jersey , USA , Revised Sep . 2016 , Reference ID : 3983525, 37 pages . U . S . C . 154 (b ) by 0 days. ORAVIG® (miconazole ) , Highlights of Prescribing Information , Label ; Patient Information approved by the U . S . Food and Drug Administration ; Copyright 2012 Praelia Pharmaceuticals , Inc . , North (21 ) Appl. No. : 15/ 596 ,585 Carolina, USA (Manufactured For: Vestiq Pharmaceuticals , Inc. , North Carolina , USA ) , Initial U . S . Approval: Jan . 1974 , Revised ( 22 ) Filed : May 16 , 2017 Aug. 2012 , Reference ID : 3270873 , 2 pages. SPORANOX® ( itraconazole ), Label; Patient Information approved (65 ) Prior Publication Data by the U . S . Food and Drug Administration , Reference ID : 4071289 , Copyright 2001 Janssen Pharmaceutical Companies, New Jersey , US 2018 /0333409 A1 Nov. 22 , 2018 USA , Revised Mar. 2017 , 40 pages . VFEND® (voriconazole ), Highlights of Prescribing Information , (51 ) Int. Ci. Label ; Patient Information approved by the U . S . Food and Drug A61K 31 /496 ( 2006 .01 ) Administration , Roerig , Division of Pfizer Inc ., New York , NY, Initial U . S . Approval : 2002 , Revised Feb . 2015 , Reference ID : A61K 31/ 4985 ( 2006 . 01 ) 3696601 , 42 pages. A61K 31/ 495 ( 2006 .01 ) “ Drug Development and Drug Interactions: Table of Substrates, (52 ) U .S . CI. Inhibitors , and Inducers .” US Food and Drug Administration . Avail able at : https: / /www . fda . gov /drugs /developmentapprovalprocess / CPC ...... A61K 31/ 496 (2013 .01 ) ; A61K 31/ 495 developmentresources /druginteractionslabeling /ucm093664 . htm (2013 .01 ) ; A61K 31/ 4985 (2013 .01 ) Accessed Dec . 13, 2017 , 16 pages . ( 58 ) Field of Classification Search Center for Drug Research and Evaluation , Food and Drug Admin None istration . Application No . 2075000rigls000 / 2075010rigls000 . See application file for complete search history. Clinical Pharmacology and Biopharmaceutics Review ( s ) .NDA207500 ( Trade Name: Cresemba , Generic Name: Isavuconazonium sulfate ) , Dosage Form / Strength : Capsules / 186 . 3 mg of isavuconazonium ( 56 ) References Cited sulfate ( equivalent to 100 mg isavuconazole ) , Submission Date : Jul. U .S . PATENT DOCUMENTS 8 , 2014 ( Original Submission ), Sep . 26 , 2014 ( Sequence 0006 ) , Oct . 8 , 2014 ( Sequence 0008 ) , Dec . 11 , 2014 (Sequence 0015 ), Dec . 18 , 2014 /0221424 AL 8 / 2014 Zha 2014 ( Sequence 0017 ) , Date of Review : Dec . 23 , 2014 , Reference 2014 / 0350060 A1 * 11/ 2014 Bradford ...... A61K 31/ 15 ID : 3606431. Available at: https :/ /www .accessdata .fda . gov/ drugsatfda _ 514 / 345 docs/ nda /2015 /2075000rig12075010rig1s000ClinPharmR . pdf 2017 /0100331 A1 4 /2017 Klein et al . Accessed Dec. 13 , 2017 , 78 pages . 2017 / 0258720 A19 / 2017 Pottier et al . 2018 / 0333410 AL 11/ 2018 Srinivasan et al . ( Continued ) 2018 /0333411 AL 11/ 2018 Srinivasan et al . 2019 /0076425 A1 3 / 2019 Srinivasan et al. Primary Examiner — Jeffrey S Lundgren Assistant Examiner — William Y Lee FOREIGN PATENT DOCUMENTS ( 74 ) Attorney , Agent, or Firm — Cooley LLP WO WO 2007 / 140299 A2 12 / 2007 WO WO - 2007140299 A2 * 12 /2007 . . . . A61K 31427 (57 ) ABSTRACT WO WO 2017 / 165635 AL 9 / 2017 The present disclosure provides for methods of treating a WO WO 2018 /089687 A1 5 /2018 patient with a CYP3A4 substrate drug contraindicated for WO WO 2018 /212764 A1 11 / 2018 concomitant administration with a strong CYP3A4 inhibitor, wherein the patient is treated with multiple doses of posa OTHER PUBLICATIONS conazole , stops posaconazole treatment, and then is treated Bawa et al. ( Innovations in Clinical Neuroscience 2015 ; 12 ( 1 - 2 ) : with the CYP3A4 substrate drug . In some embodiments , 21 - 23 ) . * treatment with the CYP3A4 substrate drug is delayed for Brill et al. ( Clin Pharmacokinet 2012 : 51 (5 ): 277 - 304 ). * about 2 -21 after stopping posaconazole . In some embodi Krishna et al . ( Clinical Therapeutics /vol . 31, No . 2 , 2009 , pp . ments , the patient is treated with or prescribed a reduced 286 - 298 ). * dose of the CYP3A4 substrate drug for about 2 - 21 after Loebel et al. ( Am J Psychiatry. Feb . 2014 ; 171 ( 2 ) : 160 - 8 ). * stopping posaconazole . Roxane Laboratories , Inc. v . Vanda Pharmaceuticals Inc ( " Vanda ” ) , Case IPR2016 -00690 , PTAB decision , Aug. 30 , 2016 ( Year : 2016 ). * 17 Claims, No Drawings US 10 ,376 ,507 B2 Page 2

References Cited City, CA 94404 , Revised Jan . 2016 , Initial U . S . Approval: 2006 , ( 56 ) Reference ID : 3869690 , 23 pages . Ta, C ., et al ., “ Predicting Interactions with PDE5 Inhibitors ." Pharmacy Times ( 2005 ) ; pp . 16 and 28 , 2 pages . OTHER PUBLICATIONS TARCEVA® (erlotinib ) , Highlights of Prescribing Information , Label ; Patient Information ; NDA021743, Copyright © 2016 Astel Lipp , Hans- Peter ,“ Clinical pharmacodynamics and pharmacokinet las Pharma US, Inc. , and Genentech , Inc ., Initial U .S . Approval: ics of the antifungal extended -spectrum triazole posaconazole: an 2004 , Revised Oct. 2016 , 29 pages. overview .” British Journal of Pharmacology ( 2010 ) ; 70 (4 ) : 471 -480 . VESIcare® (solifenacin succinate ) , Highlights of Prescribing Infor Lempers , et al. , “ Inhibitory Potential of Antifungal Drugs on mation , Label ; Patient Information ; NDA021518 , Astellas Pharma ATP - Binding Cassette Transporters P -Glycoprotein , MRP1 to MRP5 , US , Inc ., Initial U . S . Approval: 2004 , Revised Mar. 2017 , 22 pages. BCRP, and BSEP. ” Antimicrob . Agents Chemother. (2016 ); 60 (6 ): ZORTRESS® ( everolimus ) , Highlights of Prescribing Information , 3372 - 3379 . Label; Patient Information ; NDA021560 , Novartis Pharmaceuticals Miceli, M . H . , et al ., " Serum posaconazole levels among haematologi Corporation , Initial U . S . Approval: 2010 , Revised Oct. 2016 , 42 pages . cal cancer patients taking extended release tablets is affected by Chiu , et al. , “ Lurasidone drug -drug interaction studies : a compre body weight and diarrhoea : single centre retrospective analysis ." hensive review .” Drug Metab Drug Interact ( 2014 ) ; 29 ( 3 ) : 191 - 202. Mycoses (2015 ) ; 58 ( 7 ) : 432 - 436 . LATUDA ( lurasidone ) , 18 . 5 mg film -coated tablets , 37 mg film Sandherr and Maschmeyer, “ Pharmacology and metabolism of coated tablets , 74 mg film - coated tablets ; Package Leaflet, Infor voriconazole and posaconazole in the treatment of invasive aspergil mation for the patient, European Medicines Agency , Revised : Mar. losis review of the literature .” European Journal ofMedical Research 2018 ; Marketed by LAziende Chimiche Riunite Angelini Francesco ( 2011 ) ; 16 : 139 - 144 . A . C . R . A . F . S . p . A ., Rome, Italy , Manufactured by Anderson Brecon AFINITOR® Prescribing Information, published 2010 . ( Year : 2010 ), (UK ) Ltd . , 7 pages. 25 pages . Payne and Hall, “ Dosing of antifungal agents in obese people .” TARCEVA® Prescribing Information , published 2010 . ( Year : 2010 ) , Expert Review of Anti - infective Therapy ( 2016 ) ; 14 ( 2 ) : 257 - 267 . 24 pages. Li, et al. , “ Pharmacokinetic /pharmacodynamic profile of posaconazole. " VESIcare® Prescribing Information , published 2009 . ( Year : 2009 ), Clin Pharmacokinet . ( 2010 ) ; 49( 6 ) : 379 - 396 . 16 pages. U . S . Department of Health and Human Services, Food and Drug International Search Report and Written Opinion in International Administration . Guidance for Industry . “ E14 Clinical Evaluation of Application No. PCT/ US2017 /032924 , dated Aug . 28 , 2017 , 11 QT / QTc Interval Prolongation and Proarrhythmic Potential for pages . Non - Antiarrhythmic Drugs. ” (Oct . 2005 ) ; 20 pages. Available at: AFINITOR® ( everolimus ), Highlights of Prescribing Information , https : / / www . fda. gov / downloads / Drugs / Label ; Patient Information ; NDA203985, Novartis Pharmaceuticals GuidanceComplianceRegulatoryInformation Guidances /UCM073153 . Corporation , Initial U .S . Approval: 2009, Revised Jun . 2016 , 79 pdf. (Accessed : Jan . 31 , 2018 ) . pages . International Search Report and Written Opinion in International Bawa and Scarff , “ Lurasidone : A New Treatment Option for Bipolar Application No. PCT/ US2018 /061141 , dated Jan . 25 , 2019 , 14 Depression - A Review .” Innov Clin Neurosci. (2015 ) ; 12 ( 1- 2) : pages . 21 - 23 . Chow , et al. , “ Persistence of a Posaconazole -Mediated Drug -Drug Brill , M . J . E ., et al. , “ Impact of Obesity on Drug Metabolism and Interaction With Ranolazine After Cessation of Posaconazole Admin Elimination in Adults and Children .” Clinical Pharmacokinetics istration : Impact of Obesity and Implications for Patient Safety .” J ( 2012 ) ; 51( 5 ) : 277 - 304 . Clin Pharmacol. (Nov . 2018 ) ; 58 ( 11 ) : 1436 - 1442 . Epub May 11 , Masters , J . C ., et al ., “ Drug Interaction between Sirolimus and 2018 . Ranolazine in a Kidney Transplant Patient. ” Case Reports in Trans Greenblatt , et al. , “ Sustained Impairment of Lurasidone Clearance plantation (2014 ) ; vol. 2014 , Article ID 548243 , 4 pages . After Discontinuation of Posaconazole .” J . Clin . Psychopharmacol. RANEXA® ( ranolazine ) , Highlights of Prescribing Information , (2018 ) ; 38 : 289 - 295 . Label ; Patient Information approved by the U . S . Food and Drug Administration ; Copyright © 2016 Gilead Sciences , Inc . , Foster * cited by examiner US 10 , 376 ,507 B2

METHOD OF TREATING A PATIENT WITH azole , CYP3A4 substrate drugs cannot always be safely A CYP3A4 SUBSTRATE DRUG administrated immediately after a patient has stopped posa conazole treatment. Applicants have discovered that posa BACKGROUND conazole accumulation in the body of patients, particularly 5 for specific patient populations as described herein , can Posaconazole , also called Noxafil and Posanol , is indi- result in serious and potentially life - threatening side effects cated for the prophylaxis of invasive Aspergillus and Can - if a CYP3A4 substrate drug is administered too soon , dida infections in patients who are at high risk of developing subsequent to the cessation of a posaconazole regimen . these infections due to being severely immunocompromised , Accordingly , for CYP3A4 substrate drugs , particularly those such as hematopoietic stem cell transplant (HSCT ) recipi- 10 contraindicated for coadministration with a strong CYP3A4 ents with graft - versus -host disease (GVHD ) or those with inhibitor ( including but not limited to posaconazole ) , a hematologic malignancies with prolonged neutropenia from washout or delay period of about 2 -21 days between ceasing chemotherapy , for the treatment of oropharyngeal candidi- administration of the posaconazole regimen and starting asis (OPC ) , including OPC refractory (rOPC ) to itracon - administration of the CYP3A4 substrate drug is required in azole and /or fluconazole , the treatment of invasive aspergil - 15 order to avoid or reduce the incidence of side effects losis , and the treatment of zygomycosis . Posaconazole has resulting from administration of the CYP3A4 substrate drug . also been used “ off - label” for treating allergic bronchopul Alternatively , rather than delaying administering the monary aspergillosis ; prophylaxis or treatment of recurrent CYP3A4 substrate drug after ceasing administration of the candidiasis for the esophagus , secondary to HIV infection ; posaconazole regimen , in some embodiments , the Appli Fusarium infectionsmycosis ; and chronic or cavitary necro - 20 cants have discovered that patients can safely be adminis tizing pulmonary aspergillosis . tered a reduced dose of the CYP3A4 substrate drug ( reduced Posaconazole is a strong inhibitor of the CYP3A4 relative to the recommended dose of the CYP3A4 substrate enzyme, a member of the cytochrome P450 family of drug ) for a period of time (about 2 - 21 days ) following oxidizing enzymes found in the liver . These Cytochrome cessation of the posaconazole regimen , after which the dose P450 enzymes , such as CYP3A4 , oxidize small organic 25 of the CYP3A4 substrate drug can be safely increased to the molecules in the body, such as toxins or certain drugs, recommended level. thereby deactivating and /or degrading them . Organic mol - In certain embodiments , the disclosed methods of delay ecules in the body (such as a drug ) which are primarily ing treatment with a CYP3A4 substrate drug , or reducing the oxidized by a particular enzyme can be referred to as dose of a CYP3A4 substrate drug , for about 2 - 21 days after “ substrates ” for the relevant enzyme. A drug which is 30 ceasing administration of a posaconazole regimen are primarily oxidized by the CYP3A4 enzyme can be referred directed to a normal patient, e . g. , non -obese patients and to as a “ CYP3A4 substrate drug ." normal CYP3A4 metabolizers . In certain embodiments, the The Noxafil label specifically contraindicates the co disclosed methods of delaying treatment of a CYP3A4 administration of CYP3A4 substrate drug with specific substrate drug , or reducing the dose of a CYP3A4 substrate drugs metabolized by CYP3A4 such as sirolimus, CYP3A4 35 drug , for about 2 -21 days after ceasing administration of a substrates such as pimozide and quinidine , HMG -CoA posaconazole regimen are directed to patients having spe Reductase Inhibitors primarily metabolized through cific physiological characteristics as described herein . Such CYP3A4 , and ergot alkaloids, and indicates that dosage patients can exhibit a substantially greater exposure to the adjustments should be considered when concomitantly CYP3A4 substrate drug after ceasing administration of a administering posaconazole with other drugs metabolized 40 posaconazole regimen than was previously known , and by CYP3A4, including Tacrolimus, cyclosporine , vinca therefore after ceasing administration of posaconazole , alkaloids such as vincristine and vinblastine , and calcium require substantially longer “ washout” periods prior to start channel blockers such as verapamil, diltiazem , nifedipine , ing treatment of a CYP3A4 substrate drug, or require nicardipine , and felodipine . However, while the Noxafil treatment of a reduced dose of the CYP3A4 substrate drug label does identify specific drug - drug interactions related to 45 for a substantially longer period in order to avoid or reduce concomitant administration of posaconazole and CYP3A4 the incidence of side effects associated with treatment of the substrate drugs, it does not indicate any concerns regarding CYP3A4 substrate drug . More specifically , the present the administration of CYP3A4 substrate drugs after ceasing applicants have found that patients having specific physi the administration of posaconazole . ological characteristics as described herein exhibit higher The present inventors have surprisingly discovered that a 50 than expected exposure to a CYP3A4 substrate drug dosed delay in administration of a CYP3A4 substrate drug , or in after ceasing administration of a posaconazole regimen , some instances a dose adjustment of a CYP3A4 substrate compared to “ normal” patients ( e . g . , a patient who is oth drug for a specified time interval is required after ceasing the erwise the same except for having specific physiological administration of posaconazole in order to prevent or reduce characteristics as described herein ) . For example , patients the incidence of dangerous side effects of the CYP3A4 55 with e . g . , BMI values in the “ normal” range (about 18 .5 substrate drug . 24 . 9 ) can exhibit substantially reduced CYP3A4 substrate drug elimination , such patients may be described as poor or SUMMARY OF THE INVENTION intermediate CYP3A4 metabolizers. Thus , as disclosed herein , the present inventors have found that specific patient The present disclosure provides for methods of treating a 60 populations may require substantially different and longer patient with a CYP3A4 substrate drug contraindicated for washout periods after ceasing administration of posacon concomitant administration with a strong CYP3A4 inhibitor , azole and prior to starting treatment with a CYP3A4 sub wherein the patient was previously administered a therapeu strate drug , or alternatively treating with a reduced dose of tically effective regimen of posaconazole. a CYP3A4 substrate drug for a particular period of time after Applicants have discovered that although CYP3A4 sub - 65 stopping posaconazole treatment . strate drugs are generally only contraindicated for coadmin - In various embodiments , the present disclosure provides istration with strong CYP3A4 inhibitors , such as posacon - for methods of treating a patient by delaying a first use of a US 10 ,376 , 507 B2 CYP3A4 substrate drug until about 2 -21 days after stopping advanced or metastatic , advanced renal cell carcinoma administration of posaconazole . In embodiments , the (RCC ) , e . g . , after failure of treatment with sunitinib or CYP3A4 substrate drug is a drug contraindicated for con sorafenib , renal angiomyolipoma and tuberous sclerosis comitant use with a strong CYP3A4 inhibitor , such as but complex ( TSC ) , not requiring immediate surgery, TSC in not limited to posaconazole. Accordingly, in various 5 patients who have subependymal giant cell astrocytoma embodiments , the present disclosure provides for methods (SEGA ) that require therapeutic intervention but are not candidates for surgical resection , type 2 diabetes mellitus in of treating a patient who has previously been treated with adults as an adjunct to diet and exercise to improve glycemic multiple doses of posaconazole, with a CYP3A4 substrate control, major depressive disorder (MDD ) , thrombotic car drug contraindicated for concomitant treatment with a strong diovascular events ( e . g ., cardiovascular death , myocardial CYP3A4 inhibitor, said method comprising first treating the 10 infarction , or stroke ) in patients with acute coronary syn patient, or prescribing the first treatment to begin , with a drome (ACS ) , stroke and systemic embolism in patients dose of the CYP3A4 substrate drug at least 2 - 21 days after with nonvalvular atrial fibrillation , deep vein thrombosis stopping a posaconazole treatment . (DVT ) , which may lead to pulmonary embolism (PE ) in In various embodiments , the present disclosure provides patients who have undergone hip or knee replacement sur for methods of treating a patient, or prescribing the first 15 gery , DVT, PE , recurrent DVT and PE following initial treatment to begin , with a CYP3A4 substrate drug at a dose therapy, moderate to severe active rheumatoid arthritis in which is less than or equal to about 50 % of the reference patients who have had inadequate response or tolerance to dose , e . g ., for a period of at least about 2 - 21 days after methotrexate , acute migraine with or without aura , chronic stopping posaconazole treatment. Accordingly , in various phase and accelerated phase Philadelphia chromosome posi embodiments , the methods include treating , or prescribing 20 tive chronic myeloid leukemia (Ph + CML ) in newly diag the first treatment to begin , with a therapeutically effective nosed patients or in patients resistant to or intolerant to prior amount of a CYP3A4 substrate drug contraindicated for therapy that included imatinib , atrial fibrillation (AF ) in concomitant use with a strong CYP3A4 inhibitor to a patient patients with a history of paroxysmal or persistant AF or in need thereof. In some embodiments , the patient has atrial flutter (AFK ) , who are in sinus rhythm or will be previously been treated with posaconazole . In some embodi- 25 cardioverted , asthma in patients aged 4 years and older, ments , the patient is treated , or prescribed to be treated , with airflow obstruction and reducing exacerbations in patients a CYP3A4 substrate drug at a dose which is no more than with chronic obstructive pulmonary disease , erectile dys about 50 % of the reference dose for at least about 2 - 21 days function (ED ) , benign prostatic hyperplasia (BPH ) , pulmo after discontinuation of the posaconazole regimen . nary arterial hypertension ( PAH ) (WHO Group 1 ) to In various embodiments , the present disclosure provides 30 improve exercise ability , gout flares , Familial Mediterranean for methods of treating patients , or prescribing treatment for favorfever , antiretroviral therapy, anxiety disorders , panic disor patients , having a disease or condition selected from the ders , seizures , insomnia , hypertension , cardiovascular dis group consisting of schizophrenia in adults and adolescents ease , hyperlipidemia , cancer, such as primary kidney cancer , ( 13 to 17 years ) , depressive episodes associated with Bipolar advanced primary liver cancer , radioactive iodine resistant I Disorder (bipolar depression ) in adults , monotherapy or 35 advanced thyroid carcinoma , renal cell carcinoma, imatinib adjunctive therapy with lithium or valproate , chronic angina , resistant gastrointestinal stromal tumor, mantle cell lym cystic fibrosis in patients 6 years and older who are homozy phoma in patients who have received at least one prior gous for the F508del mutation in the CFTR gene, chronic therapy, chronic lymphocytic leukemia / small lymphocytic lymphocytic leukemia in patients with 17p deletion , who lymphoma, chronic lymphocytic leukemia /small lympho have received at least one prior therapy , unresectable or 40 cytic lymphoma with 17p deletion , Waldenström ' s macro metastatic liposarcoma or leiomyosarcoma in patients who globulinemia , marginal zone lymphoma who require sys received a prior anthracycline - containing regimen , temic therapy and have received at least one prior anti advanced or metastatic breast cancer in postmenopausal CD20 -based therapy, unresectable or metastatic melanoma women with hormone receptor (HR ) -positive , human epi- with a BRAF V600E or V600K mutation , allergies , and dermal growth factor receptor 2 (HER2 ) - negative advanced 45 transplantation . In some embodiments , the methods include or metastatic breast cancer, negative advanced or metastatic treating the disease or condition with a CYP3A4 substrate breast cancer in combination with an aromatase inhibitor for drug which is contraindicated for concomitant use with a postmenopausal women , Duchenne muscular dystrophy strong CYP3A4 inhibitor, wherein the patient is also in need (DMD ) , secondary hyperparathyroidism (HPT ) in patients of treatment with a strong CYP3A4 inhibitor ( i . e . , posacon with chronic kidney disease (CKD ) on dialysis , hypercal- 50 azole ) . In some embodiments , the methods include (a ) cemia in patients with parathyroid carcinoma or in patients delaying a first treatment of the CYP3A4 substrate drug for with primary HPT for who parathyroidectomy would be at least about 2 -21 days after stopping posaconazole ; and indicated on the basis of serum calcium levels , but who are then ( b ) treating , or prescribing a first treatment, with the unable to undergo parathyroidectomy, hallucinations and CYP3A4 substrate drug . In other embodiments , the methods delusions associated with Parkinson ' s disease psychosis , 55 include (a ) delaying a first treatment of the CYP3A4 sub schizophrenia , acute manic or mixed episodes associated strate drug for at least about 2 - 21 days after stopping with bipolar I disorder , chronic hepatitis C (CHC ) infection administration of the posaconazole regimen , and then ( b ) as a component of a combination antiviral treatment regimen treating or prescribing a first treatment the CYP3A4 sub with peginterferon alfa and ribavirin in HCV genotype 1 strate drug at a dose which is less than or equal to about 50 % infected subjects with compensated liver disease , postmeno - 60 of the reference dose for at least about 2 - 21 days after pausal women with advanced hormone receptor- positive , stopping administration of the posaconazole regimen . HER2 -negative breast cancer (advanced HR + BC ), e. g ., in combination with exemestane after failure of treatment with DETAILED DESCRIPTION letrozole or anastrozole , progressive neuroendocrine tumors of pancreatic origin (PNET ) , progressive , well -differenti - 65 All documents , including patents , applications, and non ated , non - functional neuroendocrine tumors (NET ) of gas - patent publications cited herein are incorporated herein in trointestinal (GI ) or lung origin that are unresectable , locally their entireties for all purposes. US 10 ,376 , 507 B2 6 As used herein , the term “ about ” refers to an amount treated with the strong CYP3A4 inhibitor ( e. g ., posacon somewhat more or less than the stated parameter value , for azole ). For example, when the CYP3A4 substrate drug is example plus or minus five or ten percent of the object that ranolazine, the “ normal baseline Cmax ” of ranolazine refers " about” modifies , or as one of skill in the art would to the average Cmax of ranolazine measured at the same recognize from the context ( e . g . , approximately 50 % of the 5 dosage of ranolazine in an otherwise identical patient which interval between values ). The term “ about" also includes the was not previously treated with the strong CYP3A4 inhibitor value referenced . For example , a BMI of about 40 includes (e . g ., posaconazole ). As another example , when the 40 , as well as values somewhat below or above 40 . CYP3A4 substrate drug is lurasidone, the “ normal baseline As used herein , the term " patient” refers to a human C mar " of lurasidone refers to the average of lurasidone subject . In some embodiments , the patient can be a male or 10 measured at the same dosage of lurasidone in an otherwise a female . In some embodiments , the patient can be an adult , identical patient which was not previously treated with the or a pediatric patient. strong CYP3A4 inhibitor ( e . g . , posaconazole ) . As another As used herein “ treating or " prescribing ” as it pertains to example , when the CYP3A4 substrate drug is tadalafil , the the CYP3A4 substrate drug during the 2 -21 day period after " normal baseline C ” of tadalafil refers to the average ceasing posaconazole treatment, refers to the overall thera - 15 Cmor of tadalafil measuredmax at the same dosage of tadalafil in peutic regimen of the CYP3A4 substrate drug . For example , an otherwise identical patient which was not previously a patient may be prescribed or administered ( including treated with the strong CYP3A4 inhibitor (e . g ., posacon self- administering ) a reduced dose of the CYP3A4 substrate azole ) . drug ( e . g . , no more than about 50 % of the reference dose of As used herein , the term “ normal baseline AUC ” refers to the CYP3A4 substrate drug ) during this period . In some 20 the average AUC of a drug measured at the same dosage in embodiments , the patient would not be administered , or an otherwise identical patient which was not previously would , in the physician ' s prescribed dosing regimen , be treated with the strong CYP3A4 inhibitor ( e . g ., posacon advised not to take the CYP3A4 substrate drug during the azole ). For example , when the CYP3A4 substrate drug is 2 - 21 day period ; afterwards , the patient could (or would be ranolazine , the “ normal baseline AUC ” of ranolazine refers prescribed to ) resume taking e . g ., the reference amount of 25 to the average AUC of ranolazine measured at the same the CYP3A4 substrate drug . dosage of ranolazine in an otherwise identical patient which As used herein , the terms " treating, " " treatment" and was not previously treated with the strong CYP3A4 inhibitor “ treat” include ( i) preventing a particular disease or disorder ( e . g . , posaconazole ) . As another example , when the from occurring in a subject who may be predisposed to the CYP3A4 substrate drug is lurasidone , the “ normal baseline disease or disorder but has not yet been diagnosed as having 30 AUC ” of lurasidone refers to the average AUC of lurasidone it ; (ii ) curing , treating , or inhibiting the disease , i . e . , arrest measured at the same dosage of lurasidone in an otherwise ing its development ; or (iii ) ameliorating the disease by identical patient which was not previously treated with the reducing or eliminating symptoms, conditions, and / or by strong CYP3A4 inhibitor ( e . g . , posaconazole ) . As another causing regression of the disease . In some embodiments , example , when the CYP3A4 substrate drug is tadalafil, the " treating , " " treatment” and “ treat” may include administer - 35 " normal baseline AUC ” of tadalafil refers to the average ing a therapeutically effective regimen as defined herein . AUC of tadalafil measured at the same dosage of tadalafil in As used herein , a " therapeutically effective regimen ” an otherwise identical patient which was not previously refers to a treatment regimen of a duration and dosage treated with the strong CYP3A4 inhibitor ( e. g ., posacon sufficient to treat a disease or condition for which a drug is azole ) . prescribed . 40 As used herein , “ normal, ” “ reference , " or other deriva As used herein , a “ patient” refers to human subject that tions or variations thereof refers to a non -obese state in a has an indication amendable to treatment with posaconazole person who can have at least one of the following charac and is also in need of treatment with a CYP3A4 substrate teristics: BMI less than about 35 , % IBW less than about drug . For example , the patient, prior to being treated with or 150 % , waist size less than about 42 , % body fat less than prescribed posaconazole , can simultaneously have a first 45 about 40 % , % android body fat less than about 40 % , % indication amendable to treatment with posaconazole and a gynoid body fat less than about 40 % , and total body fat less second indication amendable to treatment the CYP3A4 than about 40 kg . Unless otherwise modified “ normal substrate drug. In some such embodiments , the patient is metabolizer” also means an extensive CYP3A4 metabolizer . first treated with posaconazole , and then , after stopping the As used herein , a " reference dose ” refers to the dosage of posaconazole regimen , the patient is switched to a treatment 50 a particular CYP3A4 substrate drug , as indicated on the described herein for the CYP3A4 substrate drug . In other manufacture ’ s FDA - approved label, prescribed for an iden embodiments , the patient , while being treated with posacon - tical patient not previously treated with the strong CYP3A4 azole , develops an indication amendable to treatment with a inhibitor ( e . g . , posaconazole ) . CYP3A4 substrate drug . In some such embodiments , after D isclosed herein are methods of treating , or prescribing stopping the posaconazole regimen , the patient is switched 55 treatment for, a patient with a CYP3A4 substrate drug to a treatment descried herein for the CYP3A4 substrate contraindicated for concomitant administration with a strong drug . As used herein , a “ patient” does not include a subject CYP3A4 inhibitor, wherein the patient was previously that, at some point after stopping posaconazole treatment, treated with posaconazole , particularly when patients having subsequently develops an indication which is amendable to one or more of the physiological characteristics described treatment with a CYP3A4 substrate drug . 60 herein are subsequently treated with a CYP3A4 substrate As used herein , a " patient treated with posaconazole ” or drug . That is , the disclosure provides for methods of treating a “ patient previously on posaconazole ” refers to a patient different patient populations - e . g ., " normal" patients , obese having an indication which was amenable to treatment with patients , and /or intermediate or worse ( e . g ., poor ) CYP3A4 posaconazole . metabolizers — with a CYP3A4 substrate drug contraindi As used herein , the term “ normal baseline Cmax” refers to 65 cated for concomitant administration with a strong CYP3A4 the average Cmor of a drug measured at the same dosage in inhibitor after said patient has ceased posaconazole treat an otherwise identical patient which was not previously ment. Methods of initiating treatment with a CYP3A4 US 10 , 376 ,507 B2 substrate drug intended to treat various conditions or disor- dicated . The presence of concomitant and clinically signifi ders in patients previously treated with posaconazole are cant plasma levels of posaconazole and such CYP3A4 also described herein . The present disclosure also provides substrate drugs can result in significantly elevated levels of methods of preventing or decreasing the risk of side effects the CYP3A4 substrate drug , which creates a risk of pro associated with overexposure to a CYP3A4 substrate drug in 5 longing QT . Consequences of prolonged QT include normal patients , obese patients and / or patients with impaired arrhythmias , rapid heartbeat, abnormal heart rhythm , heart CYP3A4 function ( e . g ., poor or intermediate CYP3A4 palpitations , dizziness , lightheadedness , sudden fainting , metabolizers ) and who had previously been treated with a posaconazole regimen prior to treating or prescribing a seizure , torsades de pointes , and cardiac death . CYP3A4 substrate drug to said patient. (including those for 10 N For example , according to the drug label for posaconazole treating conditions described herein ). (NOXAFIL® label, revised November 2015) , patients are In various embodiments , the present disclosure provides advised not to co -administer specific CYP3A4 substrate methods for treating , or prescribing treatment for, a patient drugs such as serolimus , pimozide , quinidine , HMG - CoA who had been treated with a therapeutically effective posa reductase inhibitors , ergot alkaloids, or drugs known to conazole regimen with a CYP3A4 substrate drug , after a 15 prolong the QTc interval and cause cases of TdP, with “ washout” period of about 2 - 21 days after ceasing admin posaconazole . The NOXAFIL® label also warns that dose istration of posaconazole . This washout period allows for the adjustments should be considered for concomitant adminis blood plasma concentrations of posaconazole to be reduced tration of posaconazole and other drugs metabolized by to appropriate levels after which a CYP3A4 substrate drug CYP3A4 such as tacrolimus , cyclosporine , vinca alkaloids , can be administered without creating an elevated risk of 20 and calcium channel blockers . However , the drug label of serious side effects from the CYP3A4 substrate drug . As posaconazole does not recognize that any washout period or described herein , the present Applicants have found that any stratification of the patient populations are required after CYP3A4 substrate drugs can be safely administrated to a ceasing administration of posaconazole and before initiating patient previously treated with posaconazole , by first treat- administration of a CYP3A4 substrate . ing , or prescribing a first treatment, with the CYP3A4 25 In some embodiments , the strong CYP3A4 inhibitor is substrate drug ( i. e ., initiating the treatment with the posaconazole ( i . e . , Noxafil, Posanol) . Posaconazole is cur CYP3A4 substrate drug ) following a “ washout” period of rently formulated as an oral suspension solution (40 about 2 - 21 days starting at the time the patient has stopped mg/ mL ) , and intravenous solution ( 18 mg/ mL ) , and delayed posaconazole treatment. However , the need for such a release tablets ( 100 mg ). According to the drug label (Merck washout period has been hitherto unknown , as such 30 & Co . , Inc . , ) , current recommended dosing levels for pro CYP3A4 substrate drugs are conventionally contraindicated phylaxis of invasive Aspergillus and Candida infections by for concomitant administration with posaconazole . As also intraveneous injection or by delayed - release tablet are 300 described herein , in some embodiments the present Appli - mg twice a day on the first day and 300 mg once a day cants have found that instead of a washout period , the thereafter , or 200 mg three times a day by oral suspension . CYP3A4 substrate drug can potentially be safely adminis - 35 Current recommended dosing levels for treatment of oro trated to a patient previously treated with posaconazole , at a pharyngeal candidiasis by oral suspension are 100 mg twice dose which is no more than about 50 % of the reference dose a day on the first day and 100 mg once a day for 13 days. of the CYP3A4 substrate drug for a period of about 2 - 21 Current recommended dosing levels for treatment of oro days after ceasing the posaconazole treatment. Similarly , pharyngeal candidiasis refractory to itraconazole and /or such a dosing regime has been hitherto unknown . 40 fluconazole by oral suspension is 400 mg twice a day . Cytochrome P450 3A4 (CYP3A4 ) is an enzyme that In some embodiments , posaconazole can be indicated for modifies small organic molecules , such as particular drugs the treatment of fungal infections. In one embodiment, (specifically including drugs referred to herein as “ CYP3A4 posaconazole can be indicated for the treatment of infections substrate drugs” ) , so that the molecules are metabolized and caused by Candida , e . g . , oropharyngeal candidiasis . In one eliminated from the body . Some substances , termed 45 embodiment, posaconazole can be indicated for the treat " CYP3A4 inhibitors ,” reduce the activity of the CYP3A4 ment of oropharyngeal candidiasis which is refractory to enzyme, and therefore these CYP3A4 inhibitors can itraconazole and/ or fluconazole . In one embodiment, posa increase the exposure of a patient to CYP3A4 substrate conazole can be indicated for the treatment of infections drugs . Strong CYP3A4 inhibitors can deactivate CYP3A4 if caused by Aspergillus . In one embodiment, posaconazole administered in an appropriate dose , which can result in 50 can be indicated for the treatment of infections caused by excessive and potentially dangerous blood plasma levels of Zygomycetes . In some embodiments , posaconazole can be a concomitantly administered CYP3A4 substrate drugs. indicated for the prophylaxis of Aspergillus or Candida Consequently , concomitant administration of CYP3A4 sub infections, e . g . , in immunocompromised patients at high risk strate drugs is contraindicated with strong CYP3A4 inhibi- of developing such infections, such as hematopoietic stem tors . 55 cell transplant ( HSCT ) recipients with graft -versus - host As used herein , a “ strong CYP3A4 inhibitor” refers to a disease (GVHD ) or patients with hematologic malignancies drug deemed so by the FDA and /or which causes at least with prolonged neutropenia from chemotherapy . In one about a 5 - fold increase in the AUC of a sensitive CYP3A4 embodiment, posaconazole can be indicated for the treat substrate drug , or more than about an 80 % decrease in the ment of zygomycosis . In one embodiment, posaconazole can clearance of a sensitive CYP3A4 substrate drug . The meth - 60 be indicated for the treatment of allergic bronchopulmonary ods disclosed herein can be applied to treat a patient with aspergillosis . In one embodiment, posaconazole can be any CYP3A4 substrate drug which is contraindicated for indicated for the treatment or prophylaxis of recurrent concomitant administration with any strong CYP3A4 inhibi candidiasis for the esophagus, secondary to HIV infections. tor, wherein the patient has been treated with a strong In one embodiment, posaconazole can be indicated for the CYP3A4 inhibitor, such as posaconazole . 65 treatment of Fusarium infections mycosis . In one embodi Co - administration of posaconazole and CYP3A4 sub - ment, posaconazole can be indicated for the treatment of and strate drugs known to prolong the QT interval are contrain chronic or cavitary necrotizing pulmonary aspergillosis . US 10 , 376 ,507 B2 10 As used herein , a " CYP3A4 substrate drug ” refers to any dipine (Baymycard , Sular , Syscor ), nitrendipine (Cardif , drug which is primarily metabolized by the CYP3A4 Nitrepin , Baylotensin ) , and pranidipine (Acalas ) , enzyme which is administered in any pharmaceutically hydroxymethylglutaryl coenzyme A - reductase inhibitors , acceptable formulation ( e . g . tablet , capsule , oral solution , such as atorvastatin (Lipitor , Ator ) , lovastatin (Mevacor , injection , infusion , or delayed or extended release formula - 5 Altocor , Altoprev ) , mevastatin (Compactin ) and simvastatin tions thereof) . In some embodiments , the CYP3A4 drug is (Zocor , Lipex ), antineoplastic drugs , such as sorafenib lurasidone (Latuda ) . In some embodiments , the CYP3A4 is (Nexavar ) and sunitinib (Sutent ) , nonsedating antihista ranolazine (Ranexa ). In some embodiments , the CYP3A4 mines , such as fexofenadine ( Allegra ), loratadine ( Claritin ), substrate drugs can include lumacaftor/ ivacaftor (Orkambi ). desloratadine (Clarinex ) , cetirizine (Zyrtec ) , levocetirizine In some embodiments , the CYP3A4 substrate drugs can 10 (Xyza ) and immunosuppressants , such as cyclosporin . include venetoclax ( Venclexta ). In some embodiments , the In some embodiments , the CYP3A4 substrate drug used CYP3A4 substrate drugs can include trabectedin ( Yondelis ) . in the methods disclosed herein can be any drug metabolized In some embodiments , the CYP3A4 substrate drugs can by CYP3A4 , in particular drugs metabolized by CYP3A4 include ribociclib succinate (Kisqali ). In some embodi - and which are contraindicated for use with strong CYP3A4 ments , the CYP3A4 substrate drugs can include deflazacort 15 inhibitors or include dose adjustment recommendations for (Emflaza ) . In some embodiments, the CYP3A4 substrate concomitant administration with CYP3A4 inhibitors . In drugs can include cinacalcet hydrochloride (Sensipar ) . In some embodiments , the methods described herein can be some embodiments , the CYP3A4 substrate drugs can applied to any therapeutic regimen in which one or more include pimavanserin tartrate (Nuplazid ) . In some embodi- CYP3A4 substrate drug (s ) described herein are used to treat ments, the CYP3A4 substrate drugs can include aripiprazole 20 a patient previously on posaconazole , including therapeutic lauroxil ( Aristada ) . In some embodiments , the CYP3A4 regimens that entail treating a patient with a CYP3A4 substrate drugs can include cariprazine hydrochloride ( Vray - substrate drug in combination with other drugs . lar ) . In some embodiments , the CYP3A4 substrate drugs can In some embodiments , the CYP3A4 substrate drug can be include simeprevir sodium (Olysio ) . In some embodiments, indicated for the treatment of disease or condition selected the CYP3A4 substrate drugs can include everolimus ( Afini - 25 from the group consisting of schizophrenia in adults and tor, Afinitor Disperz , Zortress ) . In some embodiments , the adolescents ( 13 to 17 years ) , depressive episodes associated CYP3A4 substrate drugs can include saxagliptin hydrochlo - with Bipolar I Disorder ( bipolar depression ) in adults , as ride ( Onglyza ). In some embodiments, the CYP3A4 sub - monotherapy or adjunctive therapy with lithium or val strate drugs can include saxagliptin /metformin hydrochlo - proate , chronic angina , cystic fibrosis in patients 6 years and ride (Kombiglyze XR ) . In some embodiments , the CYP3A4 30 older who are homozygous for the F508del mutation in the substrate drugs can include ticagrelor (Brilinta ) . In some CFTR gene , chronic lymphocytic leukemia in patients with embodiments , the CYP3A4 substrate drugs can include 17p deletion , who have received at least one prior therapy , vilazodone hydrochloride (Viibryd ) . In some embodiments, unresectable or metastatic liposarcoma or leiomyosarcoma the CYP3A4 substrate drugs can include apixaban ( Eliquis ) . in patients who received a prior anthracycline -containing In some embodiments , the CYP3A4 substrate drugs can 35 regimen , advanced or metastatic breast cancer in postmeno include tofacitinib citrate (Xeljanz ) . In some embodiments , pausal women with hormone receptor (HR ) - positive , human the CYP3A4 substrate drugs can include eletriptan hydro - epidermal growth factor receptor 2 (HER2 ) -negative bromide (Relpax ). In some embodiments , the CYP3A4 advanced or metastatic breast cancer, negative advanced or substrate drugs can include nilotinib hydrochloride mono - metastatic breast cancer in combination with an aromatase hydrate ( Tasigna ) . In some embodiments , the CYP3A4 40 inhibitor for postmenopausal women , Duchenne muscular substrate drugs can include dronedarone hydrochloride dystrophy (DMD ) , secondary hyperparathyroidism (HPT ) in (Multaq ) . In some embodiments , the CYP3A4 substrate patients with chronic kidney disease (CKD ) on dialysis , drugs can include fluticasone propionate / salmeterol xin - hypercalcemia in patients with parathyroid carcinoma or in afoate (Advair Diskus ). In some embodiments , the CYP3A4 patients with primary HPT for who parathyroidectomy substrate drugs can include rivaroxaban (Xarelto ) . In some 45 would be indicated on the basis of serum calcium levels , but embodiments , the CYP3A4 substrate drugs can include who are unable to undergo parathyroidectomy, hallucina tadalafil (Cialis , Adcirca ). In some embodiments , the tions and delusions associated with Parkinson ' s disease CYP3A4 substrate drugs can include colchicine (Colcrys ). psychosis , schizophrenia , acute manic or mixed episodes In some embodiments , the CYP3A4 substrate drugs can associated with bipolar I disorder , chronic hepatitis C (CHC ) include ibrutinib ( Imbruvica ) . In some embodiments , the 50 infection as a component of a combination antiviral treat CYP3A4 substrate drugs can include cobimetinib (Cotellis ). ment regimen with peginterferon alfa and ribavirin in HCV Other non - limiting examples of CYP3A4 substrate drugs genotype 1 infected subjects with compensated liver disease , include HIV protease inhibitors , such as amprenavir ( Agen advanced hormone receptor -positive , HER2 -negative breast erase ) , atazanavir (Reyataz ), darunavir (Prezista ) , fosampre cancer (advanced HR + BC ) in postmenopausal women in navir ( Lexiva , Telzir ), indinavir (Crixivan ), lopinavir (Kale - 55 combination with exemestane after failure of treatment with tra ) , nelfinavir ( Viracept) , ritonavir (Norvir ) , Saquinavir letrozole or anastrozole, progressive neuroendocrine tumors ( Invirase , Forovase ) , and tipranavir (Aptivus ) , benzodiaz of pancreatic origin (PNET ) , progressive , well -differenti epines , such as alprazolam ( Xanax ) , clonazepam (Klono - ated , non - functional neuroendocrine tumors (NET ) of gas pin ) , and diazepam ( Valium ), calcium channel blockers such trointestinal (GI ) or lung origin that are unresectable , locally as amlodipine (Norvasc ) , aranidipine (Sapresta ) , azelni- 60 advanced or metastatic , advanced renal cell carcinoma dipine (Calblock ) , barnidipine (HypoCa ) , benidipine (Con - (RCC ) , e . g ., after failure of treatment with sunitinib or iel) , cilnidipine ( Atelec, Cinalong, Siscard ), clevidipine sorafenib , renal angiomyolipoma and tuberous sclerosis ( Cleviprex ) , isradipine (DynaCirc , Prescal ), efonidipine complex ( TSC ), not requiring immediate surgery, TSC in (Landel ) , felodipine (Plendil ) , lacidipine (Motens , Lacipil ), patients who have subependymal giant cell astrocytoma lercanidipine (Zanidip ) , manidipine ( Calslot, Madipine ) , 65 (SEGA ) that require therapeutic intervention but are not nicardipine (Cardene , Carden SR ), nifedipine ( Procardia , candidates for surgical resection , type 2 diabetes mellitus in Adalat ), nilvadipine (Nivadil ), nimodipine (Nimotop ) , nisol- adults as an adjunct to diet and exercise to improve glycemic US 10 , 376 ,507 B2 11 12 control, major depressive disorder (MDD ) , thrombotic car breast cancer in postmenopausal women e . g . , in combina diovascular events ( e . g . , cardiovascular death , myocardial tion with an aromatase inhibitor as initial endocrine -based infarction , or stroke) in patients with acute coronary syn - therapy . drome ( ACS ) , stroke and systemic embolism in patients In one embodiment, the CYP3A4 substrate drug can be with nonvalvular atrial fibrillation , deep vein thrombosis 5 indicated for the treatment of Duchenne muscular dystrophy (DVT ) , which may lead to pulmonary embolism (PE ) in (DMD ) . patients who have undergone hip or knee replacement sur In one embodiment, the CYP3A4 substrate drug can be gery , DVT, PE , recurrent DVT and PE following initial indicated for the treatment of secondary hyperparathyroid therapy, moderate to severe active rheumatoid arthritis in i sm (HPT ) , e . g. , in patients with chronic kidney disease patients who have had inadequate response or tolerance to " (CKD ) on dialysis . In one embodiment, the CYP3A4 sub methotrexate , acute migraine with or without aura , chronic strate drug can be indicated for the treatment of hypercal phase and accelerated phase Philadelphia chromosome posi - cemia , e . g . , in patients with parathyroid carcinoma. In one tive chronic myeloid leukemia ( Ph + CML ) in newly diag - embodiment , the CYP3A4 substrate drug can be indicated nosed patients or in patients resistant to or intolerant to prior 15 for the treatment of hypercalcemia , e . g ., in patients with therapy that included imatinib , atrial fibrillation ( AF ) in primary HPT for who parathyroidectomy would be indicated patients with a history of paroxysmal or persistent AF or on the basis of serum calcium levels , but who are unable to atrial flutter ( AFK ) , who are in sinus rhythm or will be undergo parathyroidectomy. cardioverted , asthma in patients aged 4 years and older, In one embodiment, the CYP3A4 substrate drug can be airflow obstruction and reducing exacerbations in patients 20 indicated for the treatment of hallucinations and delusions with chronic obstructive pulmonary disease , erectile dys associated with Parkinson ' s disease psychosis . function ( ED ) , benign prostatic hyperplasia (BPH ) , pulmo- In one embodiment, the CYP3A4 substrate drug can be nary arterial hypertension ( PAH ) (WHO Group 1 ) to indicated for the treatment of schizophrenia . improve exercise ability , gout flares, Familial Mediterranean In one embodiment, the CYP3A4 substrate drug can be fever , antiretroviral therapy , anxiety disorders , panic disor - 25 indicated for the acute treatment of manic or mixed episodes ders , seizures , insomnia , hypertension , cardiovascular dis associated with bipolar I disorder. ease , hyperlipidemia , cancer , such as primary kidney cancer, In one embodiment, the CYP3A4 substrate drug can be advanced primary liver cancer, radioactive iodine resistant indicated for the treatment of chronic hepatitis C (CHC ) advanced thyroid carcinoma, renal cell carcinoma, imatinib infection , e . g . , as a component of a combination antiviral resistant gastrointestinal stromal tumor. mantle cell lym - 30 treatment regimen with peginterferon alfa and ribavirin in HCV genotype 1 infected subjects with compensated liver phoma in patients who have received at least one prior disease . therapy, chronic lymphocytic leukemia / small lymphocytic In one embodiment, the CYP3A4 substrate drug can be lymphoma, chronic lymphocytic leukemia /small lympho indicated for the treatment of postmenopausal women with cytic lymphoma with 17p deletion , Waldenström ' s macro 35 advanced hormone receptor -positive , HER2- negative breast globulinemia , marginal zone lymphoma who require sys cancer (advanced HR + BC ) , e . g . , in combination with temic therapy and have received at least one prior anti exemestane after failure of treatment with letrozole or CD20 -based therapy, unresectable or metastatic melanoma anastrozole. In one embodiment, the CYP3A4 substrate drug with a BRAF V600E or V600K mutation , allergies , and can be indicated for the treatment of patients with progres transplantation . 40 sive neuroendocrine tumors of pancreatic origin (PNET ) . In In some embodiments , the CYP3A4 substrate drug can be one embodiment, the CYP3A4 substrate drug can be indi indicated for the treatment of schizophrenia in adults and cated for the treatment of patients with progressive , well adolescents ( 13 to 17 years ) , depressive episodes associated differentiated , non - functional neuroendocrine tumors (NET ) with Bipolar I Disorder (bipolar depression ) in adults, as of gastrointestinal (GI ) or lung origin that are unresectable , monotherapy or as adjunctive therapy with lithium or val- 45 locally advanced or metastatic . In one embodiment , the proate . CYP3A4 substrate drug can be indicated for the treatment of In one embodiment, the CYP3A4 substrate drug can be patients with advanced renal cell carcinoma (RCC ), e . g. , indicated for the treatment of chronic angina . after failure of treatment with sunitinib or sorafenib . In one In one embodiment , the CYP3A4 substrate drug can be embodiment, the CYP3A4 substrate drug can be indicated indicated for the treatment of cystic fibrosis , e . g . , in patients 50 for the treatment of patients with renal angiomyolipoma and 6 years and older who are homozygous for the F508del tuberous sclerosis complex ( TSC ) , not requiring immediate mutation in the CFTR gene . surgery . In one embodiment , the CYP3A4 substrate drug can In one embodiment, the CYP3A4 substrate drug can be be indicated for the treatment of patients with TSC who have indicated for the treatment of chronic lymphocytic leukemia , subependymal giant cell astrocytoma (SEGA ) that require e . g ., in patients with 17p deletion , who have received at least 55 therapeutic intervention but are not candidates for surgical one prior therapy . resection . In one embodiment, the CYP3A4 substrate drug can be In one embodiment, the CYP3A4 substrate drug can be indicated for the treatment of unresectable or metastatic indicated for the treatment of type 2 diabetes mellitus, e . g . , liposarcoma or leiomyosarcoma, e . g . , in patients who as an adjunct to diet and exercise to improve glycemic received a prior anthracycline - containing regimen . 60 control in adults . In one embodiment, the CYP3A4 substrate drug can be In one embodiment, the CYP3A4 substrate drug can be indicated for the treatment of advanced or metastatic breast indicated to reduce the rate of thrombotic cardiovascular cancer, e . g . , in postmenopausal women with hormone recep - events ( e . g . , cardiovascular death , myocardial infarction , or tor (HR ) - positive , human epidermal growth factor receptor stroke ) in patients with acute coronary syndrome (ACS ) . 2 (HER2 ) -negative advanced or metastatic breast cancer. In 65 In one embodiment, the CYP3A4 substrate drug can be a further embodiment, the CYP3A4 substrate drug can be indicated for the treatment of major depressive disorder indicated for a treatment of negative advanced or metastatic (MDD ) . US 10 , 376 ,507 B2 13 14 In one embodiment, the CYP3A4 substrate drug can be hypertension , cardiovascular disease ( e. g. , myocardial indicated to reduce the risk of stroke and systemic embolism infarction , stroke , and angina ) , hyperlipidemia , cancer, such in patients with nonvalvular atrial fibrillation . In one as primary kidney cancer, advanced primary liver cancer, embodiment, the CYP3A4 substrate drug can be indicated radioactive iodine resistant advanced thyroid carcinoma , for the prophylaxis of deep vein thrombosis (DVT ) , which 5 renal cell carcinoma, imatinib - resistant gastrointestinal may lead to pulmonary embolism (PE ) , e . g ., in patients who stromal tumor, allergies, and transplantation . have undergone hip or knee replacement surgery. In one As discussed above , after stopping treatment with a strong embodiment, the CYP3A4 substrate drug can be indicated for the treatment of DVT or PE . In one embodiment, the CYP3A4 inhibitor ( including but not limited to posacon CYP3A4 substrate drug can be indicated to reduce the risk 10 azole ) , posaconazole accumulates in the body of patients , of recurrent DVT and PE following initial therapy. and reduces or prevents metabolism of CYP3A4 substrate In one embodiment, the CYP3A4 substrate drug can be drugs. Thus, patients previously on posaconazole that are indicated for the treatment of moderate to severe active concomitantly treated with CYP3A4 substrate drugs may rheumatoid arthritis , e . g . , in patients who have had inad have plasma levels of the CYP3A4 substrate drug that equate response or tolerance to methotrexate . 15 exceed the plasma levlevels of an otherwise identical patient In one embodiment, the CYP3A4 substrate drug can be that was not previously treated with posaconazole . indicated for the acute treatment of migraine with or without Described herein , in various embodiments, are treatment aura . regimens for CYP3A4 substrate drugs which are applicable In one embodiment, the CYP3A4 substrate drug can be to patients who previously received multiple doses of a indicated for the treatment of chronic phase and accelerated 20 strong CYP3A4 inhibitor ( e .g ., posaconazole ) for a period of phase Philadelphia chromosome positive chronic myeloid about 2 - 21 days after stopping treatment with the strong leukemia (Ph + CML ), e. g ., in newly diagnosed patients or in CYP3A4 inhibitor. In some embodiments , the treatment patients resistant to or intolerant to prior therapy that regimen provides for treating or prescribing a dose which is included imatinib . less than about 50 % of the reference dose of the CYP3A4 In one embodiment, the CYP3A4 substrate drug can be 25 substrate drug for a period of about 2 - 21 days after stopping indicated to reduce the risk of hospitalization for atrial posaconazole treatment. As used herein , a dose that is less fibrillation (AF ) , e . g ., in patients with a history of paroxys than 50 % of the reference dose of the CYP3A4 inhibitor can mal or persistent AF or atrial flutter ( AFK ) , who are in sinus include any amount from 0 % ( i . e . , no dose ) to about 50 % of rhythm or will be cardioverted . the CYP3A4 inhibitor for the period of 2 - 21 days. Therefore , In one embodiment, the CYP3A4 substrate drug can be 30 the treatment regimen disclosed herein can include , in some indicated for maintenance treatment of asthma, e . g . , in embodiments , delaying a first dose of a CYP3A4 substrate patients aged 4 years and older . In one embodiment, the drug for about 2 - 21 days after stopping posaconazole treat CYP3A4 substrate drug can be indicated for maintenance m ent, or alternatively , treating with a reduced dose of the treatment of airflow obstruction and reducing exacerbations CYP3A4 substrate drug for about 2 -21 days after stopping in patients with chronic obstructive pulmonary disease . 35 posaconazole treatment. The methods described herein can In one embodiment, the CYP3A4 substrate drug can be be applied to any patient that was previously on posacon indicated for the treatment of erectile dysfunction (ED ) . In azole and having an indication amendable to treatment with one embodiment, the CYP3A4 substrate drug can be indi- a CYP3A4 substrate drug , including normal patients ( non cated for the treatment of benign prostatic hyperplasia obese and normal metabolizers ), obese patients , and poor or (BPH ) . In one embodiment, the CYP3A4 substrate drug can 40 intermediate metabolizers , or combinations thereof. be indicated for treatment of pulmonary arterial hyperten - In some embodiments , between about 2 and about 21 sion (PAH ) (WHO Group 1 ) to improve exercise ability . days , e . g ., about 2 , about 3 , about 4 , about 5 , about 6 , about In one embodiment, the CYP3A4 substrate drug can be 7 , about 8 , about 9 , about 10 , about 11 , about 12 days , about indicated for the treatment of gout flares . In one embodi- 13 , about 14 , about 15 , about 16 , about 17 , about 18 , about ment, the CYP3A4 substrate drug can be indicated for the 45 19 , about 20 , or about 21 days , inclusive of all ranges and treatment of Familial Mediterranean fever. subranges therebetween , should elapse between discontinu In one embodiment, the CYP3A4 substrate drug can be ation of posaconazole ( i . e ., the last dose in a posaconazole indicated for mantle cell lymphoma in patients who have regimen ) and initiation of treatment with a CYP3A4 sub received at least one prior therapy . In one embodiment, the strate drug ( i . e . , the first dose in a CYP3A4 regimen of any CYP3A4 substrate drug can be indicated for chronic lym - 50 of the CYP3A4 substrate drugs described herein ). In some phocytic leukemia / small lymphocytic lymphoma In one embodiments , the patient is a “ normal” patient (i . e . , a patient embodiment , the CYP3A4 substrate drug can be indicated with “ normal ” CYP3A4 enzyme function , often termed an for chronic lymphocytic leukemia / small lymphocytic lym - " extensive metabolizer ” in the art ; and having a normal phoma with 17p deletion . weight - e . g . , a BMIin the range of about 18 . 5 - 24 . 9 ) , and in In one embodiment, the CYP3A4 substrate drug can be 55 other embodiments the patient has one of the physiological indicated for Waldenström ’s macroglobulinemia . characteristics described herein , e . g . , is considered obese In one embodiment, the CYP3A4 substrate drug can be and /or has a level of CYP3A4 enzyme activity termed in the indicated for marginalzone lymphoma who require systemic art as poor or intermediate . therapy and have received at least one prior anti- CD20 - This " delay ” or waiting period between ceasing or stop based therapy. 60 ping the treatment of posaconazole and initiating treatment In one embodiment, the CYP3A4 substrate drug can be with a CYP3A4 substrate drug can equivalently be charac indicated for unresectable or metastatic melanoma with a terized as the time that elapses between stopping treatment BRAF V600E or V600K mutation . of posaconazole and treating with the first dose of CYP3A4 Other non - limiting examples of conditions or diseases for substrate drug. The skilled artisan will recognize that addi which CYP3A4 substrate drugs are prescribed include anti - 65 tional doses of the CYP3A4 substrate drug are typically retroviral therapy , e . g . , for the treatment of HIV / AIDS , administered or prescribed subsequently , but the " delay " or anxiety disorders , panic disorders, seizures , insomnia , “ washout” period as described herein is the time that elapses US 10 ,376 , 507 B2 15 16 between stopping treatment of posaconazole and the first intermediate or poor CYP3A4 metabolizers) , and / or a dose that initiates treatment with a CYP3A4 substrate drug . weight or body fat status variously characterized as In alternative embodiments, rather than delaying the treat- described herein . In some embodiments , the patients can ment of the CYP3A4 substrate drug , after stopping treat - have various characteristics of body fat status. The term ment of posaconazole the CYP3A4 substrate drug is treated 5 " body fat status , " " body fat characteristics , " " obese status, " or prescribed at a dose which is no more than about 50 % of " obese characteristics , " or other derivations or variations a reference dose (the dose recommended for the patient on thereof refer to at least seven characteristics (BMI , % IBW , the FDA -approved label for the CYP3A4 substrate drug ), waist size, % body fat, % android fat , % gynoid fat, and total including e . g ., no more than about 50 % , no more than about body fat) as described herein . In some embodiments , the 49 % , no more than about 48 % , no more than about 47 % , no 10 body fat status may be referred to as obesity , and the patients more than about 46 % , no more than about 45 % , no more may be referred to as obese , or obese patients . than about 44 % , no more than about 43 % , no more than As described herein , the present Applicants have found about 42 % , no more than about 41 % , no more than about that certain classes of patients , i . e . , patients having the 40 % , no more than about 39 % , no more than about 38 % , no particular physiological characteristics described herein more than about 37 % , no more than about 36 % , no more 15 such as body fat and weight status and / or hepatic metabo than about 35 % , no more than about 34 % , no more than lizing enzyme status , after stopping treatment with posacon about 33 % , no more than about 32 % , no more than about azole , may have substantially higher plasma levels of posa 31 % , no more than about 30 % , no more than about 29 % , no conazole , and /or exhibit substantially longer elimination more than about 28 % , no more than about 27 % , no more half - lives (t1 ) of posaconazole than previously known or than about 26 % , no more than about 25 % , no more than 20 contemplated , e . g . , in the NOXAFIL® label, and therefore about 24 % , no more than about 23 % , no more than about require either a delay as described herein after stopping 22 % , no more than about 21 % , no more than about 20 % , no posaconazole treatment, before treating, or prescribing a first more than about 19 % , no more than about 18 % , no more treatment to begin , with a CYP3A4 substrate drug , or a dose than about 17 % , no more than about 16 % , no more than adjustment (reduction ) of the CYP3A4 substrate drug for a about 15 % , no more than about 14 % , no more than about 25 time period after stopping posaconazole treatment, as 13 % , no more than about 12 % , no more than about 11 % , or described herein . In some embodiments , the duration of the no more than about 10 % of the reference dose , inclusive of delay period or dose adjustment period , or the degree of dose all ranges and subranges therebetween , for at least about adjustment is greater than the corresponding delay or dose 2 - 21 days after discontinuation of the posaconazole regi- reduction period /amount compared to those considered to be men , e . g . , for about 2 , about 3 , about 4 , about 5 , about 6 , 30 “ normal ” patients . These classes of patients which exhibit about 7 , about 8 , about 9 , about 10 , about 11 , about 12 days , substantially higher plasma levels of posaconazole , and / or about 13 , about 14 , about 15 , about 16 , about 17 , about 18 , exhibit substantially longer elimination half -lives (t1 / 2 ) of about 19 , about 20 , or about 21 days , inclusive of all ranges posaconazole compared to the expected level ( e . g . , as and subranges therebetween . embodied in the recommendations of the NOXAFIL® In other alternative embodiments , depending on the 35 label) , or who require a longer delay time, dose adjustment CYP3A4 substrate drug , the patient can be treated with or time, or dose adjustment level include obese patients who prescribed a CYP3A4 substrate drug at a dose which is less exhibit one or more of e . g . , a BMI of at least about 35 , % than 100 % of a reference dose (the dose recommended for IBW of at least about 150 % , waist size greater than about 42 the patient on the FDA -approved label for the CYP3A4 inches , % body fat greater than about 40 % , % android body substrate drug ) , including e . g . , about 95 % , about 90 % , about 40 fat greater than about 40 % , % gynoid body fat greater than 85 % , about 80 % , about 75 % , about 70 % , about 65 % , about about 40 % , total body fat greater than about 40 kg, option 60 % , about 55 % , or about 50 % of the reference dose , ally in combination with impaired hepatic function , e . g ., inclusive of all ranges and subranges therebetween , for at intermediate or poor CYP3A4 metabolizers . Alternatively , least about 2 - 21 days after discontinuation of the posacon patients who are not obese ( e . g . , have any of the various azole treatment, e . g . , for about 2 , about 3 , about 4 , about 5 , 45 measures of body fat status described herein which are not about 6 , about 7 , about 8 , about 9 , about 10 , about 11 , about considered as indicative of obesity , such as a BMI less than 12 days, about 13 , about 14 , about 15 , about 16 , about 17 , about 35 , % IBW of less than about 150 % , waist size less about 18 , about 19 , about 20 , or about 21 days, inclusive of than about 42 inches, % body fat less than about 40 % , % all ranges and subranges therebetween . android body fat less than about 40 % , % gynoid body fat less In addition to providing methods of treating or prescribing 50 than about 40 % , or total body fat less than about 40 kg ) but treatment for “ normal” patients ( e . g . , non - obese and normal have impaired hepatic metabolic function , e . g . , are consid CYP3A4 metabolizers ) , the present disclosure also provides ered intermediate or poor CYP3A4 metabolizers, have also methods for treating , or prescribing treatment for, patients been found by the present Applicants to have substantially with at least one of the physiological characteristics higher steady state plasma levels of posaconazole , and /or described herein , who had been treated with multiple doses 55 exhibit a substantially longer elimination half- lives (t12 ) of of posaconazole, with a CYP3A4 substrate drug . The treat posaconazole compared to those expected in “ normal” ment with the CYP3A4 substrate drug is initiated or pre - patients — i . e ., patients who do not exhibit the specific physi scribed to be initiated ( or the first dosing begins after ological characteristics described herein — or as embodied in stopping treatment with posaconazole ) after a delay time as the recommendations of the NOXAFIL® label may also described herein , or is treated or prescribed at a reduced dose 60 require an extended washout period ( as described herein ) ( e . g . , any amount less than 100 % of a reference dose , after stopping administration of posaconazole before begin including but not limited to about 1/ 3 , about 12 , about 2/ 3 , etc . ning treatment with a CYP3A4 substrate drug . Alternatively , of a reference dose ) for a time period after treatment with such patients may require an extended period ( as described posaconazole is stopped as described herein . The physi- herein ) after stopping administration of posaconazole before ological characteristics of such patients include reduced 65 beginning treatment with a reduced dose ( as described hepatic enzyme function , specifically reduced CYP3A4 herein ) relative to the reference dose of the CYP3A4 sub enzyme function (such patients are characterized in the art as strate drug in order to minimize or avoid adverse effects such US 10 ,376 , 507 B2 18 as QTc prolongation or other side effects of the CYP3A4 about 125 , at least about 126 , at least about 127 , at least substrate drug than has hitherto been recognized in the art . about 128 , at least about 129 , at least about 130 , at least Conventionally , no such distinction between patients having about 131, at least about 132 , at least about 133 , at least such physiological characteristics has been recognized as about 134 , at least about 135 , at least about 136 , at least requiring increased “ washout” periods between dosing with 5 about 137, at least about 138 , at least about 139, at least posaconazole and a CYP3A4 substrate drug , or as requiring about 140 , at least about 141 , at least about 142 , at least time periods during which a patient is treated , or prescribed about 143 , at least about 144, at least about 145 , at least to be treated , with a reduced reference dose of the CYP3A4 about 146 , at least about 147 , at least about 148 , at least substrate drug after stopping administration of posacon - about 149 , at least about 150 , at least about 151 , at least azole , as the effects of such physiological characteristics on 10 about 152, at least about 153 , at least about 154 , at least steady state plasma levels of posaconazole and / or elimina about 155 , at least about 156 , at least about 157 , at least tion half - life was not previously known . about 158 , at least about 159 , at least about 160 , at least Posaconazole can be metabolized primarily through oxi about 161, at least about 162 , at least about 163 , at least dation via Cytochrome P450 isozymes , in particular about 164 , at least about 165 , at least about 166 , at least CYP3A4. Studies indicate that other CYP isozymes , such as 15 about 167 , at least about 168, at least about 169, at least A2, 208 , 209 , 2D6 and 2E1, are not involved in the about 170 , at least about 171 , at least about 172 , at least metabolism of posaconazole . Each individual may have about 173, at least about 174 , at least about 175 , at least different activity levels of the P450 isozymes that metabo - about 176 , at least about 177 , at least about 178 , at least lize posaconazole . Categorizations of metabolizers may about 179 , at least about 180 , at least about 181, at least include , but are not limited to , allelic heterogeneity in the 20 about 182 , at least about 183 , at least about 184 , at least P540 isozymes gene . For instance , the CYP3A4 gene can about 185 , at least about 186 , at least about 187 , at least have allelic heterogeneity and expression of CYP3A4 * 22 about 188, at least about 189, at least about 190 , at least allele can be used to classify individuals as reduced - express - about 191, at least about 192 , at least about 193 , at least ers of CYP3A4 ( i . e . , individuals possessing one about 194 , at least about 195 , at least about 195 , at least CYP3A4 * 22 allele ) , and normal - expressers of CYP3A4 25 about 196 , at least about 197 , at least about 198 , at least ( i. e ., individuals not possessing any CYP3A4 * 22 allele ) . about 199 , at least about 200 , at least about 201 , at least In some embodiments , the class of patients treated by the about 202 , at least about 203 , at least about 204 , at least methods of the present disclosure have a body mass index about 205 , at least about 206 , at least about 207 , at least (BMI ; expressed in units of kg /m² unless otherwise speci- about 208 , at least about 209 , or at least about 210 , inclusive fied ) of less than about 25 , e . g . , about 24 . 5 , about 24 , about 30 of all ranges and subranges therebetween , and any BMI 23 . 5 , about 23 , about 22 . 5 , about 22 , about 21. 5 , about 21, described herein . In one embodiment, the patient has a body about 20 . 5 , about 20 , about 19 . 5 , about 19 , or about 18 .5 or mass index (BMI ) of at least about 35 . In another embodi less , inclusive of all values and ranges therebetween . ment , the patient has a body mass index (BMI ) of at least In some embodiments , the class of patients treated by the about 40 . In another embodiment, the patient has a body methods of the present disclosure have a body mass index 35 mass index (BMI ) of at least 50 . (BMI ; expressed in units of kg /m² unless otherwise speci - In some embodiments , a patient treated according to the fied ) of at least about 25 , at least about 26 , at least about 27 , methods of the present invention has a BMI of at least about at least about 28 , at least about 29 , at least about 30 , at least 25 to at least about 29. 9 , at least about 25 . 5 to at least about about 31 , at least about 32 , at least about 33 , at least about 29 , at least about 26 to at least about 28 . 5 , at least about 26 . 5 34 , at least about 35 , at least about 36 , at least about 37 , at 40 to at least about 28 , or at least about 27 to at least about 27 . 5 , least about 38 , at least about 39 , at least about 40 , at least inclusive of all ranges and subranges therebetween , and can about 41, at least about 42 , at least about 43 , at least about be termed overweight or pre- obese . In some embodiments , 44 , at least about 45 , at least about 46 , at least about 47 , at a patient with a BMI of at least about 30 to at least about least about 48, at least about 49 , at least about 50 , at least 34 . 9 , at least about 30 . 5 to at least about 34 , at least about about 51, at least about 52 , at least about 53 , at least about 45 31 to at least about 33 . 5 , at least about 31 . 5 to at least about 54 , at least about 55 , at least about 56 , at least about 57 , at 33 , or at least about 32 to at least about 32 . 5 , inclusive of all least about 58 , at least about 59 , at least about 60 , at least ranges and subranges therebetween can be considered obese . about 61 , at least about 62 , at least about 63 , at least about In some embodiments , a patient with a BMI of at least about 64 , at least about 65 , at least about 66 , at least about 67 , at 35 to at least about 39 . 9 , at least about 35 . 5 to at least about least about 68 , at least about 69 , at least about 70 , at least 50 39 , at least about 36 to at least about 38 . 5 , at least about 36 . 5 about 71 , at least about 72 , at least about 73 , at least about to at least about 38 , or at least about 37 to at least about 37 .5 , 74 , at least about 75 , at least about 76 , at least about 77 , at inclusive of all ranges and subranges therebetween , and any least about 78 , at least about 79 , at least about 80 , at least BMI described herein , can be considered obese . In other about 81 , at least about 82 , at least about 83 , at least about embodiments , a patient treated by themethods of the present 84 , at least about 85 , at least about 86 , at least about 87 , at 55 disclosure has a BMI of at least about 35 or more , 40 or least about 88 , at least about 89 , at least about 90 , at least more , 50 or more , 60 or more , 70 or more , 80 or more , 90 about 91 , at least about 92 , at least about 93 , at least about or more , 100 or more , 110 or more, 120 or more, 130 or 94 , at least about 95 , at least about 96 , at least about 97 , at more , 140 or more , 150 or more , 160 or more , 170 or more , least about 98 , at least about 99 , at least about 100 , at least 180 or more , 190 or more , 200 or more , or 210 or more , about 101, at least about 102 , at least about 103 , at least 60 inclusive of all ranges and subranges therebetween . about 104 , at least about 105 , at least about 106 , at least In some embodiments , the patient treated according to the about 107 , at least about 108 , at least about 109 , at least methods of the present disclosure is a child or an adolescent about 110 , at least about 111 , at least about 112 , at least with a BMI of at least about the 85th percentile to at least about 113 , at least about 114 , at least about 115 , at least about 95in percentile , at least about the 86 percentile to at about 116 , at least about 117 , at least about 118 , at least 65 least about 94 percentile , at least about the 87th percentile about 119 , at least about 120 , at least about 121, at least to at least about 93th percentile , at least about the 88th about 122 , at least about 123 , at least about 124 , at least percentile to at least about 92th percentile , at least about the US 10 ,376 , 507 B2 19 20 89th percentile to at least about 90th percentile , inclusive of at least about 179 % , at least about 180 % , at least about all ranges and subranges therebetween , can be considered 181 % , at least about 182 % , at least about 183 % , at least overweight or pre -obese . In some embodiments , the patient about 184 % , at least about 185 % , at least about 186 % , at is a patient with a BMI of at least about the 95th percentile , least about 187 % , at least about 188 % , at least about 189 % , at least about 96 "" percentile , at least about the 97th percen - 5 at least about 190 % , at least about 191 % , at least about tile , at least about 98th percentile , at least about 99th percen tile , or at least about 100th percentile , inclusive of all ranges 192 % , at least about 193 % , at least about 194 % , at least and subranges therebetween , and any BMI percentile about 195 % , at least about 196 % , at least about 197 % , at described herein , and can be considered obese . In one least about 198 % , at least about 199 % , at least about 200 % , embodiment, the patient is about 5 to about 19 years old or 10 at least about 201 % , at least about 202 % , at least about about 7 to about 18 years old . 203 % , at least about 204 % , at least about 205 % , at least In some embodiments , the patient treated according to the about 206 % , at least about 207 % , at least about 208 % , at methods of the present disclosure is a female patient in the least about 209 % , at least about 210 % , at least about 211 % , first trimester through third trimester of a pregnancy and has at least about 212 % , at least about 213 % , at least about a BMI of at least 25 to at least about 29. 9 , at least about 25 .5 15 214 % , at least about 215 % , at least about 216 % , at least to at least about 29, at least about 26 to at least about 28 . 5 , about 217 % , at least about 218 % , at least about 219 % , at at least about 26 . 5 to at least about 28 . or at least about 27 least about 220 % , at least about 221 % , at least about 222 % , to at least about 27 . 5 , inclusive of all ranges and subranges at least about 223 % , at least about 224 % , at least about therebetween , and can be considered overweight or pre - 225 % , at least about 226 % , at least about 227 % , at least obese . In some embodiments , the patient is a female patient 20 about 228 % , at least about 229 % , at least about 230 % , at in the first trimester through third trimester of a pregnancy least about 231 % , at least about 232 % , at least about 233 % , and has a BMI of at least about 30 to at least about 34 . 9 , at at least about 234 % , at least about 235 % , at least about least about 30 . 5 to at least about 34 , at least about 31 to at 236 % , at least about 237 % , at least about 238 % , at least least about 33 . 5 , at least about 31 . 5 to at least about 33 , or about 239 % , at least about 240 % , at least about 241 % , at at least about 32 to at least about 32 . 5 , inclusive of all ranges 25 least about 242 % , at least about 243 % , at least about 244 % , and subranges therebetween , and can be considered obese . at least about 245 % , at least about 246 % , at least about In some embodiments , the patent treated according to the 247 % , at least about 248 % , at least about 249 % , at least methods of the present invention is a female patient in the about 250 % , at least about 251 % , at least about 252 % , at first trimester through third trimester of a pregnancy and has least about 253 % , at least about 254 % , at least about 255 % , a BMI of at least about 35 to at least about 39 . 9 , at least 30 at least about 256 % , at least about 257 % , at least about about 35 . 5 to at least about 39 , at least about 36 to at least 258 % , at least about 259 % , at least about 260 % , at least about 38 . 5 , at least about 36 . 5 to at least about 38 , at least about 261 % , at least about 262 % , at least about 263 % , at about 37 to at least about 37 . 5 , inclusive of all ranges and least about 264 % , at least about 265 % , at least about 266 % , subranges therebetween , and can be considered severely at least about 267 % , at least about 268 % , at least about obese . 35 269 % , at least about 270 % , at least about 271 % , at least In some embodiments , methods of calculating BMImay about 272 % , at least about 273 % , at least about 274 % , at include , but are not limited to body weight in kilogram / least about 275 % , at least about 276 % , at least about 277 % ( height in meters ), body weight in pounds/ (height in at least about 278 % , at least about 279 % , or at least about inches ) ] x703 , and the like . 280 % , inclusive of all ranges and subranges therebetween , In some embodiments , the patient treated according to the 40 and any % ideal body weight described herein . In one methods of the present disclosure can alternatively be embodiment, the patient has % ideal body weight ( IBW ) of described as having a % ideal body weight % IBW ) of at at least about 150 % . In one embodiment, the patient has % least about 110 % , at least about 111 % , at least about 112 % , ideal body weight ( IBW ) of at least about 250 % . In other at least about 113 % , at least about 114 % , at least about embodiment, the patient has % IBW of at least 150 % and 115 % , at least about 116 % , at least about 117 % , at least 45 can be considered obese . about 118 % , at least about 119 % , at least about 120 % , at In some embodiments , the patient treated according to the least about 121 % , at least about 122 % , at least about 123 % , present disclosure can alternatively be described as having a at least about 124 % , at least about 125 % , at least about waist size or waist circumference greater than about 32 , 126 % , at least about 127 % , at least about 128 % , at least greater than about 33 , greater than about 34 , greater than about 129 % , at least about 130 % , at least about 131 % , at 50 about 35 inches, greater than about 36 , greater than about 37 , least about 132 % , at least about 133 % , at least about 134 % , greater than about 38 , greater than about 39 , greater than at least about 135 % , at least about 136 % , at least about about 40 , greater than about 41, greater than about 42 , 137 % , at least about 138 % , at least about 139 % , at least greater than about 43 , greater than about 44 , greater than about 140 % , at least about 141 % , at least about 142 % , at about 45 , greater than about 46 , greater than about 47 , least about 143 % , at least about 144 % , at least about 145 % , 55 greater than about 48 , greater than about 49, greater than at least about 146 % , at least about 147 % , at least about about 50 , greater than about 51 , greater than about 52 , 148 % , at least about 149 % , at least about 150 % , at least greater than about 53 , greater than about 54 , greater than about 151 % , at least about 152 % , at least about 153 % , at about 55 , greater than about 56 , greater than about 57 , least about 154 % , at least about 155 % , at least about 156 % , greater than about 58 , greater than about 59 , greater than at least about 157 % , at least about 158 % , at least about 60 about 60 inches , greater than about 61 inches , greater than 159 % , at least about 160 % , at least about 161 % , at least about 62 inches , greater than about 63 inches , greater than about 162 % , at least about 163 % , at least about 164 % , at about 64 inches, greater than about 65 inches , inclusive of all least about 165 % , at least about 166 % , at least about 167 % , ranges and subranges therebetween , and any waist size or at least about 168 % , at least about 169 % , at least about circumference described herein . In one embodiment, a 170 % , at least about 171 % , at least about 172 % , at least 65 patient having a waist size or waist circumference of about about 173 % , at least about 174 % , at least about 175 % , at 42 inches can be considered obese . In another embodiment, least about 176 % , at least about 177 % , at least about 178 % , the patienthas waist size or waist circumference greater than US 10 , 376 ,507 B2 22 about 48 inches . In other embodiment , the patient has waist 48 % , at least about 49 % , at least about 50 % , at least about or waist circumference of at least 42 inches . 51 % , at least about 52 % , at least about 53 % , at least about In some embodiments , the patient treated according to the 54 % , at least about 55 % , at least about 56 % , at least about methods of the present disclosure can alternatively be 57 % , at least about 58 % , at least about 59 % , at least about described as having a % body fat greater than about 20 % , 5 60 % , at least about 61 % , at least about 62 % , at least about greater than about 21 % , greater than about 22 % , greater than 63 % , at least about 64 % , at least about 65 % , at least about about 23 % , greater than about 24 % , greater than about 25 % , 66 % , at least about 67 % , at least about 68 % , at least about greater than about 26 % , greater than about 27 % , greater than 69 % , at least about 70 % , at least about 71 % , at least about about 28 % , greater than about 29 % , greater than about 30 % , 72 % , at least about 73 % , at least about 74 % , at least about greater than about 31 % , greater than about 32 % , greater than 10 75 % , at least about 76 % , at least about 77 % , at least about about 33 % , greater than about 34 % , greater than about 35 % , 78 % , at least about 79 % , or at least about 80 % , inclusive of greater than about 36 % , greater than about 37 % , greater than all ranges and subranges therebetween , and % android body about 38 % , greater than about 39 % , greater than about 40 % , fat described herein . In one embodiment, the patient has % greater than about 41 % , greater than about 42 % , greater than android body fat of at least about 50 % . about 43 % , greater than about 44 % , greater than about 45 % , 15 In other embodiments , the patient can alternatively be greater than about 46 % , greater than about 47 % , greater than described as having a % gynoid body fat greater than about about 48 % , greater than about 49 % , or greater than about 30 % , greater than about 31 % , greater than about 32 % , 50 % , inclusive of all ranges and subranges therebetween , greater than about 33 % , greater than about 34 % , greater than and any % body fat described herein . In one embodiment, about 35 % , greater than about 36 % , greater than about 37 % , the patient has a % body fat greater than about 40 % . In one 20 greater than about 38 % , greater than about 39 % , greater than embodiment, the patient has a % body fat of at least about about 40 % , greater than about 41 % , greater than about 42 % , 50 % . In another embodiment, a patient having a % body fat greater than about 43 % , greater than about 44 % , greater than greater than about 40 % can be considered obese . In some about 45 % , greater than about 46 % , greater than about 47 % , embodiments , methods of calculating % body fat can greater than about 48 % , greater than about 49 % , greater than include , but are not limited to total body fat expressed as a 25 about 50 % , greater than about 51 % , greater than about 52 % , percentage of total body weight . Other standards for obesity greater than about 53 % , greater than about 54 % , greater than can be used . For example, the American Council on Exercise about 55 % , greater than about 56 % , greater than about 57 % , suggests that an “ average " percentage of body fat for women greater than about 58 % , greater than about 59 % , greater than is about 25 - 31 % , and for men , about 18 - 24 % , and for obese about 60 % , greater than about 61 % , greater than about 62 % , women , about 32 % and higher, and obese men , about 25 % 30 greater than about 63 % , greater than about 64 % , greater than and higher. about 65 % , greater than about 66 % , greater than about 67 % , In other embodiments , the patient can alternatively be greater than about 68 % , greater than about 69 % , greater than described as having a % android body fat greater than about about 70 % , greater than about 71 % , greater than about 72 % , 30 % , greater than about 31 % , greater than about 32 % , greater than about 73 % , greater than about 74 % , greater than greater than about 33 % , greater than about 34 % , greater than 35 about 75 % , greater than about 76 % , greater than about 77 % , about 35 % , greater than about 36 % , greater than about 37 % , greater than about 78 % , greater than about 79 % , or greater greater than about 38 % , greater than about 39 % , greater than than about 80 % , inclusive of all ranges and subranges about 40 % , greater than about 41 % , greater than about 42 % , therebetween , and any % gynoid body fat described herein . greater than about 43 % , greater than about 44 % , greater than In one embodiment, a patient having a % gynoid body fat about 45 % , greater than about 46 % , greater than about 47 % , 40 greater than about 40 % can be considered obese . In one greater than about 48 % , greater than about 49 % , greater than embodiment, a patient having a % gynoid body fat greater about 50 % , greater than about 51 % , greater than about 52 % , than about 50 % can be considered obese . greater than about 53 % , greater than about 54 % , greater than In other embodiments , the patient can alternatively be about 55 % , greater than about 56 % , greater than about 57 % , described as having a total body fat content greater than greater than about 58 % , greater than about 59 % , greater than 45 about 30 kg , greater than about 31 kg , greater than about 32 about 60 % , greater than about 61 % , greater than about 62 % , kg , greater than about 33 kg , greater than about 34 kg , greater than about63 % , greater than about 64 % , greater than greater than about 35 kg , greater than about 36 kg , greater about 65 % , greater than about 66 % , greater than about 67 % , than about 37 kg , greater than about 38 kg , greater than greater than about 68 % , greater than about 69 % , greater than about 39 kg , greater than about 40 kg , greater than about 41 about 70 % , greater than about 71 % , greater than about 72 % , 50 kg , greater than about 42 kg , greater than about 43 kg , greater than about 73 % , greater than about 74 % , greater than greater than about 44 kg, greater than about 45 kg, greater about 75 % , greater than about 76 % , greater than about 77 % , than about 46 kg , greater than about 47 kg , greater than greater than about 78 % , greater than about 79 % , or greater about 48 kg , greater than about 49 kg , greater than about 50 than about 80 % , inclusive of all ranges and subranges kg , greater than about 51 kg , greater than about 52 kg , therebetween , and any % android body fat described herein . 55 greater than about 53 kg, greater than about 54 kg , greater In one embodiment, a patient having a % android body fat than about 55 kg , greater than about 56 kg , greater than greater than about 40 % can be considered obese . In one about 57 kg , greater than about 58 kg, greater than about 59 embodiment, a patient having a % android body fat greater kg , greater than about 60 kg , greater than about 61 kg , than about 50 % can be considered obese greater than about 62 kg , greater than about 63 kg , greater In other embodiments , the patient can alternatively be 60 than about 64 kg , greater than about 65 kg , greater than described as having a % android body fat of at least about about 66 kg, greater than about 67 kg , greater than about 68 30 % , at least about 31 % , at least about 32 % , at least about kg, greater than about 69 kg , greater than about 70 kg , 33 % , at least about 34 % , at least about 35 % , at least about greater than about 71 kg , greater than about 72 kg, greater 36 % , at least about 37 % , at least about 38 % , at least about than about 73 kg , greater than about 74 kg , greater than 39 % , at least about 40 % , at least about 41 % , at least about 65 about 75 kg , greater than about 76 kg , greater than about 77 42 % , at least about 43 % , at least about 44 % , at least about kg , greater than about 78 kg , greater than about 79 kg , 45 % , at least about 46 % , at least about 47 % , at least about greater than about 80 kg, greater than about 81 kg , greater US 10 , 376 , 507 B2 24 than about 82 kg, greater than about 83 kg , greater than example a BMI of at least about 35 , a % IBW of at least about 84 kg , greater than about 85 kg , greater than about 86 150 % , and waist size greater than about 42 inches . In some kg , greater than about 87 kg , greater than about 88 kg , embodiments , the patient can have a BMI of at least about greater than about 89 kg , greater than about 90 kg , greater 35 , a % IBW of at least 150 % , and a % body fat greater than than about 91 kg , greater than about 92 kg , greater than 5 about 40 % . In some embodiments , the patient can have a about 93 kg , greater than about 94 kg , greater than about 95 BMI of at least about 35 , a % IBW of at least 150 % , and a kg , greater than about 96 kg , greater than about 97 kg , android body fat greater than about 40 % . In some embodi greater than about 98 kg , greater than about 99 kg, greater ments , the patient can have a BMI of at least about 35 , a % than about 100 kg, at least 101 kg, at least 102 kg , at least IBW of at least 150 % , and a % gynoid body fat greater than 103 kg , at least 104 kg , at least 105 kg , at least 106 kg , at 10 about 40 % . In some embodiments, the patient can have a least 107 kg, at least 108 kg , at least 109 kg , or at least 110 BMI of at least about 35 , a % IBW of at least 150 % , and total kg , inclusive of all ranges and subranges therebetween , and body fat greater than about 40 kg . In various other embodi any total body fat described herein . In one embodiment, a ments , the patient can have any combination of three or patient having total body fat greater than about 40 kg can be more of any of the specific physiological parameters considered obese . In one embodiment , a patient having total 15 described herein . body fat greater than about 50 kg can be considered obese . In some embodiments , the patient can have four or more In other embodiments , the obesity status of patients of the physiological parameters described herein , for treated with the methods of the present disclosure can be example the patient can have a BMI of at least about 35 , a measured by waist - to - hip ratio . In other embodiments , the % IBW of at least 150 % , waist size greater than about 42 obesity status of patients can be measured by skinfold 20 inches , and a % body fat greater than about 40 % . In some thickness . In other embodiments , the obesity status of embodiments , the patient can have a BMI of at least about patients can be measured by bioelectric impedance . In other 35 , a % IBW of at least 150 % , waist size greater than about embodiments , the obesity status of patients can bemeasured 42 inches, and a % android body fat greater than about 40 % . by underwater weighing or densitometry. In other embodi- In some embodiments , the patient can have a BMIof at least ments , the obesity status of patients can be measured by 25 about 35 , a % IBW of at least 150 % , waist size greater than air -displacement plethysmography. In other embodiments, about 42 inches , and a % gynoid body fat greater than about the obesity status of patients can be measured by dilution 40 % . In some embodiments , the patient can have a BMI of method or hydrometry . In other embodiments , the obesity at least about 35 , a % IBW of at least 150 % , a waist size status of patients can be measured by dual energy X - ray greater than about 42 inches , and total body fat greater than absorptiometry . In other embodiments , the obesity status of 30 about 43 kg . In some a embodiments , the patient can have patients can be measured by computerized tomography and a BMI of at least about 35 , a % IBW of at least 150 % , a waist magnetic resonance imaging . In some embodiments , the size greater than about 42 inches , a % body fat greater than obesity status can be defined by , but is not limited to about 40 % , and a % android body fat greater than about adopting the clinical standards, conventional standards , and 40 % . In some embodiments, the patient can have a BMI of or the standards published by the World Health Organization 35 at least about 35 , a % IBW of at least 150 % , a waist size and Center of Disease Control (both of which are herein greater than about 42 inches , a % body fat greater than about incorporated by reference in their entireties for all purposes ) 40 % , and a % gynoid body fat greater than about 40 % . In when using the methods described herein . For example , the some embodiments , the patient can have a BMI of at least WHO defines an obese person as a person with a BMI of 30 about 35 , a % IBW of at least 150 % , a waist size greater than or more , an overweight person is one with a BMI equal to 40 about 42 inches , a % body fat greater than about 40 % , and or more than 25 (to less than 30 ) . Similarly , the CDC defines total body fat greater than about 40 kg . In some embodi normal as a BMIof 18 . 5 to less than 25 , 25 . 0 to less than 30 ments , the patient can have a BMI of at least about 35 , a % as overweight, and 30 .0 or higher as obese. The CDC further IBW of at least 150 % , a waist size greater than about 42 subdivides obesity into 3 classes : Class 1 , a BMI of 30 to inches , a % body fat greater than about 40 % , a % android less than 35 ; Class 2 , a BMI of 35 to less than 40 ; and Class 45 body fat greater than about 40 % , in % gynoid body fat 3 , as a BMI of 40 or higher . The CDC sometimes refers to greater than about 40 % , and total body fat greater than about Class 3 obesity as “ extreme" or " severe ” obesity . 40 kg. In one embodiment, the patient who has a BMI of at In some embodiments , the patient treated by the methods least about 35 , in % IBW of at least 150 % , a waist size of the present disclosure can be characterized by two or greater than about 42 inches , and a % body fat greater than more of the physiological characteristics described herein . 50 about 40 % , a % android body fat greater than about 40 % , a For example the patient can have a BMI of at least about 35 % gynoid body fat greater than about 40 % , and total body and can have a % IBW of at least 150 % . In some embodi- fat greater than about 40 kg . In various other embodiments , ments , the patient can have a BMI of at least about 35 and the patient can have any combination of any or all of the can have a waist size greater than about 42 inches . In some specific physiological parameters described herein . embodiments , the patient can have a BMI of at least about 55 In some embodiments , the patient can have a waist size 35 and can have a % body fat greater than about 40 % . In greater than about 42 inches , a body fat greater than about some embodiments , the patient can have a BMI of at least 40 % , and a % android body fat greater than about 40 % . In about 35 and can have a % android body fat greater than some embodiments , the patient can have a waist size greater about 40 % . In some embodiments, the patient can have a than about 42 inches , a % body fat greater than about 40 % , BMI of at least about 35 and can have a % gynoid body fat 60 and a % gynoid body fat greater than about 40 % . In some greater than about 40 % . In some embodiments, the patient embodiments , the patient can have a waist size greater than can have a BMI of at least about 35 and can have total body about 42 inches, a % body fat greater than about 40 % , and fat greater than about 40 kg . In various other embodiments , total body fat greater than about 40 kg . the patient can have any combination of two or more of any In some embodiments , the patient can have a % body fat of the specific physiological parameters described herein . 65 greater than about 40 % , a android body fat greater than In some embodiments , the patient can have three or more about 40 % , and a % gynoid body fat greater than about 40 % . of the physiological parameters described herein , for In some embodiments , the patient can have a % body fat US 10 , 376 ,507 B2 25 26 greater than about 40 % , a % android body fat greater than ranolazine , and the AUC of ranolazine is maintained at a about 40 % , and total body fat greater than about 40 kg. In level of no more than about 150 % of a normal baseline AUC some embodiments , the patient can have a % body fat of ranolazine. As used herein , the “ normal baseline AUC of greater than about 40 % , a % gynoid body fat greater than ranolazine” refers to the steady state AUC0- 12 measured for about 40 % , and total body fat greater than about 40 kg . In 5 a particular dose of ranolazine in the absence of other drugs . some embodiments , a % android body fat greater than about In some embodiments , the steady state AUC . .12 % CV ) is 40 % , and a % gynoid body fat greater than about 40 % , and 13 , 720 (67 . 0 % ) ng * h /mL measured after administration of total body fat greater than about 43 kg . In some embodi- 500 mg ranolazine . In some embodiments , the steady state ments, the patient can have any combinations of obesity AUC . ( % CV ) is 32 , 091 ( 42 . 2 % ) ng * h /mL measured after characteristics described herein 10 administration of 1 ,000 mg ranolazine . In other particular In some embodiments, patients with at least one of the embodiments , the CYP3A4 substrate drug is lurasidone , and obesity characteristics described herein can be an interme the AUC of lurasidone is maintained at a level of no more diate CYP3A4 metabolizer . In other embodiments , the than about 216 % of a normal baseline AUC of lurasidone. patients with at least one of the obesity characteristics As used herein , the “ normal baseline AUC of lurasidone ” described herein can be a poor CYP3A4 metabolizer. In 15 refers to the mean AUCoto measured for a particular dose some embodiments , the patients with at least one of the of lurasidone in the absence of other drugs . In some embodi obesity characteristics described herein can be an extensive ments , the mean AUCO - tou21/ , is about 743 ng * h /mL measured CYP3A4 metabolizer . In still other embodiments , the patient after administration of 120 mg lurasidone administered in is not obese , e . g . , can have normal weight, and be an the fed state after a 350 kcal meal. In other particular intermediate or poor CYP3A4 metabolizer . 20 embodiments , the CYP3A4 drug is tadalafil , and the AUC of Alternatively , in some embodiments , the CYP3A4 geno - tadalafil is maintained at a level of no more than about410 % type can be tested by using targeted variant analysis . In some of a normal baseline AUC of tadalafil. As used herein , the embodiments , the CYP3A4 genotype can be tested by using " normal baseline AUC of tadalafil ” refers to the mean sequence analysis of select exons. AUCO- C . ( % CV ) measured for a particular dose of tadalafil In various embodiments , the present disclosure also pro - 25 in the absence of other drugs . In some embodiments , the vides for methods of treating patients previously treated with mean AUCO- % CV ) is about 3647 ( 34 . 0 % ) ug * h / L posaconazole with a CYP3A4 substrate drug which is con - measured after administration of 10 mg tadalafil. In some traindicated for concomitant use with a strong CYP3A4 embodiments , the mean AUCO1 .- 0 . ( % CV ) is about 13, 006 inhibitor , such as posaconazole , wherein the CYP3A4 sub - ( 43 . 9 % ) ug * h / L for 20 mg tadalafil . In some embodiments , strate drug maintains an AUC which is no more than about 30 themean AUCO . ( % CV ) is within the range of about 7 ,000 450 % of a normal baseline AUC (as defined above ) of the to about 13 ,000 ( 40 . 0 % ) ug * h / L for 20 mg tadalafil. CYP3A4 substrate drug , e . g . , no more than about 445 % , no In various other embodiments , the present disclosure more than about 440 % , no more than about 435 % , no more provides for methods of treating patients previously treated than 430 % , no more than about 425 % , no more than about with posaconazole , comprising treating or prescribing a 420 % , no more than about 415 % , no more than about 410 % , 35 reduced dose of a CYP3A4 substrate drug which is con no more than about 405 % , no more than about 400 % , no traindicated for concomitant use with a strong CYP3A4 more than about 395 % , no more than about 390 % , no more inhibitor ( e . g . , about 10 % - 90 % , of the reference dose ) for a than about 385 % , no more than about 380 % , no more than period of about 2 -21 days after stopping posaconazole about 375 % , no more than about 370 % , no more than about treatment as described herein , wherein the CYP3A4 sub 365 % , no more than about 360 % , no more than about 355 % , 40 strate drug is maintained an AUC which is no more than no more than about 350 % , no more than about 345 % , no about 450 % of the baseline AUC of the CYP3A4 substrate more than about 340 % , no more than about 335 % , no more drug , e . g . , no more than about 445 % , no more than about than 330 % , no more than about 325 % , no more than about 440 % , no more than about 435 % , no more than 430 % , no 320 % , no more than about 315 % , no more than about 310 % , more than about 425 % , no more than about 420 % , no more no more than no more than about 305 % , or no more than 45 than about 415 % , no more than about 410 % , no more than about 300 % , no more than about 295 % , no more than about about 405 % , no more than about 400 % , no more than about 290 % , no more than about 285 % , no more than about 280 % , 395 % , no more than about 390 % , no more than about 385 % , no more than about 275 % , no more than about 270 % , no no more than about 380 % , no more than about 375 % , no more than about 265 % , no more than about 260 % , no more more than about 370 % , no more than about 365 % , no more than about 255 % , no more than about 250 % , no more than 50 than about 360 % , no more than about 355 % , no more than about 245 % , no more than about 240 % , no more than about about 350 % , no more than about 345 % , no more than about 235 % , no more than 230 % , no more than about 225 % , no 340 % , no more than about 335 % , no more than 330 % , no more than about 220 % , no more than about 216 % , no more more than about 325 % , no more than about 320 % , no more than about 215 % , no more than about 210 % , no more than than about 315 % , no more than about 310 % , no more than about 205 % , no more than about 200 % , no more than about 55 no more than about 305 % , or no more than about 300 % , no 195 % , no more than about 190 % , no more than about 185 % , more than about 295 % , no more than about 290 % , no more no more than about 180 % , no more than about 175 % , no than about 285 % , no more than about 280 % , no more than more than about 170 % , no more than about 165 % , no more about 275 % , no more than about 270 % , no more than about than about 160 % , no more than about 155 % , no more than 265 % , no more than about 260 % , no more than about 255 % , about 150 % , no more than about 145 % , no more than about 60 no more than about 250 % , no more than about 245 % , no 140 % , no more than about 135 % , no more than 130 % , no more than about 240 % , no more than about 235 % , no more more than about 125 % , no more than about 120 % , no more than 230 % , no more than about 225 % , no more than about than about 115 % , no more than about 110 % , no more than 220 % , no more than about 216 % , no more than about 215 % , no more than about 105 % , or no more than about 100 % of no more than about 210 % , no more than about 205 % , no the normal baseline AUC of the CYP3A4 substrate drug , 65 more than about 200 % , no more than about 195 % , no more inclusive of all ranges and subranges therebetween . In than about 190 % , no more than about 185 % , no more than particular embodiments , the CYP3A4 substrate drug is about 180 % , no more than about 175 % , no more than about US 10 , 376 ,507 B2 27 28 170 % , no more than about 165 % , no more than about 160 % , herein , the “ normal baseline Cmax of tadalafil ” refers to the no more than about 155 % , no more than about 150 % , no mean Cmor measured for a particular dose of tadalafil in the more than about 145 % , no more than about 140 % , no more absence ???of other drugs. In some embodiments , the mean than about 135 % , no more than 130 % , no more than about Cmax % CV ) is 190 ( 21 . 7 % ) ug/ L measured after adminis 125 % , no more than about 120 % , no more than about 115 % , 5 tration of 10 mg tadalafil. In some embodiments, the mean no more than about 110 % , no more than no more than about Cmor ( % CV ) is 548 ( 24 . 0 % ) ug / L measured after adminis 105 % , or no more than about 100 % of the normal baseline tration of 20 mg tadalafil . AUC of the CYP3A4 substrate drug , inclusive of all ranges in various other embodiments, the present disclosure and subranges therebetween . In particular embodiments, the provides for methods of treating patients previously on CYP3A4 substrate drug is ranolazine , and the AUC of 10 posaconazole with a reduced dose of a CYP3A4 substrate ranolazine is maintained at a level of no more than about drug ( e . g . , about 10 % -50 % of the reference dose ) which is 150 % of the normal baseline AUC of ranolazine. In other contraindicated for concomitant use with a strong CYP3A4 particular embodiments , the CYP3A4 substrate drug is inhibitor, wherein the CYP3A4 substrate drug is maintained lurasidone , and the AUC of lurasidone is maintained at a at a dose which provides a Cmor which is no more than about level of no more than about 216 % of the normal baseline 15 250 % of the normal baseline Cmor of the CYP3A4 substrate AUC of lurasidone . In other particular embodiments , the drug for a period of at least about 2 to at least about 21 days CYP3A4 substrate drug is tadalafil , and the AUC of tadalafil after stopping posaconazole treatment, e . g ., no more than is maintained at a level of no more than about 410 % of the about 250 % , no more than about 245 % , no more than about normal baseline AUC of tadalafil . In other particular 240 % , no more than about 235 % , no more than 230 % , no embodiments , the CYP3A4 substrate drug is tadalafil , and 20 more than about 225 % , no more than about 220 % , no more the AUC of tadalafil is maintained at a level of no more than than about 215 % , no more than about 210 % , no more than about 260 % of the normal baseline AUC of tadalafil. In other 205 % , no more than about 200 % , no more than about 195 % , particular embodiments , the CYP3A4 substrate drug is no more than about 190 % , no more than about 185 % , no tadalafil , and the AUC of tadalafil is maintained at a level of more than about 180 % , no more than about 175 % , no more no more than about 207 % of the normal baseline AUC of 25 than about 170 % , no more than about 165 % , no more than tadalafil . about 160 % , no more than about 155 % , no more than about In various embodiments, the present disclosure also pro - 150 % , no more than about 145 % , no more than about 140 % , vides for methods of treating patients previously treated with no more than about 135 % , no more than 130 % , no more than posaconazole , with a CYP3A4 substrate drug which is about 125 % , no more than about 120 % , no more than about contraindicated for concomitant use with a strong CYP3A4 30 115 % , no more than about 110 % , no more than no more than inhibitor , such as posaconazole , wherein the CYP3A4 sub - about 105 % , or no more than about 100 % inclusive of all strate drug maintains a Cmax which is no more than about ranges and subranges therebetween . In particular embodi 210 % of the normal baseline Cmor of the CYP3A4 substrate ments , the CYP3A4 substrate drug is ranolazine , and the drug , e . g . , no more than about 210 % , no more than about Cmax of ranolazine is maintained at a level of no more than 205 % , no more than about 200 % , no more than about 195 % , 35 about 150 % of the normal baseline Cmor of ranolazine . In no more than 190 % , no more than about 185 % , no more than other particular embodiments , the CYP3A4 substrate drug is about 180 % , no more than about 175 % , no more than about lurasidone , and the Cmormax of lurasidone is maintained at a 170 % , no more than 165 % , no more than about 160 % , no level of no more than about 210 % of the normal baseline more than about 155 % , no more than about 150 % , no more Cmax of lurasidone . In other particular embodiments , the than about 145 % , no more than about 140 % , no more than 40 CYP3A4 substrate drug is tadalafil, and the Cmor of tadalafil about 135 % , no more than about 130 % , no more than about is maintained at a level of no more than about 120 % of the 125 % , no more than about 120 % , no more than about 115 % , normal baseline Cmax of tadalafil . no more than about 110 % , no more than about 105 % , or no In embodiments in which the CYP3A4 substrate drug is more than about 100 % inclusive of all ranges and subranges ranolazine , the daily dose of ranolazine is no more than therebetween . In particular embodiments , the CYP3A4 sub - 45 about 500 mg, e . g ., about 490 mg, about 480 mg, about 470 strate drug is ranolazine , and the Cmor of ranolazine is mg, out 460 mg, about 450 mg, about 440 mg, about 430 mg , maintained at a level of no more than about 150 % of the about 420 mg, about 410 mg, about 400 mg, about 390 mg, normal baseline Cmax of ranolazine . As used herein , the about 380 mg, about 370 mg, 360 mg, about 350 mg, about " normal baseline C of ranolazine ” refers to the steady 340 mg, about 330 mg, about 320 mg, about 310 mg, about state Cmaxmeasured for a particular dose of ranolazine in the 50 300 mg, about 290 mg, about 280 mg, about 270 mg, 260 absence of other drugs . In some embodiments , the steady mg, about 250 mg, about 240 mg, about 230 mg, about 220 state Cmax ( % CV ) is 1081 (49 . 1 % ) ng/ mL measured after mg, about 210 mg, about 100 mg, about 190 mg, about 180 administration of 500 mg ranolazine . In some embodiments , mg , about 170 mg, 160 mg, about 150 mg, about 140 mg, the steady state Cm % CV ) is 1955 ( 54 . 0 % ) ng /mL about 130 mg , about 120 mg , about 110 mg, about 100 mg , measured after administration of 1 ,000 mg ranolazine . In 55 about 90 mg, about 80 mg, about 70 mg, about 60 mg, or other particular embodiments, the CYP3A4 substrate drug is about 50 mg, inclusive of all values and ranges therebe lurasidone , and the Cmax710X of lurasidone is maintained at a tween , and treatment is delayed for at least about 2 -21 days level of no more than about 210 % of the normal baseline after discontinuation of the posaconazole regimen , or Cmax of lurasidone. As used herein , the “ normal baseline reduced for the time period of about 2 - 21 days after discon

Cmor of lurasidone” refers to the mean CmorQ2 % measured for a 60 tinuation of the posaconazole regimen . particular dose of lurasidone in the absence of other drugs . In embodiments in which the CYP3A4 substrate drug is In some embodiments , the mean Cmar771 AX ( % CV ) is about 160 lurasidone , the daily dose of lurasidone is no more than ng /mL measured after administration of 120 mg lurasidone about 80 mg, e. g ., about 75 , about 70 mg, about 65 mg , in the fed state following a 350 kcalmeal . In other particular about 60 mg, about 55 mg, about 50 mg, about 45 mg, about embodiments , the CYP3A4 substrate drug is tadalafil , and 65 40 mg, about 35 mg , about 30 mg, about 25 mg, about 20 the Cmor of tadalafil is maintained at a level of no more than mg, about 15 mg, or about 10 mg, inclusive of all values and about 120 % of the normal baseline Cmar??? of tadalafil . As used ranges therebetween , and treatment is delayed for at least US 10 , 376 ,507 B2 29 30 about 2 -21 days after discontinuation of the posaconazole which CYP3 substrate drug is administered . In some regimen , or reduced for the time period of about 2 - 21 days embodiments, the disease or condition is selected from the after discontinuation of the posaconazole regimen . group consisting of schizophrenia in adults and adolescents In embodiments in which the CYP3A4 substrate drug is ( 13 to 17 years ), depressive episodes associated with Bipolar tadalafil , the daily dose of tadalafil is no more than about 2 . 5 5 I Disorder (bipolar depression ) in adults , as monotherapy or mg, e . g ., about 2 . 25 mg, about 2 . 0 mg, about 1 .75 mg, about as adjunctive therapy with lithium or valproate , chronic 1 . 5 mg, about 1 .25 mg, about 1 . 0 mg, about 0 .75 mg, or angina , erectile dysfunction ( ED ) , benign prostatic hyper about 0 . 5 mg, inclusive of all values and ranges therebe plasia (BPH ), and pulmonary arterial hypertension (PAH ) tween , and treatment is delayed for at least about 2 - 21 daysays after discontinuation of the posaconazole regimen , or 10 (WHO Group 1 ) to improve exercise ability . In some reduced for the time period of about 2 - 21 days after discon embodiments , the timeperiod for delaying administration of tinuation of the posaconazole regimen . the CYP3A4 substrate drug , or the timeperiod during which In other embodiments in which the CYP3A4 substrate the CYP3A4 substrate drug is administered at no more than drug is tadalafil, the 72 hr dose of tadalafil is no more than 50 % of the reference dose , is greater than about 21 days , about 10 mg, e . g . , about 9 . 5 mg, about 9 . 0 mg, about 8 . 5 mg, 15 e .S g ., forTor patientspatients with one or more physiological character about 8 . 0 mg, about 7 . 5 mg, about 7 . 0 mg, about 6 . 5 mg, istics described herein . about 6 . 0 mg, about 5 . 5 mg, about 5 . 0 mg, about 4 . 5 mg, Other particular embodiments are provided herein below : about 4 . 0 mg, about 3 . 5 mg, about 3 . 0 mg, about 2 . 5 mg, 1. A method of treating a patient who has previously been about 2 . 0 mg, about 1 . 5 mg, about 1 . 0 mg, or about 0 . 5 mg, administered a therapeutically effective regimen of posacon inclusive of all values and ranges therebetween , and treat- 20 azole , with a CYP3A4 substrate drug contraindicated for ment is delayed for at least about 2 - 21 days after discon - concomitant administration with a strong CYP3A4 inhibitor, tinuation of the posaconazole regimen , or reduced for the said method comprising : time period of about 2 -21 days after discontinuation of the first treating the patient, or prescribing a first treatment to posaconazole regimen . begin , with the CYP3A4 substrate drug at least 2 - 21 days In some embodiments , the time period for delaying treat- 25 after stopping administration of posaconazole . ment of the CYP3A4 substrate drug , or the time period 2 . The method of embodiment 1, wherein said CYP3A4 during which the patient is treated with a reduced dose ( e .g ., substrate drug is selected from the group consisting of no more than about 90 % , about 75 % , about 50 % , about 25 % , lurasidone , ranolazine , lumacaftor/ ivacaftor , venetoclax , tra etc . of the reference dose ) of the CYP3A4 substrate , is at bectedin , ribociclib succinate , deflazacort , cinacalcet hydro least about 1 . 5 times the reported average ty of posacon - 30 chloride , pimavanserin tartrate, aripiprazole lauroxil, carip azole , e . g . , about 2 times , about 2 . 5 times, about 3 times , razine hydrochloride , simeprevir sodium , everolimus, about 3 . 5 times , about 4 times , about 4 . 5 times , about 5 saxagliptin hydrochloride , saxagliptin /metformin hydro times , about 5 . 5 times , about 6 times , about 6 . 5 times , about chloride , ticagrelor , vilazodone hydrochloride , apixaban , 7 times, about 7 .5 times, about 8 times , about 8 . 5 times , tofacitinib citrate, eletriptan hydrobromide, nilotinib hydro about 9 times , about 9 . 5 times , about 10 times , inclusive of 35 chloride monohydrate , dronedarone hydrochloride , flutica all values and subranges therebetween . sone propionate / salmeterol xinafoate , rivaroxaban , tadalafil , The present disclosure also provides methods for treating , ibrutinib , cobimetinib , and colchicine. or prescribing treatment , with a CYP3A4 substrate drug 3 . The method of embodiment 2 , wherein the CYP3A4 intended to treat any of the disorders or conditions described substrate drug is lurasidone . herein , to a patientwho has been administered posaconazole 40 4 . The method of embodiment 2 , wherein the CYP3A4 prior to the administration of the CYP3A4 substrate drug . In substrate drug is ranolazine . addition to treating the disorder or condition treatable with 5 . The method of embodiment 2 , wherein the CYP3A4 the CYP3A4 substrate drug , in some embodiments the substrate drug is tadalafil . methods of the present invention reduce the severity or 6 . The method of any of embodiments 1 - 5 , wherein the incidence of side effects associated with administration of 45 patient is obese . the CYP3A4 substrate drug after stopping administration of 7 . The method of embodiment 6 , wherein the patient has posaconazole . In embodiments , these methods include ( a ) at least one of the following characteristics : treating a patient with multiple doses of posaconazole , ( b ) i ) BMI of at least about 35 ; not administering the CYP3A4 substrate drug during the ii ) % IBW of at least about 150 % ; administration of the posaconazole regimen , ( c ) stopping 50 iii) waist size greater than about 42 inches ; administration of posaconazole , ( d ) delaying treatment of a iv ) % body fat greater than about 40 % ; CYP3A4 substrate drug , or prescribing treatment of the v ) total body fat greater than about 40 kg; and CYP3A4 substrate drug to be delayed , for at least 2 - 21 days vi) medically diagnosed as obese . after stopping the posaconazole regimen , and then ( e ) treat- 8 . The method of any of embodiments 1 - 7 , wherein the ing with a CYP3A4 substrate drug . In other embodiments, 55 CYP3A4 substrate drug is ranolazine, and the AUC of the methods include ( a ) treating a patient with multiple ranolazine is maintained at a level of no more than about doses of posaconazole , ( b ) not treating the patient with the 150 % of a normal baseline AUC of ranolazine . CYP3A4 substrate drug during the posaconazole regimen , 9 . The method of any of embodiments 1 - 7 , wherein the ( c ) stopping the posaconazole regimen ; and ( d ) for at least CYP3A4 substrate drug is ranolazine, and the Cmax of about 2 -21 days after stopping the posaconazole regimen , 60 ranolazine is maintained at a level of no more than about treating the patient with the CYP3A4 substrate drug at a 150 % of a normal baseline Cmor of ranolazine. dose which is no more than about 50 % of the reference dose 10 . The method of any of embodiments 1 - 7 , wherein the of the CYP3A4 substrate drug ( e . g . , an amount in the range CYP3A4 substrate drug is lurasidone , and the AUC of of about 10 % to about 50 % , or about 10 % to about 90 % , of lurasidone is maintained at a level of no more than about the reference dose , as described above ) . The disease or 65 216 % of a normal baseline AUC of lurasidone. condition treated with the CYP3A4 substrate drug can 11 . The method of any of embodiments 1 - 7 , wherein the include any disease or condition described herein or for CYP3A4 substrate drug is lurasidone, and the Cmax* of US 10 , 376 ,507 B2 31 32 lurasidone is maintained at a level of no more than about 25 . The method of any of embodiments 15 -21 , wherein 210 % of a normal baseline C of lurasidone . the CYP3A4 substrate drug is lurasidone, and the Cmar of 12 . The method of any of embodiments 1 - 7 , wherein the lurasidone is maintained at a level of no more than about a CYP3A4 substrate drug is tadalafil, and the AUC of tadalafil normal baseline Cmormax of lurasidone to about 210 % of the is maintained at a level of no more than about 410 % of a 5 normal baseline Cmar of lurasidone . normal baseline AUC of tadalafil . 26 . The method of any of embodiments 15 - 21 , wherein 13 . The method of any of embodiments 1 - 7 , wherein the the CYP3A4 substrate drug is tadalafil , and the AUC of CYP3A4 substrate drug is tadalafil, and the a Cmax of tadalafil is maintained at a level of no more than about 410 % tadalafil is maintained at a level of no more than about 120 % of a normal baseline AUC of tadalafil . of a normal baseline Cmax of tadalafil . 10 27 . The method of any of embodiments 15 -21 , wherein 14 . The method of embodiments 1 - 10 , wherein the patient the CYP3A4 substrate drug is tadalafil, and the a Cmax of is a poor or intermediate CYP3A4 metabolizer. tadalafil is maintained at a level of no more than about 120 % 15 . A method of treating a patient with a CYP3A4 of a normal baseline Cmax of tadalafil . substrate drug contraindicated for concomitant administra 28 . The method of embodiments 15 - 27 , wherein the tion with a strong CYP3A4 inhibitor, comprising : 15 patient is a poor or intermediate CYP3A4 metabolizer . treating or prescribing a therapeutically effective amount 29 . The method of embodiment 15 , wherein the CYP3A4 of a CYP3A4 substrate drug to a patient in need thereof, substrate drug is ranolazine and the daily dose is no more wherein : than about 500 mg for at least about 2 - 21 days after said patient has previously been administered a therapeuti - discontinuation of the posaconazole regimen . cally effective regimen of posaconazole , and 20 30 . A method of treating a disease or condition in a patient for at least about 2 - 21 days after discontinuation of the with a CYP3A4 substrate drug which is contraindicated for posaconazole regimen , said patient is treated with the concomitant use with a strong CYP3A4 inhibitor, wherein CYP3A4 substrate drug is at a dose which is no more than the patient is also in need of treatment with posaconazole , about 50 % of the reference dose . comprising : 16 . The method of embodiment 15 , wherein said CYP3A4 25 ( a ) treating a patient with a therapeutically effective substrate drug is selected from the group consisting of regimen of posaconazole ; lurasidone , ranolazine , lumacaftor / ivacaftor, venetoclax , tra - (b ) not treating the patient with the CYP3A4 substrate bectedin , ribociclib succinate , deflazacort , cinacalcet hydro - drug during the posaconazole regimen , and for at least 2 - 21 chloride , pimavanserin tartrate , aripiprazole lauroxil , carip - days after stopping the posaconazole regimen ; and then razine hydrochloride , simeprevir sodium , everolimus , 30 ( c ) treating , or prescribing treatment to begin , with a saxagliptin hydrochloride , saxagliptin /metformin hydro - therapeutically effective amount of the CYP3A4 substrate chloride , ticagrelor, vilazodone hydrochloride , apixaban , drug ; tofacitinib citrate , eletriptan hydrobromide, nilotinib hydro wherein the disease or condition treated with the CYP3A4 chloride monohydrate , dronedarone hydrochloride , flutica - substrate drug is selected from the group consisting of sone propionate / salmeterol xinafoate , rivaroxaban , tadalafil, 35 schizophrenia in adults and adolescents ( 13 to 17 years ) , ibrutinib , cobimetinib , and colchicine . depressive episodes associated with Bipolar I Disorder (bi 17. The method of embodiment 16 , wherein the CYP3A4 polar depression ) in adults , as monotherapy or as adjunctive substrate drug is lurasidone . therapy with lithium or valproate, chronic angina , cystic 18 . The method of embodiment 16 , wherein the CYP3A4 fibrosis in patients 6 years and older who are homozygous substrate drug is ranolazine . 40 for the F508del mutation in the CFTR gene , chronic lym 19 . Themethod of embodiment 16 , wherein the CYP3A4 phocytic leukemia in patients with 17p deletion , who have substrate drug is tadalafil . received at least one prior therapy , unresectable or metastatic 20 . The method of any of embodiments 15 - 19 , wherein liposarcoma or leiomyosarcoma in patients who received a the patient is obese . prior anthracycline - containing regimen , advanced or meta 21 . The method of embodiment 20 , wherein the patient 45 static breast cancer in postmenopausal women with hormone has at least one of the following characteristics: receptor (HR ) -positive , human epidermal growth factor i ) BMI of at least about 35 ; receptor 2 (HER2 ) -negative advanced or metastatic breast ii ) % IBW of at least about 150 % ; cancer, negative advanced or metastatic breast cancer in iii ) waist size greater than about 42 inches ; combination with an aromatase inhibitor for postmeno iv ) % body fat greater than about 40 % ; 50 pausal women , Duchenne muscular dystrophy (DMD ) , sec v ) total body fat greater than about 40 kg ; and ondary hyperparathyroidism (HPT ) in patients with chronic vi ) medically diagnosed as obese . kidney disease (CKD ) on dialysis , hypercalcemia in patients 22 . The method of any of embodiments 15 - 21 , wherein with parathyroid carcinoma or in patients with primary HPT the CYP3A4 substrate drug is ranolazine , and the AUC of for who parathyroidectomy would be indicated on the basis ranolazine is maintained at a level of no more than about a 55 of serum calcium levels, but who are unable to undergo normal baseline AUC of ranolazine to about 150 % of the parathyroidectomy, hallucinations and delusions associated normal baseline AUC of ranolazine . with Parkinson ' s disease psychosis, schizophrenia , acute 23 . The method of any of embodiments 15 - 21, wherein manic or mixed episodes associated with bipolar I disorder, the CYP3A4 substrate drug is ranolazine , and the Cmax of chronic hepatitis C (CHC ) infection as a component of a ranolazine is maintained at a level of no more than about a 60 combination antiviral treatment regimen with peginterferon normal baseline Cmar71AN of ranolazine to about 150 % of the alfa and ribavirin in HCV genotype 1 infected subjects with normal baseline Cmor of ranolazine . compensated liver disease , postmenopausal women with 24 . The method of any of embodiments 15 -21 , wherein advanced hormone receptor -positive , HER2- negative breast the CYP3A4 substrate drug is lurasidone , and the AUC of cancer (advanced HR + BC ) , e . g . , in combination with lurasidone is maintained at a level of no more than about a 65 exemestane after failure of treatment with letrozole or normal baseline AUC of lurasidone to about 216 % of the anastrozole, progressive neuroendocrine tumors of pancre normal baseline AUC of lurasidone. atic origin ( PNET ) , progressive , well - differentiated , non US 10 , 376 ,507 B2 33 34 functional neuroendocrine tumors (NET ) of gastrointestinal 36 . The method of embodiment 35 , wherein the patient (GI ) or lung origin that are unresectable , locally advanced or has at least one of the following characteristics : metastatic , advanced renal cell carcinoma (RCC ) , e . g . , after i ) BMI of at least about 35 ; failure of treatment with sunitinib or sorafenib , renal angio ii ) % IBW of at least about 150 % ; myolipoma and tuberous sclerosis complex ( TSC ) , not 5 iii ) waist size greater than about 42 inches ; requiring immediate surgery, TSC in patients who have iv ) % body fat greater than about 40 % ; subependymal giant cell astrocytoma (SEGA ) that require v ) total body fat greater than about 40 kg ; and therapeutic intervention but are not candidates for surgical vi) medically diagnosed as obese . resection , type 2 diabetes mellitus in adults as an adjunct to 37. The method of any of embodiments 30 -36 , wherein diet and exercise to improve glycemic control , major depres - 10 the CYP3A4 substrate drug is ranolazine, and the AUC of sive disorder (MDD ) , thrombotic cardiovascular events ranolazine is maintained at a level of no more than about ( e. g ., cardiovascular death , myocardial infarction , or stroke ) 150 % of a normal baseline AUC of ranolazineHocine . in patients with acute coronary syndrome ( ACS ) , stroke and 38 . The method of any of embodiments 30 - 36 , wherein systemic embolism in patients with nonvalvular atrial fibril - the CYP3A4 substrate drug is ranolazine , and the Cmax of lation , deep vein thrombosis (DVT ) , which may lead to 15 ranolazine is maintained at a level of no more than about pulmonary embolism (PE ) in patients who have undergone 150 % of a normal baseline Cmor of ranolazine . hip or knee replacement surgery , DVT, PE , recurrent DVT 39 . The method of any of embodiments 30 - 36 , wherein and PE following initial therapy, moderate to severe active the CYP3A4 substrate drug is lurasidone, and the AUC of rheumatoid arthritis in patients who have had inadequate lurasidone is maintained at a level of no more than about response or tolerance to methotrexate , acute migraine with 20 216 % of a normal baseline AUC of lurasidone . or without aura , chronic phase and accelerated phase Phila 40 . The method of any of embodiments 30 - 36 , wherein delphia chromosome positive chronic myeloid leukemia the CYP3A4 substrate drug is lurasidone , and the Cmor of ( Ph + CML) in newly diagnosed patients or in patients lurasidone is maintained at a level of no more than about resistant to or intolerant to prior therapy that included 210 % of a normal baseline Cmor of lurasidone . imatinib , atrial fibrillation (AF ) in patients with a history of 25 41. The method of any of embodiments 30 - 36 , wherein paroxysmal or persistant AF or atrial flutter (AFK ) , who are the CYP3A4 substrate drug is tadalafil , and the AUC of in sinus rhythm or will be cardioverted , asthma in patients tadalafil is maintained at a level of no more than about 410 % aged 4 years and older , airflow obstruction and reducing of a normal baseline AUC of tadalafil . exacerbations in patients with chronic obstructive pulmo - 42 . The method of any of embodiments 30 - 36 , wherein nary disease , erectile dysfunction (ED ) , benign prostatic 30 the CYP3A4 substrate drug is tadalafil , and the a Cmax of hyperplasia (BPH ) , pulmonary arterial hypertension (PAH ) tadalafil is maintained at a level of no more than about 120 % (WHO Group 1 ) to improve exercise ability , gout flares , of a normal baseline Cmax of tadalafil . Familial Mediterranean fever antiretroviral therapy, anxiety 43 . The method of any of embodiments 30 - 42 , wherein disorders, panic disorders, seizures , insomnia , hypertension , the patient is a poor or intermediate CYP3A4 metabolizer. cardiovascular disease , hyperlipidemia , cancer, such as pri - 35 44 . A method of treating a disease or condition in a patient mary kidney cancer, advanced primary liver cancer, radio with a CYP3A4 substrate drug which is contraindicated for active iodine resistant advanced thyroid carcinoma, renal concomitant use with a strong CYP3A4 inhibitor, wherein cell carcinoma , imatinib - resistant gastrointestinal stromal the patient is also in need of treatment with posaconazole , tumor, mantle cell lymphoma in patients who have received comprising : at least one prior therapy , chronic lymphocytic leukemia / 40 ( a ) treating a patient with a therapeutically effective small lymphocytic lymphoma, chronic lymphocytic leuke regimen of posaconazole to the patient; mia / small lymphocytic lymphoma with 17p deletion , ( b ) not administering the CYP3A4 substrate drug during Waldenström ’ s macroglobulinemia , marginal zone lym - the administration of the posaconazole regimen ; phoma who require systemic therapy and have received at (c ) for at least about 2 -21 days after stopping the posa least one prior anti -CD20 -based therapy , unresectable or 45 conazole regimen , treating the patient with , or prescribing , metastatic melanoma with a BRAF V600E or V600K muta - the CYP3A4 substrate drug at a dose which is no more than tion , allergies , and transplantation . about 50 % of the reference dose ; 31. The method of embodiment 30 , wherein said CYP3A4 wherein the disease or condition treated with the CYP3A4 substrate drug is selected from the group consisting of substrate drug is selected from the group consisting of lurasidone , ranolazine , lumacaftor/ ivacaftor , venetoclax , tra - 50 schizophrenia in adults and adolescents ( 13 to 17 years ) , bectedin , ribociclib succinate , deflazacort , cinacalcet hydro - depressive episodes associated with Bipolar I Disorder (bi chloride, pimavanserin tartrate , aripiprazole lauroxil , carip polar depression ) in adults , as monotherapy or as adjunctive razine hydrochloride , simeprevir sodium , everolimus, therapy with lithium or valproate, chronic angina , cystic saxagliptin hydrochloride , saxagliptin /metformin hydro fibrosis in patients 6 years and older who are homozygous chloride , ticagrelor, vilazodone hydrochloride , apixaban , 55 for the F508del mutation in the CFTR gene , chronic lym tofacitinib citrate , eletriptan hydrobromide, nilotinib hydro - phocytic leukemia in patients with 17p deletion , who have chloride monohydrate , dronedarone hydrochloride , flutica- received at least one prior therapy, unresectable or metastatic sone propionate / salmeterol xinafoate , rivaroxaban , tadalafil , liposarcoma or leiomyosarcoma in patients who received a ibrutinib , cobimetinib , and colchicine . prior anthracycline - containing regimen , advanced or meta 32 . The method of embodiment 31 , wherein the CYP3A4 60 static breast cancer in postmenopausal women with hormone substrate drug is lurasidone . receptor (HR ) - positive , human epidermal growth factor 33 . The method of embodiment 31 , wherein the CYP3A4 receptor 2 (HER2 ) - negative advanced or metastatic breast substrate drug is ranolazine . cancer, negative advanced or metastatic breast cancer in 34 . The method of embodiment 31 , wherein the CYP3A4 combination with an aromatase inhibitor for postmeno substrate drug is tadalafil . 65 pausal women , Duchenne muscular dystrophy (DMD ) , sec 35 . The method of any of embodiments 30 -34 , wherein ondary hyperparathyroidism (HPT ) in patients with chronic the patient is obese . kidney disease ( CKD ) on dialysis , hypercalcemia in patients US 10 ,376 , 507 B2 35 36 with parathyroid carcinoma or in patients with primary HPT sone propionate / salmeterol xinafoate , rivaroxaban , tadalafil, for who parathyroidectomy would be indicated on the basis ibrutinib , cobimetinib , and colchicine . of serum calcium levels , but who are unable to undergo 46 . The method of embodiment 45 , wherein the CYP3A4 parathyroidectomy, hallucinations and delusions associated substrate drug is lurasidone . with Parkinson ' s disease psychosis, schizophrenia , acute 5 47 . The method of embodiment 45 , wherein the CYP3A4 manic or mixed episodes associated with bipolar I disorder , substrate drug is ranolazine . chronic hepatitis C ( CHC ) infection as a component of a 48 . The method of embodiment 45 , wherein the CYP3A4 combination antiviral treatment regimen with peginterferon substrate drug is tadalafil . alfa and ribavirin in HCV genotype 1 infected subjects with 49 . The method of any of embodiments 44 -48 , wherein compensated liver disease , postmenopausal women with the patient is obese . advanced hormone receptor- positive , HER2 -negative breast 50 . The method of embodiment 49 , wherein the patient cancer ( advanced HR + BC ) , e .g ., in combination with has at least one of the following characteristics : exemestane after failure of treatment with letrozole or i ) BMI of at least about 35 ; anastrozole , progressive neuroendocrine tumors of pancre - 15 ii ) % IBW of at least about 150 % ; atic origin ( PNET ) , progressive , well - differentiated , non iii ) waist size greater than about 42 inches; functional neuroendocrine tumors (NET ) of gastrointestinal iv ) % body fat greater than about 40 % ; (GI ) or lung origin that are unresectable , locally advanced or v ) total body fat greater than about 40 kg ; and metastatic , advanced renal cell carcinoma (RCC ) , e . g . , after vi ) medically diagnosed as obese . failure of treatment with sunitinib or sorafenib , renal angio - 2051. The method of any of embodiments 44 -50 , wherein myolipoma and tuberous sclerosis complex ( TSC ) , not the CYP3A4 substrate drug is ranolazine , and the AUC of requiring immediate surgery , TSC in patients who have ranolazine is maintained at a level of no more than about a subependymal giant cell astrocytoma (SEGA ) that require normal baseline AUC of ranolazine to about 150 % of the therapeutic intervention but are not candidates for surgical normal baseline AUC of ranolazine. resection , type 2 diabetes mellitus in adults as an adjunct to 25 52 . The method of any of embodiments 44 - 50 , wherein diet and exercise to improve glycemic control, major depres- the CYP3A4 substrate drug is ranolazine, and the Cmax of sive disorder (MDD ) , thrombotic cardiovascular events ranolazine is maintained at a level of no more than about a ( e . g . , cardiovascular death ,myocardial infarction , or stroke ) normal baseline Cmor of ranolazine to about 150 % of the in patients with acute coronary syndrome ( ACS ) , stroke and normal baseline Cmor of ranolazine . systemic embolism in patients with nonvalvular atrial fibril - 30 53 . The method of any of embodiments 44 - 50 , wherein lation , deep vein thrombosis (DVT ) , which may lead to the CYP3A4 substrate drug is lurasidone , and the AUC of pulmonary embolism (PE ) in patients who have undergone lurasidone is maintained at a level of no more than about a hip or knee replacement surgery , DVT, PE , recurrent DVT normal baseline AUC of lurasidone to about 216 % of the and PE following initial therapy, moderate to severe active normal baseline AUC of lurasidone. rheumatoid arthritis in patients who have had inadequate 35 54 . The method of any of embodiments 44 - 50 , wherein response or tolerance to methotrexate , acute migraine with the CYP3A4 substrate drug is lurasidone , and the Cmor of or without aura , chronic phase and accelerated phase Phila - lurasidone is maintained at a level of no more than about a delphia chromosome positive chronic myeloid leukemia normal baseline Cmax of lurasidone to about 210 % of the ( Ph + CML ) in newly diagnosed patients or in patients normal baseline Cmar of lurasidone . resistant to or intolerant to prior therapy that included 40 55 . The method of any of embodiments 44 - 50 , wherein imatinib , atrial fibrillation (AF ) in patients with a history of the CYP3A4 substrate drug is tadalafil, and the AUC of paroxysmal or persistant AF or atrial flutter ( AFK ) , who are tadalafil is maintained at a level of no more than about 410 % in sinus rhythm or will be cardioverted , asthma in patients of a normal baseline AUC of tadalafil. aged 4 years and older, airflow obstruction and reducing 56 . The method of any of embodiments 44 - 50 , wherein exacerbations in patients with chronic obstructive pulmo - 45 the CYP3A4 substrate drug is tadalafil, and the a Cmax of nary disease , erectile dysfunction (ED ) , benign prostatic tadalafil is maintained at a level of no more than about 120 % hyperplasia (BPH ), pulmonary arterial hypertension (PAH ) of a normal baseline Cmax of tadalafil. (WHO Group 1 ) to improve exercise ability , mantle cell 57 . The method of embodiments 44 - 56 , wherein the lymphoma in patients who have received at least one prior patient is a poor or intermediate CYP3A4 metabolizer . therapy , chronic lymphocytic leukemia / small lymphocytic 50 58 . The method of embodiment 44 , wherein the CYP3A4 lymphoma, chronic lymphocytic leukemia /small lympho - substrate drug is ranolazine and the daily dose is no more cytic lymphoma with 17p deletion , Waldenström ' s macro - than about 500 mg for at least about 2 - 21 days after globulinemia , marginal zone lymphoma who require sys - discontinuation of the posaconazole regimen . temic therapy and have received at least one prior ontianti 59 . A method of treating a patient in need thereof com CD20 -based therapy, unresectable or metastatic melanoma 55 prising delaying a first treatment of a CYP3A4 substrate with a BRAF V600E or V600K mutation , gout flares , and drug until about 2 -21 days after stopping administration of Familial Mediterranean fever . posaconazole . 45 . The method of embodiment 44 , wherein said CYP3A4 60 . The method of embodiment 59 , wherein said CYP3A4 substrate drug is selected from the group consisting of substrate drug is selected from the group consisting of lurasidone , ranolazine , lumacaftor / ivacaftor, venetoclax , tra - 60 lurasidone , ranolazine, lumacaftor/ ivacaftor , venetoclax , tra bectedin , ribociclib succinate , deflazacort , cinacalcet hydro - bectedin , ribociclib succinate , deflazacort, cinacalcet hydro chloride , pimavanserin tartrate , aripiprazole lauroxil, carip - chloride , pimavanserin tartrate , aripiprazole lauroxil, carip razine hydrochloride , simeprevir sodium , everolimus, razine hydrochloride , simeprevir sodium , everolimus , saxagliptin hydrochloride, saxagliptin /metformin hydro - saxagliptin hydrochloride, saxagliptin /metformin hydro chloride, ticagrelor , vilazodone hydrochloride, apixaban , 65 chloride , ticagrelor, vilazodone hydrochloride , apixaban , tofacitinib citrate , eletriptan hydrobromide , nilotinib hydro - tofacitinib citrate , eletriptan hydrobromide , nilotinib hydro chloride monohydrate , dronedarone hydrochloride, flutica - chloride monohydrate , dronedarone hydrochloride, flutica US 10 , 376 ,507 B2 37 38 sone propionate /salmeterol xinafoate , rivaroxaban , tadalafil, 85 . The method of embodiment 45 , wherein the CYP3A4 ibrutinib , cobimetinib , and colchicine . substrate drug is tadalafil . 61. The method of embodiment 60 , wherein the CYP3A4 86 . The method of any of embodiments 81- 85 , wherein substrate drug is lurasidone . the patient is obese . 62 . The method of embodiment 60 , wherein the CYP3A4 5 87 . The method of embodiment 86 , wherein the patient substrate drug is ranolazine . has at least one of the following characteristics: 63 . The method of embodiment 60 , wherein the CYP3A4 i ) BMI of at least about 35 ; substrate drug is tadalafil . ii ) % IBW of at least about 150 % ; 64 . The method of any of embodiments 59 -63 , wherein iii ) waist size greater than about 42 inches; the patient is obese . 10 iv ) % body fat greater than about 40 % ; 65 . The method of embodiment 64 , wherein the patient v ) total body fat greater than about 40 kg ; and has at least one of the following characteristics: vi) medically diagnosed as obese . i ) BMI of at least about 35 ; 88 . The method of any of embodiments 81 -87 , wherein ii ) % IBW of at least about 150 % ; the CYP3A4 substrate drug is ranolazine , and the AUC of iii ) waist size greater than about 42 inches ; 15 ranolazine is maintained at a level of no more than about iv ) % body fat greater than about 40 % ; 150 % of a normal baseline AUC of ranolazine . v ) total body fat greater than about 40 kg; and 89 . The method of any of embodiments 81 - 87 , wherein vi ) medically diagnosed as obese . the CYP3A4 substrate drug is ranolazine, and the Cmax of 66 . The method of any of embodiments 59 -65 , wherein ranolazine is maintained at a level of no more than about the CYP3A4 substrate drug is ranolazine , and the AUC of 20 150 % of a normal baseline Cmax of ranolazine . ranolazine is maintained at a level of no more than about 90 . The method of any of embodiments 81 - 87 , wherein 150 % of a normal baseline AUC of ranolazine . the CYP3A4 substrate drug is lurasidone , and the AUC of 67. The method of any of embodiments 59 -65 , wherein lurasidone is maintained at a level of no more than about the CYP3A4 substrate drug is ranolazine , and the Cmor of 216 % of a normal baseline AUC of lurasidone . ranolazine is maintained at a level of no more than about 25 91 . The method of any of embodiments 81 - 87 , wherein 150 % of a normal baseline Cmar of ranolazine . the CYP3A4 substrate drug is lurasidone, and the Cmax of 68 . The method of any of embodiments 59 -65 , wherein lurasidone is maintained at a level of no more than about the CYP3A4 substrate drug is lurasidone , and the AUC of 210 % of a normal baseline Cmor of lurasidone . lurasidone is maintained at a level of no more than about 92 . The method of any of embodiments 81 - 87 , wherein 216 % of a normal baseline AUC of lurasidone . 30 the CYP3A4 substrate drug is tadalafil , and the AUC of 68 . The method of any of embodiments 59 -65 , wherein tadalafil is maintained at a level of no more than about 410 % the CYP3A4 substrate drug is lurasidone , and the Cm of of a normal baseline AUC of tadalafil . lurasidone is maintained at a level of no more than about 93 . The method of any of embodiments 81 - 87 , wherein 210 % of a normal baseline Cmor of lurasidone. the CYP3A4 substrate drug is tadalafil , and the a Cmax of 69. The method of any of embodiments 59 -65 , wherein 35 tadalafil is maintained at a level of no more than about 120 % the CYP3A4 substrate drug is tadalafil , and the AUC of of a normal baseline Cmax of tadalafil. tadalafil is maintained at a level of no more than about 410 % 94 . The method of embodiments 81 - 93 , wherein the of a normal baseline AUC of tadalafil . patient is a poor or intermediate CYP3A4 metabolizer . 70 . The method of any of embodiments 59 -65 , wherein 95 . A method of treating a patient with a CYP3A4 the CYP3A4 substrate drug is tadalafil, and the a Cmax of 40 substrate drug contraindicated for concomitant use with a tadalafil is maintained at a level of no more than about 120 % strong CYP3A4 inhibitor, comprising treating the patient, or of a normal baseline Cmax of tadalafil . prescribing a treatment of , the CYP3A4 substrate drug at a 80 . The method of embodiments 59- 70 , wherein the dose which is less than or equal to about 50 % of the patient is a poor or intermediate CYP3A4 metabolizer. reference dose for a period of at least about 2 - 21 days after 81 . A method of treating a patient previously on posa - 45 stopping administration of posaconazole . conazole with a CYP3A4 substrate drug which is contrain - 96 . The method of embodiment 95 , wherein said CYP3A4 dicated for concomitant use with a strong CYP3A4 inhibitor substrate drug is selected from the group consisting of comprising, delaying a first treatment , or prescribing a first lurasidone , ranolazine , lumacaftor / ivacaftor, venetoclax , tra treatment to be delayed , of the CYP3A4 substrate drug for bectedin , ribociclib succinate , deflazacort, cinacalcet hydro at least about 2 -21 days after posaconazole administration 50 chloride , pimavanserin tartrate , aripiprazole lauroxil, carip has ceased . razine hydrochloride , simeprevir sodium , everolimus , 82 . The method of embodiment 81 , wherein said CYP3A4 saxagliptin hydrochloride , saxagliptin /metformin hydro substrate drug is selected from the group consisting of chloride , ticagrelor, vilazodone hydrochloride , apixaban , lurasidone, ranolazine, lumacaftor / ivacaftor, venetoclax , tra - tofacitinib citrate , eletriptan hydrobromide , nilotinib hydro bectedin , ribociclib succinate , deflazacort , cinacalcet hydro - 55 chloride monohydrate , dronedarone hydrochloride , flutica chloride , pimavanserin tartrate , aripiprazole lauroxil , carip - sone propionate /salmeterol xinafoate , rivaroxaban , tadalafil , razine hydrochloride , simeprevir sodium , everolimus, ibrutinib , cobimetinib , and colchicine . saxagliptin hydrochloride , saxagliptin / metformin hydro 97 . The method of embodiment 96 , wherein the CYP3A4 chloride , ticagrelor, vilazodone hydrochloride , apixaban , substrate drug is lurasidone . tofacitinib citrate , eletriptan hydrobromide , nilotinib hydro - 60 98 . The method of embodiment 96 , wherein the CYP3A4 chloride monohydrate , dronedarone hydrochloride, flutica - substrate drug is ranolazine . sone propionate / salmeterol xinafoate , rivaroxaban , tadalafil, 99 . The method of embodiment 96 , wherein the CYP3A4 ibrutinib , cobimetinib , and colchicine . substrate drug is tadalafil. 83 . The method of embodiment 82 , wherein the CYP3A4 100 . The method of any of embodiments 95 - 99 , wherein substrate drug is lurasidone . 65 the patient is obese . 84 . The method of embodiment 82, wherein the CYP3A4 101 . The method of embodiment 100 , wherein the patient substrate drug is ranolazine . has at least one of the following characteristics : US 10 , 376 ,507 B2 39 40 i ) BMI of at least about 35 ; ondary hyperparathyroidism (HPT ) in patients with chronic ii ) % IBW of at least about 150 % ; kidney disease (CKD ) on dialysis , hypercalcemia in patients iii ) waist size greater than about 42 inches ; with parathyroid carcinoma or in patients with primary HPT iv ) % body fat greater than about 40 % ; for who parathyroidectomy would be indicated on the basis v ) total body fat greater than about 40 kg ; and 5 of serum calcium levels , but who are unable to undergo vi) medically diagnosed as obese . parathyroidectomy, hallucinations and delusions associated 102 . Themethod of any of embodiments 95 - 101, wherein with Parkinson ' s disease psychosis , schizophrenia , acute the CYP3A4 substrate drug is ranolazine , and the AUC of manic or mixed episodes associated with bipolar I disorder, ranolazine is maintained at a level of no more than about a chronic hepatitis C (CHC ) infection as a component of a normal baseline AUC of ranolazine to about 150 % of the 10 combination antiviral treatment regimen with peginterferon normal baseline AUC of ranolazine. alfa and ribavirin in HCV genotype 1 infected subjects with 103. Themethod of any of embodiments 95 - 101, wherein compensated liver disease , postmenopausal women with the CYP3A4 substrate drug is ranolazine , and the Cmor of advanced hormone receptor- positive , HER2 -negative breast ranolazine is maintained at a level of no more than about a cancer (advanced HR + BC ) , e . g ., in combination with normal baseline Cmor of ranolazine to about 150 % of the 15 exemestane after failure of treatment with letrozole or normal baseline Cmax of ranolazine . anastrozole, progressive neuroendocrine tumors of pancre 104. The method of any of embodiments 95 - 101, wherein atic origin (PNET ) , progressive , well - differentiated , non the CYP3A4 substrate drug is lurasidone, and the AUC of functional neuroendocrine tumors (NET ) of gastrointestinal lurasidone is maintained at a level of no more than about a (GI ) or lung origin that are unresectable , locally advanced or normal baseline AUC of lurasidone to about 216 % of the 20 metastatic , advanced renal cell carcinoma (RCC ) , e . g . , after normal baseline AUC of lurasidone . failure of treatment with sunitinib or sorafenib , renal angio 105 . The method of any of embodiments 95 - 101, wherein myolipoma and tuberous sclerosis complex ( TSC ) , not the CYP3A4 substrate drug is lurasidone , and the Cmax of requiring immediate surgery , TSC in patients who have lurasidone is maintained at a level of no more than about a subependymal giant cell astrocytoma ( SEGA ) that require normal baseline Cmor of lurasidone to about 210 % of the 25 therapeutic intervention but are not candidates for surgical normal baseline Cmax of lurasidone . resection , type 2 diabetes mellitus in adults as an adjunct to 106 . The method of any of embodiments 95 - 101 , wherein diet and exercise to improve glycemic control, major depres the CYP3A4 substrate drug is tadalafil , and the AUC of sive disorder (MDD ) , thrombotic cardiovascular events tadalafil is maintained at a level of no more than about 410 % ( e . g ., cardiovascular death , myocardial infarction , or stroke ) of a normal baseline AUC of tadalafil . 30 in patients with acute coronary syndrome (ACS ), stroke and 107 . The method of any of embodiments 95 - 101 , wherein systemic embolism in patients with nonvalvular atrial fibril the CYP3A4 substrate drug is tadalafil , and the a Cmax of lation , deep vein thrombosis (DVT ), which may lead to tadalafil is maintained at a level of no more than about 120 % pulmonary embolism ( PE ) in patients who have undergone of a normal baseline Cmax of tadalafil. hip or knee replacement surgery , DVT, PE , recurrent DVT 108. The method of embodiments 95 - 107, wherein the 35 and PE following initial therapy , moderate to severe active patient is a poor or intermediate CYP3A4 metabolizer. rheumatoid arthritis in patients who have had inadequate 109. The method of embodiment 95 , wherein the response or tolerance to methotrexate , acute migraine with CYP3A4 substrate drug is ranolazine and the daily dose is or without aura , chronic phase and accelerated phase Phila no more than about 500 mg for at least about 2 -21 days after delphia chromosome positive chronic myeloid leukemia discontinuation of the posaconazole regimen . 40 ( Ph + CML) in newly diagnosed patients or in patients 110 . A method of treating a disease or condition in a resistant to or intolerant to prior therapy that included patient with a CYP3A4 substrate drug which is contraindi imatinib , atrial fibrillation (AF ) in patients with a history of cated for concomitant use with a strong CYP3A4 inhibitor, paroxysmal or persistant AF or atrial flutter (AFK ) , who are comprising : in sinus rhythm or will be cardioverted , asthma in patients ( a ) delaying a first treatment, or prescribing a delay of the 45 aged 4 years and older, airflow obstruction and reducing first treatment , of the CYP3A4 substrate drug for at least exacerbations in patients with chronic obstructive pulmo 2 - 21 days after stopping administration of posaconazole ; nary disease, erectile dysfunction ( ED ) , benign prostatic and then hyperplasia (BPH ) , pulmonary arterial hypertension (PAH ) ( b ) administering the CYP3A4 substrate drug ; (WHO Group 1 ) to improve exercise ability , gout flares , wherein the disease or condition treated with the CYP3A4 50 FamilialMediterranean fever , antiretroviral therapy, anxiety substrate drug is selected from the group consisting of disorders , panic disorders , seizures , insomnia , hypertension , schizophrenia in adults and adolescents ( 13 to 17 years ) , cardiovascular disease, hyperlipidemia , cancer, such as pri depressive episodes associated with Bipolar I Disorder ( bi - mary kidney cancer, advanced primary liver cancer, radio polar depression ) in adults , as monotherapy or as adjunctive active iodine resistant advanced thyroid carcinoma , renal therapy with lithium or valproate , chronic angina , cystic 55 cell carcinoma, imatinib - resistant gastrointestinal stromal fibrosis in patients 6 years and older who are homozygous tumor, mantle cell lymphoma in patients who have received for the F508del mutation in the CFTR gene , chronic lym - at least one prior therapy, chronic lymphocytic leukemia / phocytic leukemia in patients with 17p deletion , who have small lymphocytic lymphoma, chronic lymphocytic leuke received at least one prior therapy , unresectable ormetastatic mia / small lymphocytic lymphoma with 17p deletion , liposarcoma or leiomyosarcoma in patients who received a 60 Waldenström ' s macroglobulinemia , marginal zone lym prior anthracycline -containing regimen , advanced or meta - phoma who require systemic therapy and have received at static breast cancer in postmenopausal women with hormone least one prior anti -CD20 -based therapy , unresectable or receptor (HR ) -positive , human epidermal growth factor metastatic melanoma with a BRAF V600E or V600K muta receptor 2 (HER2 ) -negative advanced or metastatic breast tion , allergies, and transplantation . cancer , negative advanced or metastatic breast cancer in 65 111. The method of embodiment 110 , wherein said combination with an aromatase inhibitor for postmeno - CYP3A4 substrate drug is selected from the group consist pausal women , Duchenne muscular dystrophy (DMD ), sec - ing of lurasidone, ranolazine , lumacaftor/ ivacaftor , veneto US 10 , 376 ,507 B2 42 clax , trabectedin , ribociclib succinate , deflazacort, cinacal therapy with lithium or valproate , chronic angina , cystic cet hydrochloride , pimavanserin tartrate , aripiprazole fibrosis in patients 6 years and older who are homozygous lauroxil, cariprazine hydrochloride , simeprevir sodium , for the F508del mutation in the CFTR gene , chronic lym everolimus, saxagliptin hydrochloride , saxagliptin /met phocytic leukemia in patients with 17p deletion , who have formin hydrochloride , ticagrelor, vilazodone hydrochloride , 5 received at least one prior therapy , unresectable or metastatic apixaban , tofacitinib citrate , eletriptan hydrobromide , nilo - liposarcoma or leiomyosarcoma in patients who received a tinib hydrochloride monohydrate , dronedarone hydrochlo prior anthracycline - containing regimen , advanced or meta ride, fluticasone propionate / salmeterol xinafoate , rivaroxa static breast cancer in postmenopausalwomen with hormone ban , tadalafil, ibrutinib , cobimetinib , and colchicine . receptor (HR ) - positive , human epidermal growth factor 112 . The method of embodiment 111, wherein the 10 receptor 2 (HER2 )- negative advanced or metastatic breast CYP3A4 substrate drug is lurasidone . cancer, negative advanced or metastatic breast cancer in 113. The method of embodiment 111 , wherein the combination with an aromatase inhibitor for postmeno CYP3A4 substrate drug is ranolazine . pausal women , Duchenne muscular dystrophy (DMD ) , sec 114 . The method of embodiment 111, wherein the ondary hyperparathyroidism (HPT ) in patients with chronic CYP3A4 substrate drug is tadalafil. 15 kidney disease (CKD ) on dialysis , hypercalcemia in patients 115 . The method of any of embodiments 110 - 114 , with parathyroid carcinoma or in patients with primary HPT wherein the patient is obese . for who parathyroidectomy would be indicated on the basis 116 . The method of embodiment 115 , wherein the patient of serum calcium levels , but who are unable to undergo has at least one of the following characteristics : parathyroidectomy, hallucinations and delusions associated i ) BMI of at least about 35 ; 20 with Parkinson ' s disease psychosis , schizophrenia , acute ii) % IBW of at least about 150 % ; manic or mixed episodes associated with bipolar I disorder , iii ) waist size greater than about 42 inches; chronic hepatitis C (CHC ) infection as a component of a iv ) % body fat greater than about 40 % ; combination antiviral treatment regimen with peginterferon v ) total body fat greater than about 40 kg; and alfa and ribavirin in HCV genotype 1 infected subjects with vi) medically diagnosed as obese . 25 compensated liver disease , postmenopausal women with 117 . The method of any of embodiments 110 - 116 , advanced hormone receptor -positive , HER2 -negative breast wherein the CYP3A4 substrate drug is ranolazine , and the cancer (advanced HR + BC ) , e . g ., in combination with AUC of ranolazine is maintained at a level of no more than exemestane after failure of treatment with letrozole or about 150 % of a normal baseline AUC of ranolazine . anastrozole, progressive neuroendocrine tumors of pancre 118 . The method of any of embodiments 110 - 116 , 30 atic origin (PNET ), progressive , well -differentiated , non wherein the CYP3A4 substrate drug is ranolazine , and the functional neuroendocrine tumors (NET ) of gastrointestinal Cmor of ranolazine is maintained at a level of no more than (GI ) or lung origin that are unresectable , locally advanced or about 150 % of a normal baseline Cmax of ranolazine . metastatic , advanced renal cell carcinoma (RCC ) , e . g ., after 119. The method of any of embodiments 110 - 116 , failure of treatment with sunitinib or sorafenib , renal angio wherein the CYP3A4 substrate drug is lurasidone, and the 35 myolipoma and tuberous sclerosis complex ( TSC ), not AUC of lurasidone is maintained at a level of no more than requiring immediate surgery , TSC in patients who have about 216 % of a normal baseline AUC of lurasidone . subependymal giant cell astrocytoma (SEGA ) that require 120 . The method of any of embodiments 110 - 116 , therapeutic intervention but are not candidates for surgical wherein the CYP3A4 substrate drug is lurasidone, and the resection , type 2 diabetes mellitus in adults as an adjunct to Cmar of lurasidone is maintained at a level of no more than 40 diet and exercise to improve glycemic control, major depres about 210 % of a normal baseline Cmor of lurasidone. sive disorder (MDD ) , thrombotic cardiovascular events 121 . The method of any of embodiments 110 - 116 , ( e . g . , cardiovascular death , myocardial infarction , or stroke ) wherein the CYP3A4 substrate drug is tadalafil , and the in patients with acute coronary syndrome (ACS ) , stroke and AUC of tadalafil is maintained at a level of no more than systemic embolism in patients with nonvalvular atrial fibril about 410 % of a normal baseline AUC of tadalafil . 45 lation , deep vein thrombosis (DVT ) , which may lead to 122 . The method of any of embodiments 110 - 116 , pulmonary embolism (PE ) in patients who have undergone wherein the CYP3A4 substrate drug is tadalafil , and the a hip or knee replacement surgery , DVT, PE , recurrent DVT Cmax of tadalafil is maintained at a level of no more than and PE following initial therapy, moderate to severe active about 120 % of a normal baseline Cmax of tadalafil. rheumatoid arthritis in patients who have had inadequate 123 . The method of embodiments 110 - 122 , wherein the 50 response or tolerance to methotrexate , acute migraine with patient is a poor or intermediate CYP3A4 metabolizer. or without aura , chronic phase and accelerated phase Phila 124 . A method of treating a patient with a CYP3A4 delphia chromosome positive chronic myeloid leukemia substrate drug which is contraindicated for concomitant use ( Ph + CML ) in newly diagnosed patients or in patients with a strong CYP3A4 inhibitor, comprising : resistant to or intolerant to prior therapy that included (a ) delaying a first treatment, or prescribing a delay in the 55 imatinib , atrial fibrillation (AF ) in patients with a history of first treatment , of the CYP3A4 substrate drug for at least paroxysmal or persistant AF or atrial flutter (AFK ), who are about 2 - 21 days after stopping administration of the posa in sinus rhythm or will be cardioverted , asthma in patients conazole regimen ; and then aged 4 years and older, airflow obstruction and reducing ( d ) treating the patient with the CYP3A4 substrate drug at exacerbations in patients with chronic obstructive pulmo a dose which is less than or equal to about 50 % of the 60 nary disease , erectile dysfunction (ED ) , benign prostatic reference dose for at least about 2 - 21 days after stopping hyperplasia ( BPH ) , pulmonary arterial hypertension (PAH ) administration of the posaconazole regimen ; (WHO Group 1 ) to improve exercise ability , gout flares , wherein the disease or condition treated with the CYP3A4 FamilialMediterranean fever , antiretroviral therapy, anxiety substrate drug is selected from the group consisting of disorders , panic disorders , seizures , insomnia , hypertension , schizophrenia in adults and adolescents ( 13 to 17 years ), 65 cardiovascular disease , hyperlipidemia , cancer, such as pri depressive episodes associated with Bipolar I Disorder ( bi - mary kidney cancer, advanced primary liver cancer, radio polar depression ) in adults , as monotherapy or as adjunctive active iodine resistant advanced thyroid carcinoma, renal US 10 ,376 , 507 B2 43 44 cell carcinoma, imatinib -resistant gastrointestinal stromal 134 . The method of any of embodiments 124 - 132 , tumor, mantle cell lymphoma in patients who have received wherein the CYP3A4 substrate drug is lurasidone , and the at least one prior therapy , chronic lymphocytic leukemia / Cmor of lurasidone is maintained at a level of no more than small lymphocytic lymphoma, chronic lymphocytic leuke about a normal baseline Cmor of lurasidone to about 210 % of mia / small lymphocytic lymphoma with 17p deletion , 5 the normal baseline Cmor of lurasidone . Waldenström ' s macroglobulinemia , marginal zone lym - 135 . The method of any of embodiments 124 - 132 , phoma who require systemic therapy and have received at wherein the CYP3A4 substrate drug is tadalafil, and the least one prior anti -CD20 -based therapy, unresectable or AUC of tadalafil is maintained at a level of no more than metastatic melanoma with a BRAF V600E or V600K muta - about 410 % of a normal baseline AUC of tadalafil . tion , allergies, and transplantation . 10 136 . The method of any of embodiments 124 - 132 , 125 . The method of embodiment 124 , wherein said wherein the CYP3A4 substrate drug is tadalafil , and the a CYP3A4 substrate drug is selected from the group consist - Cmax of tadalafil is maintained at a level of no more than ing of lurasidone , ranolazine , lumacaftor/ ivacaftor , veneto - about 120 % of a normal baseline Cmax of tadalafil . clax , trabectedin , ribociclib succinate , deflazacort , cinacal 137 . The method of any one of embodiments 134 - 136 , cet hydrochloride , pimavanserin tartrate , aripiprazole 15 wherein the patient is a poor or intermediate CYP3A4 lauroxil, cariprazine hydrochloride , simeprevir sodium , metabolizer . everolimus , saxagliptin hydrochloride , saxagliptin /met formin hydrochloride , ticagrelor, vilazodone hydrochloride , EXAMPLES apixaban , tofacitinib citrate , eletriptan hydrobromide , nilo tinib hydrochloride monohydrate , dronedarone hydrochlo - 20 Example 1 . Pharmacokinetic Studies with ride , fluticasone propionate / salmeterol xinafoate , rivaroxa Posaconazole and Lurasidone ban , tadalafil, ibrutinib , cobimetinib , and colchicine . 126 . The method of embodiment 125 , wherein the Inventors studied 6 obese male and female subjects ( ages CYP3A4 substrate drug is lurasidone . 18 - 50 , BMI> 35 ) taking Posaconazole oral tablets (300 mg 127 . The method of embodiment 125 , wherein the 25 qd ) and Lurasidone (20 mg qd ) . Body weights and BMI CYP3A4 substrate drug is ranolazine . measurements for the 6 subjects are provided below in Table 128 . The method of embodiment 125 , wherein the 1 . CYP3A4 substrate drug is tadalafil. 129 . The method of any of embodiments 124 - 128 , TABLE 1 wherein the patient is obese . 30 130 . The method of embodiment 129 , wherein the patient Subject Demographics has at least one of the following characteristics: Subject # Weight (kg ) BMI (kg /m² ) i ) BMI of at least about 35 ; 101 - 001 111 . 8 45 ii ) % IBW of at least about 150 % ; 101 - 002 136 . 8 44 . 4 iii ) waist size greater than about 42 inches ; 35 101 - 005 137 . 7 51 . 2 iv ) % body fat greater than about 40 % ; 101 - 007 103 . 7 36 . 8 v ) total body fat greater than about 40 kg ; and 101 - 008 122. 3 39 . 8 vi) medically diagnosed as obese . 101- 010 120 . 0 43 . 9 131. The method of any of embodiments 124 - 132 , wherein the CYP3A4 substrate drug is ranolazine , and the 40 Subjects were dosed with Lurasidone alone on Day 1 , AUC of ranolazine is maintained at a level of no more than then subsequently dosed to steady - state Posaconazole levels , about a normal baseline AUC of ranolazine to about 150 % with a loading dose of 300 mg twice a day on Day 2 and 300 of the normal baseline AUC of ranolazine . mg once a day thereafter over a period of 14 days . Posa 132 . The method of any of embodiments 124 - 132 , conazole administration was then stopped and Lurasidone wherein the CYP3A4 substrate drug is ranolazine , and the 45 (20 mg qd ) administered 2 , 4 , and 6 days after administration Cmax of ranolazine is maintained at a level of no more than had ceased ( studies days 17 , 19, and 21 respectively ) . about a normal baseline Cmor of ranolazine to about 150 % of Lurasidone AUC was measured for 24 hours after each the normal baseline Cmax of ranolazine . administration . Table 2 shows subject Lurasidone AUC 133 . The method of any of embodiments 124 - 132 , levels 2 , 4 and 6 days after Posaconazole was stopped , wherein the CYP3A4 substrate drug is lurasidone , and the 50 Posaconazole AUC levels 2 , 4 , and 6 days after Posacon AUC of lurasidone is maintained at a level of no more than azole was stopped , and the ratio of post -Posaconazole Lur about a normal baseline AUC of lurasidone to about 216 % asidone AUC to the baseline Lurasidone AUC measured of the normal baseline AUC of lurasidone . before Posaconazole treatment: TABLE 2 Lurasidone AUC Posaconazole AUC Lurasidone AUC Ratio Subject Data ( ng * h / mL ) ( ng * h / mL ) relative to Day 1 BMI Weight Subject Day 1 Day 17 Day 19 Day 21 Day 17 Day 19 Day 21 Day 17 Day 19 Day 21 (kg / m (kg ) HMS001 101 - 001 92 . 8 284 234 .4 204. 5 2886 2019 1365 3 .06 2 .53 2 .20 45 .0 111 . 8 DES005 101 - 005 26 167 . 3 186 168 2512 1954 1563 6 . 43 7 . 15 6 . 46 51 . 2 137 . 7 TRB007 101 - 007 38 . 3 173 . 8 89 . 5 124 . 7 824 542 285 4 . 54 2 . 34 3 . 26 36 . 8 103. 7 NNJO10 101 -010 71 211 . 7 163 226 4551 3688 3081 2 .98 2 . 30 3 . 18 43 . 9 120 . 0 KDHOO2 101 - 002 110 195 . 5 146 186 . 3 1299 626 284 1 . 78 1 . 33 1 .69 44 . 4 136 . 8 DTG008 101 - 008 45 . 6 57 36 . 2 27 . 8 190 78 31 1 . 25 0 .79 0 .61 39 . 8 122. 3 US 10 , 376 ,507 B2 45 46 Table 3 compares Lurasidone AUC levels after Posacon The invention claimed is : azole treatment to baseline Lurasidone AUC levels . 1 . A method of treating a patient for a condition selected from schizophrenia or bipolar depression with lurasidone, wherein the patient is treated with posaconazole , compris TABLE 3 5 ing : Lurasidone Levels vs . Base Line Days ( a ) stopping posaconazole treatment; After Posaconazole Was Ceased (b ) delaying administering a first dose of lurasidone ranging from 20 mg to 120 mg until Day 2 Day 4 Day 6 at least 9 days after stopping posaconazole in step ( a ). Mean 3 . 3x 2 .7x 2 .9x 2 . The method of claim 1 , wherein the first dose of Min 1 . 3x 0 .8x 0 .6x 10 lurasidone is 20 mg. Max 6 . 4x 7 . 2x 6 . 5x 3 . The method of claim 1 , wherein the first dose of Median 3 . 0x 2 . 3x 2 . 7x lurasidone is 40 mg. 4 . The method of claim 1 , wherein the first dose of lurasidone is 60 mg . As shown above in Table 3 , the post -Posaconazole treat - 15 5 The method of claim 1 . wherein the first dose of ment mean AUC ratios of Lurasidone are about 3 times lurasidone is 80 mg. higher than the baseline . This data indicates that Posacon 6 . The method of claim 1 , wherein the first dose of azole accumulates in obese subjects , and results in signifi lurasidone is 120 mg. cantly higher Lurasidone AUC levels compared to baseline 7 . The method of claim 1 , wherein the patient is not obese . levels measured before Posaconazole treatment. 208 . The method of claim 1 , wherein the patient has at least one characteristic selected from the group consisting of the The AUC measurements from two patients (DTG008 and following: KDH002 ) indicates that these patients were non - compliant i) BM? of at least about 35 ; with the Posaconazole treatment regimen , and the corre ii ) waist size greater than about 42 inches ; sponding AUC measurements were removed from the study. 26 iii ) % body fat greater than about 40 % ; The results are shown below in Table 4 . iv ) total body fat greater than about 40 kg, and ; v ) medically diagnosed as obese . TABLE 4 9 . The method of claim 1 , wherein the schizophrenia is schizophrenia in adults and adolescents ( 13 to 17 years ) ; and Lurasidone Levels vs. Base Line Days the bipolar depression is depressive episodes associated with After Posaconazole Was Ceased Bipolar I Disorder in adults , as monotherapy or as adjunctive Excluding DTG008 & KDH002 therapy with lithium or valproate . Day 2 Day 4 Day 6 10 . The method of claim 1 , wherein said administering in step Q is 9 -21 days after stopping posaconazole in step (a ). Mean 4 . 3x 3 .6x 3 . 8x Min 3 .0x 2 . 3x 2 .2x 11 . The method of claim 1 , wherein said administering in Max 6 .4x 7 . 2x 6 .5x 35 step is 9 days after stopping posaconazole in step (a ). Median 3 . 8x 2 .4x 3 .2x 12 . The method of claim 1 , wherein said administering in step is 10 days after stopping posaconazole in step ( a ) . 13 . The method of claim 1 , wherein said administering in These results indicate that post - Posaconazole treatment step Q is 11 days after stopping posaconazole in step ( a ) . mean AUC ratio values for Lurasidone are in the range of 40 14 . The method of claim 1 , wherein said administering in from 3 .6 - 4 . 3x for 2 -6 days after ceasing Posaconazole step Q is 12 days after stopping posaconazole in step (a ). treatment. 15 . The method of claim 1, wherein said administering in In conclusion , the results from the clinical trials reported step is 13 days after stopping posaconazole in step ( a ). in Example 1 indicate that the Posaconazole accumulates in 16 . The method of claim 1 , wherein said administering in the body of obese patients after treatment has stopped , andod 45 step Q is 14 days after stopping posaconazole in step ( a ) . patients should delay a first dose of Lurasidone or reduce the 17 . The method of claim 8 , wherein said delaying of step first dose of Lurasidone to achieve safe blood plasma levels (b ) is at least 21 days. of Lurasidone .