US 20090042935A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0042935 A1 De Porre et al. (43) Pub. Date: Feb. 12, 2009
(54) NOVEL IV FORMULATION OF TIPIFARNIB Related U.S. Application Data (63) Continuation of application No. 11/549,188, ?led on (76) Inventors: Peter M. R. De Porre, Gent (BE); Oct. 13, 2006. Willy A.M.C. Dries, Merksplas (60) Provisional application No. 60/726,911, ?led on Oct. (BE); Marc K.J. Francois, 14, 2005. Kapellen (BE); Peter A. Palmer, Publication Classi?cation Keerbergen (BE) (51) Int. Cl. C07D 401/10 (2006.01) A61K 31/4709 (2006.01) Correspondence Address: A61P 35/02 (2006.01) PHILIP S. JOHNSON A61P 35/04 (2006.01) JOHNSON & JOHNSON (52) U.S. Cl...... 514/312; 546/157 ONE JOHNSON & JOHNSON PLAZA NEW BRUNSWICK, NJ 08933-7003 (US) (57) ABSTRACT This invention concerns compositions of tipifarnib, mannitol, and hydroxypropyl-[3-cyclodextrin and, suitable for intrave (21) Appl. No.: 12/253,799 nous (IV) administration. The invention further concerns the use of such formulation and processes for preparing such formulations and methods of treating by administering said (22) Filed: Oct. 17, 2008 formulations. US 2009/0042935 A1 Feb. 12, 2009
NOVEL IV FORMULATION OF TIPIFARNIB [0005] Tipifarnib is a potent and selective nonpeptidomi metic competitive inhibitor of human famesyltransferase CROSS REFERENCE TO RELATED (FTase) in vitro and in vivo. This compound has antiprolif APPLICATIONS erative effects at nanomolar concentrations in vitro, and has [0001] This present application claims bene?t of US. Pro antitumor effects as monotherapy in several in vitro and in visional Patent Application Ser. No. 60/ 726,91 1 ?led Oct. 14, vivo models and in the clinic. The predominant antitumor 2005, Which is incorporated herein by reference in its entirety effects of tipifarnib include inhibition of angiogenesis, induc and for all purposes. tion of apoptosis, and direct antiproliferation. [0006] Famesylated targets, such as (but not limited to) FIELD OF THE INVENTION Ras, RhoB, and phosphatidyl inositol-3 kinase (PI3K)/serine [0002] This invention concerns novel formulations of tipi threonine kinase AKT that are involved in cellular homeosta famib, Which are suitable for intravenous (IV) administration. sis and proliferation are often mutated or dysregulated in The invention further concerns the use of such formulation AML. Inhibition of famesylation prevents myeloid leukemic and processes for preparing such formulations and methods cell groWth and progenitor colony formation in vitro. Leuke of treating patients by administering said formulations to said mic cells obtained from cancer patients Were signi?cantly patients. more sensitive to the groWth-inhibitory effects of tipifamib than normal bone marroW cells. The identi?cation of the BACKGROUND OF THE INVENTION speci?c doWnstream effectors by Which inhibition of fame [0003] Tipifarnib is described in WO 97/21701 . The chemi sylation results in antileukemic activity is a subject of ongo cal name for tipifamib is (R)-(+)-6-[amino94-chlorophenyl) ing research. Tipifarnib has shoWn signs of clinical activity in (1-methyl-1H-imidaZol-5-yl)methyl]-4-(3-chlorophenyl)-1 patients With hematologic malignancies including but not methyl-2(1H)quinolinone. The trade name of tipifarnib is limited to acute myelogenous leukaemia, myelodysplastic trade name ZARNESTRA®. The absolute stereochemical syndrome and multiple myeloma and in patients With solid con?guration of the compound Was not determined in the tumours including but not limited to glioblastoma and breast experiments described in the above-mentioned patent speci cancer. ?cation, but the compound Was identi?ed by the pre?x “(B)” [0007] To date, several investigators have examined the to indicate that it Was the second compound isolated from pharmacokinetics of tipifamib after oral administration. A column chromatography. The compound thus obtained has been found to have the (R)-(+)-con?guration. This compound dose-escalation trial of tipifarnib Was performed on 28 that is also referred to by its published code number R115777, patients With advanced cancer. Within the 50- to 500-mg b.i.d. has the following structure: dose range, a peak concentration range of 68-1458 ng/mL Was achieved betWeen 2 to 5 hours after oral administration. A linear increase in the plasma concentrations of tipifamib Was observed. Trough and peak plasma concentrations of tipifamib observed in this study Were Within the range of antileukemic activity. [0008] Tipifarnib is extensively metaboliZed folloWing oral administration. The data from in vitro studies With human hepatocytes indicated that tipifamib undergoes direct glu coronidation. The experiments With diagnostic inhibitors and heterologous expression systems also revealed that CYP3A4 Was a predominant metabolic pathWay for tipifamib com pared to other CYP450 enZymes such as CYP2C19, CYP2A6, CYP2D6, and CYP2C8/ 9/ 10. The metabolites of [0004] Tipifarnib is a base With very good Water solubility tipifamib Were inactive as famesyl transferase inhibitor and at acidic pH. It hydrolyZes to R110127, Wherein the amine antiproliferative agent in several preclinical studies. HoW functionality is replaced by a hydroxy functionality. The rate ever, the pharmacokinetics of its individual metabolites had of the hydrolytic degradation is loWest at acidic condition but not been studied in humans. Several metabolites of tipifamib still very fast. R110127 has the folloWing structure: Were found in plasma samples after [l4C]tipifamib Was orally administered to healthy male subjects. These metabolites included a glucuronide conjugate of tipifamib and metabo lites forrned via oxidative demethylation, deamination, and loss of the methyl-imidaZole moiety. Glucuronidation of the parent compound is a major route of biotransformation. HoW ever, metabolism of tipifamib folloWing administration of this compound to cancer subjects has not been studied. In addition, potential differences in tipifamib metabolite dispo sition that may occur after different routes of administration have not been systematically examined. [0009] Moreover, cancer patients regularly suffer from impaired oral intake due to tumoral obstruction, a surgical procedure, concomitant oral infections, signi?cant taste per version or anorexia, or nausea and vomiting. Hence, there is US 2009/0042935 A1 Feb. 12, 2009
still a desire for a formulation that allows for another route of other sugar ensures a quick solution of the lyophiliZed mate administration, such as an intravenous administration. rial. When the mannitol is not present some gel-like aggre gates are observed that only sloWly dissolve. With the man SUMMARY OF THE INVENTION nitol present these aggregates do not appear or appear to a lesser extent. Moreover the mannitol ensures that the cos [0010] It is the objective of the present invention to provide metic aspect of the lyophiliZed material is improved. Without an alternative route of administration (i.e., parenteral) of tipi the mannitol the lyophiliZed material can shoW cracks that farnib for patients for Whom oral administration is problem give the lyophiliZed material a less appealing appearance atic. The objective of the present invention Was to provide from a cosmetic point of vieW. It is a further objective of the intravenous route for the administration oftipifarnib, either as present invention to provide methods of treating in general continuous infusion or as a shorter-duration infusion (shorter and hematological malignancies and solid cancers in particu than one hour to several hours; once or more times per day) lar. that can provide an adequate exposure to tipifarnib, allowing for similar clinical outcome as the current tWice-daily oral [0016] This invention provides a method for inhibiting the administration of tipifamib. In particular, the objective of the abnormal groWth of cells, including transformed cells, by administering the pharmaceutical formulation of the inven present invention Was to provide intravenous route for the administration of tipifamib, either as continuous infusion or tion. Abnormal groWth of cells refers to cell groWth indepen dent of normal regulatory mechanisms (eg loss of contact as a tWice-daily 2-hour infusion that can provide a similar exposure to the current tWice-daily oral administration of inhibition). This includes the abnormal groWth of: (l) tumor tipifamib. It is a further objective of the present invention to cells (tumors) expressing an activated ras oncogene; (2) provide methods of treating in general and hematological tumor cells in Which the ras protein is activated as a result of malignancies and solid cancers in particular. oncogenic mutation of another gene; (3) benign and malig nant cells of other proliferative diseases in Which ras activa tion occurs. Furthermore, it has been suggested in literature DESCRIPTION OF THE INVENTION that ras oncogenes not only contribute to the groWth of tumors [0011] The present invention provides for an alternative in vivo by a direct effect on tumor cell groWth but also indi route of administration (i.e., parenteral) of tipifamib for rectly, i.e. by facilitating tumor-induced angio genesis. Hence, patients for Whom oral administration is problematic. The pharmacologically targeting mutant ras oncogenes could objective of the present invention Was to provide intravenous conceivably suppress solid tumor groWth in vivo, in part, by route for the administration of tipifarnib, either as continuous inhibiting tumor-induced angiogenesis. infusion or as a shorter-duration infusion (shorter than one [0017] This invention also provides a method for inhibiting hour to several hours; once or more times per day) that can tumor groWth by administering the present pharmaceutical provide an adequate exposure to tipifamib, alloWing for simi formulation of the present invention, to a subject, eg a mam lar clinical outcome as the current tWice-daily oral adminis mal (and more particularly a human) in need of such treat tration of tipifamib. In particular, the objective of the present ment. In particular, this invention provides a method for invention Was to provide intravenous route for the adminis inhibiting the groWth of tumors expressing an activated ras tration of tipifarnib, either as continuous infusion or as a oncogene by the administration of the pharmaceutical formu tWice-daily 2-hour infusion that can provide a similar expo lation of the present invention. Examples of tumors Which sure to the current tWice-daily oral administration of tipi may be inhibited, but are not limited to, lung cancer (e.g. famib. adenocarcinoma), pancreatic cancers (e.g. pancreatic carci [0012] It is a further objective of the present invention to noma such as, for example exocrine pancreatic carcinoma), provide a dry formulation of tipifarnib that can be solubiliZed colon cancers (e.g. colorectal carcinomas, such as, for With a solution so as to alloW for a formulation of tipifamib example, colon adenocarcinoma and colon adenoma), that can be administered intravenously. Persons skilled in the hematopoietic tumors of lymphoid lineage (e.g. acute lym art are aWare of the limitations that are applicable to the phocytic leukemia, B-cell lymphoma, Burkitt’s lymphoma), formulations for intravenous administration. A number of myeloid leukemias (for example, acute myelogenous leuke limitations Will be discussed hereinafter. The formulation that mia (AML)), thyroid (for example, follicular) cancer, myelo is administered intravenously should have a certain pH. The dysplastic syndrome (MDS), tumors of mesenchymal origin solution that is entered into the veins cannot be too basic nor (e.g. ?brosarcomas and rhabdomyosarcomas), melanomas, can it be to acidic. The formulation should not contain excipi teratocarcinomas, neuroblastomas, gliomas, benign tumor of ents that Would cause adverse reaction When entered into the the skin (e.g. keratoacanthomas), breast carcinoma, kidney blood. Furthermore, the formulation should alloW for the carcinoma, ovary carcinoma, bladder carcinoma and epider active ingredient to remain soluble once entered into the mal carcinoma. blood. This list of limitations is not exhaustive. [0018] This invention may also provide a method for inhib [0013] The formulation of the present invention comprises iting proliferative diseases, both benign and malignant, tipifamib in appropriate amounts. These amounts Will depend Wherein ras proteins are aberrantly activated as a result of upon Whether the resulting IV formulation Will be used for oncogenic mutation in genes, i.e. the ras gene itself is not single dose administration or Whether it Will be used for activated by mutation to an oncogenic mutation to an onco continuous IV administration. genic form, With said inhibition being accomplished by the [0014] The formulation preferably comprises further some administration of the pharmaceutical formulation described cyclodextrin or a derivative thereof. Other solubiliZing agents herein, to a subject in need of such a treatment. For example, may also be used. Preferred cyclodextrin is hydroxypropyl the benign proliferative disorder neuro?bromatosis, or [3-cyclodextrine. Other cyclodextrines may also be used. tumors in Which ras is activated due to mutation or overex [0015] Optionally, mannitol or another sugar, such as, for pression of tyrosine kinase oncogenes may be inhibited by the example, trealose or sucrose may be used. The mannitol or pharmaceutical formulation of this invention. US 2009/0042935 A1 Feb. 12, 2009
[0019] Hence, the present invention discloses the pharma ceutical formulation of the present invention for use as a medicine as Well as the use of these compounds of formula (I) (mass levorotatory) % levorotatory : X 100 for the manufacture of a medicament for treating one or more (mass dextrorotatory) + (mass levorotatory) of the above-mentioned conditions.
Terms & De?nitions [0030] Similarly, an example of an enantiomerically enriched form isolated from a racemic mixture includes a [0020] To provide a more concise description, some of the levorotatory enantiomer, Wherein the mixture is substantially quantitative expressions given herein are not quali?ed With free of the dextrorotatory isomer. In this context, substantially the term “about”. It is understood that Whether the term free means the dextrorotatory isomer may, in a range, com “about” is used explicitly or not, every quantity given herein prise less than 25% of the mixture, less than 10%, less than is meant to refer to the actual given value, and it is also meant 5%, less than 2% or less than 1% of the mixture according to to refer to the approximation to such given value that Would the formula: reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value. (mass dextrorotatory) % dextrorotatory : X 100 [0021] The term “subject” as used herein, refers to an ani (mass dextrorotatory) + (mass levorotatory) mal, preferably a mammal, mo st preferably a human, Who has been the object of treatment, observation or experiment. [0022] The term “therapeutically effective amount” as used [0031] The term “geometric isomer” means isomers that herein, means that amount of active compound or pharma differ in the orientation of substituent atoms in relationship to ceutical agent that elicits the biological or medicinal response a carbon-carbon double bond, to a cycloalkyl ring, or to a in a tissue system, animal or human that is being sought by a bridgedbicyclic system. Substituent atoms (other than hydro researcher, veterinarian, medical doctor or other clinician, gen) on each side of a carbon-carbon double bond may be in Which includes alleviation of at least one of the symptoms of an E or Z con?guration. In the “E” con?guration, the sub the disease or disorder being treated and/ or reduction in the stituents are on opposite sides in relationship to the carbon frequency and/or severity of at least one of the symptoms of carbon double bond. In the “Z” con?guration, the substituents the disease or disorder being treated. are oriented on the same side in relationship to the carbon [0023] The term “stereoisomer” refers to a isomers that carbon double bond. have the same molecular formula and the same sequence of [0032] Substituent atoms (other than hydrogen) attached to covalently bonded atoms but a different spatial orientation. a ring system may be in a cis or trans con?guration. In the [0024] The term “optical isomer” means isomers of identi “cis” con?guration, the substituents are on the same side in cal constitution that differ only in the spatial arrangement of relationship to the plane of the ring; in the “trans” con?gura their groups. Optical isomers rotate the plane of polariZed tion, the substituents are on opposite sides in relationship to light in different directions. The term “optical activity” means the plane of the ring. Compounds having a mixture of “cis” the degree to Which an optical isomer rotates the plane of and “trans” species are designated “cis/trans”. polariZed light. [0033] The isomeric descriptors (“R,” “S,” “E,” and “Z”) [0025] The term “racemate” or “racemic mixture” means indicate atom con?gurations and are intended to be used as an equimolar mixture of tWo enantiomeric species, Wherein de?ned in the literature. each of the isolated species rotates the plane of polarized light [0034] The compounds of the invention may be prepared as in the opposite direction such that the mixture is devoid of individual isomers by either isomer-speci?c synthesis or optical activity. resolved from an isomeric mixture. Conventional resolution [0026] The term “enantiomer” means a stereoisomer that is techniques include combining the free base (or free acid) of not nonsuperimposable With its mirror image. The term “dias each isomer of an isomeric pair using an optically active acid tereomer” means stereoisomers that are not enantiomers. (or base) to form an optically active salt (folloWed by frac [0027] The term “chiral molecule” means a molecule that tional crystallization and regeneration of the free base), form has at least one pair of enantiomers. This is in contrast to ing an ester or amide of each of the isomers of an isomeric pair achiral molecules Which can be superimposed on their mirror by reaction With an appropriate chiral auxiliary (folloWed by images. fractional crystallization or chromatographic separation and [0028] The tWo distinct mirror image versions of the chiral removal of the chiral auxiliary), or separating an isomeric molecule are also knoWn as levo (left-handed), abbreviated L, mixture of either an intermediate or a ?nal product using or dextro (right-handed), abbreviated D, depending on Which various Well knoWn chromatographic methods. Way they rotate polariZed light. The symbols “R” and “S” [0035] Furthermore, compounds of the present invention represent the con?guration of groups around a stereogenic may have one or more polymorph or amorphous crystalline carbon atom(s). forms and, as such, are intended to be included in the scope of [0029] An example of an enantiomerically enriched form the invention. In addition, some of the compounds may form isolated from a racemic mixture includes a dextrorotatory solvates With Water (i.e., hydrates) or common organic sol enantiomer, Wherein the mixture is substantially free of the vents (e.g., organic esters such as ethanolate and the like) and, levorotatory isomer. In this context, substantially free means as such, are also intended to be encompassed Within the scope the levorotatory isomer may, in a range, comprise less than of this invention. 25% ofthe mixture, less than 10%, less than 5%, less than 2% [0036] The folloWing Examples are set forth to aid in the or less than 1% of the mixture according to the formula: understanding of the invention, and are not intended and US 2009/0042935 A1 Feb. 12, 2009
should not be construed to limit in any Way the invention set of Formulation 1 With WFI is ~3. The reconstituted solution forth in the claims Which folloW thereafter. can be administered via a central vein.
EXPERIMENTAL PART Manufacturing Process Formulations [0043] (a) Manufacturing of Formulation 1 (10 L batch) [0044] (1 ) Add 2 kg of hydroxypropyl-[3-cyclodextrin to [0037] Tipifarnib 10 mg/ml lnjectable Solution for Lyo a suitable container. philization (Formulation 1) [0045] (2) Add 500 g mannitol to (1) [0046] (3) Add 8 kg Water for Injections to (2) and stir until solution [0047] (4) Add 164.0 g HCl 10% to (3) and mix to homo tipifamib 10 mg geneous. mannitol 50 mg concentrated hydrochloric acid 3.75 [11 [0048] (5)Add 100 g R1 15777 to (4) andmix to solution. hydroxypropyl-[5-cyclodextrin 200 mg [0049] (6) Filter through a sterile 0.22 pm ?lter. Water for injections qs ad 1000 [11 [0050] (7) Fill 10 ml of (6) into 20 ml vials. [0051] (b) Lyophilization of Formulation 1 Release pH = 2.0 r 0.2 [0052] (8) Stopper the vials and transfer to lyo trays. [0053] (9) Transfer (8) to the lyophilizer. Solution for Reconstituting Tipifamib lnjectable Freeze [0054] (10) Lyophilize: Dried Powders (Formulation 2) [0055] freezing: —400 C. at atmospheric atmosphere [0056] primary drying: 100 C. at 0.1 mbar [0038] [0057] secondary drying: 30° C. at 0.01 mbar [0058] (11) Crimping of the vials.
citric acid monohydrate 1.97 mg Clinical Trials disodium hydrogen phosphate anhydrous 4.44 mg Water for injections qs ad 1000 [11 Methods and Materials
Release pH = 6.0 r 0.5 [0059] This randomized, open-label, comparative trial Was performed in accordance With good clinical practice. Ethics Committee approval Was obtained before the trial, and Preparation of the Formulations patients gave their Written, informed consent to participate. [0060] Tipifamib Was supplied as either 100-mg oral tab Formulation 1 lets or as lyophilized poWders in vials containing 100 mg [0039] 10 ml of Formulation 1 is ?lled in a 20 ml vial and tipifamib and 2.0 g hydroxy-propyl-[3-cyclodextrin (HP lyophilized (100 mg tipifamib per vial). Before use the lyo BCD). The lyophilized poWders Were reconstituted With For philized poWders are dissolved in 8.6 ml of Formulation 2 to mulation 2 immediately prior to intravenous infusion. This obtain 10 ml of a tipifamib 10 mg/ml injectable solution (pH aliquot Was diluted in 0.9% NaCl and administered through a ~4-5). This tipifarnib 10 mg/ml solution is then further syringe driver With appropriate infusion lines. diluted With a 0.9% NaCl solution to the desired concentra tion (0.5 to 2 mg/ml). Study Subjects [0040] The pH value of Formulation 1 is very acidic (1) for [0061] Men and Women aged 18 years and older With solubilization of tipifarnib, (2) to have a minimal formation of pathologically con?rmed cancer, not amenable for curative R1 10127 during manufacturing (manufacturing is done pref therapy, Were eligible for this study. Patients Were required to erably at cold temperature ~10o C.). have ECOG (Eastern Cooperative Oncology Group) Perfor [0041] Hydroxypropyl-[3-cyclodextrin is added to Formu mance Status§2. Other requirements included an absence of lation 1 to solubilize tipifarnib When it is reconstituted With radiation therapy and/ or chemotherapy at least 4 Weeks prior Formulation 2. The pH value of the reconstituted solution is to study entry (6 Weeks for nitrosoureas or mitomycin C) and 4.5 . At this pH value tipifarnib precipitates if no Hydroxypro adequate oral intake to maintain a reasonable state of nutri pyl-[3-cyclodextrin is present. The risk of local irritation dur tion. ing infusion into a peripheral vein (arm) is at an acceptable [0062] Patients Were excluded if they had signi?cantly level at this pH value. abnormal hematological status as judged by a neutrophil [0042] During the tests in humans some thrombophlebitis count<1,500/mm3 , a platelet count<100,000/mm3 , serum Was found at the place of infusion When administered over bilirubin>2.0 mg/dL, transaminase>5 times the upper limit of longer periods of time (e.g. 24 hours). This may be caused by institutional normal, or creatinine>1.5 mg/dL. Concomitant the hydroxypropyl-[3-cyclodextrin itself and not by the administration of proton pump inhibitors (e.g., omeprazole, vehicle. It Was therefore decided not to administer via a lansoprazole, pantoprazole) Was not alloWed during the oral peripheral vein but via a central vein. A central vein has a administration period of tipifamib (this Was only so in cycle 1, much higher blood debit so that mixing and dilution of the When PK assessment Was done, to avoid any potential inter infusion solution is faster and higher. As the pH value of the ference). Patients Who underWent surgery of the gastrointes infusion solution is less critical When infusion is done via a tinal (GI) tract likely to interfere With drug absorption through central vein, it Was decided to reconstitute With WFI (Water impaired gastric acidity or deviation of the upper GI tract for injection) instead of With Formulation 2. The pH value of Were not eligible. The presence of any concurrent disease a solution obtained by reconstituting the lyophilized poWders that, in the opinion of the investigator, Would constitute a US 2009/0042935 A1 Feb. 12, 2009
hazard for participating in this study, and speci?cally samples Were taken immediately before, and 1, 2 (i.e. just grade§2 peripheral neuropathy also rendered a patient ineli before the end ofthe infusion), 2.25, 3, 4, 6, 8, and 10 hours gible. after dosing. Blood samples Were taken immediately before, and 2, 4, 6, 8, and 10 hours after the start of the continuous Study Design intravenous infusion. [0070] A minimum of 7 mL of blood for each PK sample [0063] The objective of the ?rst (dose-determination) Was collected. Whole blood samples Were immediately phase of the study Was to identify an intravenous regimen that placed on ice and centrifuged Within 2 hours after collection Was Well tolerated. It Was expected that this regimen Would be (10 min, 1000>
forti?ed plasma samples Were subj ected to equilibrium dialy the primary objective of this study, an attempt Was made to sis against a 0.067 M phosphate buffer, pH 7.17 at 370 C. for obtain appropriate measurements to assess response. All 4 hours in a Dianorm system With identical macro-1 Te?on adverse events and clinically relevant laboratory abnormali cells and Diachema 10.17 dialysis membranes (MW cut-off ties Were graded according to Common Toxicity Criteria 10,000). Radioactivity levels Were measured in duplicate (CTC version 2.0) 100-pl aliquots of the forti?ed plasma before and after equi librium dialysis, and in 1000-p.l duplicate aliquots of the RESULTS contents of buffer compartments of the dialysis cells admixed With methanol after dialysis in a Packard Tri-Carb 1900 TR Subject Disposition liquid scintillation spectrometer. The total protein concentra tion Was determined With a calorimetric biureet method, kit [0078] A total of 32 subjects (10 male and 22 female), Were Roche Diagnostics 1929917. The albumin concentration Was enrolled; 6 subjects participated in the dose-determination determined With a calorimetric bromocresol green method kit phase and 26 subjects in the bridging phase. Thirty-one sub Roche Diagnostics 1970909. The oq-acid glycoprotein con jects in this study Were diagnosed With advanced solid tumor. centration Was determined With an immuno -turbidimetric One subject had high-risk myelodysplastic syndrome. In the method, kit Roche Diagnostics 1557602. All these tests Were bridging phase, 12 subjects Were randomly assigned to performed on a Roche Hitachi Modular analyser. receive Treatment Sequence 1 (2-hour intravenous infusion [0074] The fraction of unbound tipifarnib (fu), Was calcu b.i.d./oral administration b.i.d./continuous intravenous infu lated as the ratio of the unbound concentration (Cu) to the total sion) and 14 subjects received Treatment Sequence 2 (con concentration (C) as determined by radioactivity measure tinuous intravenous infusion/ oral administration b.i .d./ 2 -hour ments in the buffer (CM) and plasma (C) compartments of the intravenous infusion b.i.d.). One subject randomized to Treat dialysis cells: ffCM/C. The bound fraction fb:1 —fu. ment Sequence 1 Was WithdraWn from the study on Day 4 because of a protocol violation and one subject on Treatment Noncompartmental Pharmacokinetic Analysis Sequence 2 Was WithdraWn on Day 8 due to hepatic failure related to disease-progression. [0075] Individual plasma concentration-time data of tipi [0079] Demographic data of the 32 subjects recruited to the famib during the 10-hour period from the start of the morning study Was as folloWs. The age of patients ranged from 35 to 70 dose on Day 4 of each administration periodWere analyzed by years, the Weight range Was 48 to 92 kg, and the height range non-compartmental methods using the program WinNonlin Was 149 to 176 cm. There Were no obvious differences version 3.1 (Pharsight Corporation, Cary, NC). The area betWeen the 2 randomized groups of Cohort 3 (bridging under the concentration-versus-time curve (AUCO_lOh) from phase). time 0 to 10 hours Was calculated using the linear trapezoidal method. Maximum plasma concentrations (Cmax), plasma Determination of the Intravenous Dose of Tipifamib concentration at steady state (CS5, only for the continuous intravenous infusion), and time to reach the peak plasma [0080] The ?rst cohort consisted of 3 subjects Who received concentration (tmax) Were the observed values. The bioavail 4-day tipifarnib regimens of 30 mg tWice daily as a 2-hour ability of tipifarnib after oral administration Was calculated intravenous infusion folloWed by 200 mg tWice daily as an based on AUCO_1O h values according to oral administration and 60 mg per day as a continuous infu [AUCPOXDOSEZ-V/(AUCZ-VXDOSEpo)]>< 100%. sion. On average, systemic exposures to tipifarnib based on AUCO_ 10h for 30 mg bid. as a 2-hour intravenous infusion and 60 mg per day as a continuous intravenous infusion Were Statistical Analysis approximately 64% and 59% loWer, respectively, relative to [0076] Demographic information Was summarized as the exposure folloWing a 200 mg oral dose received by these median, minimum, and maximum. The pharmacokinetic data individuals. No dose limiting toxicity after intravenous of tipifarnib and its metabolites Were also summarized using administration Was observed. Therefore, the intravenous descriptive statistics. The systemic exposures (plasma Cmax administration dose Was escalated to the next dose level. and AUCO_ 1Oh) to tipifarnib after oral and intravenous admin [0081] In the second cohort, 3 additional subjects received istrations from the subjects Whose pharmacokinetic samples 4-day regimens of 60 mg tipifarnib tWice daily as a 2-hour for all 3 treatments Were available Were evaluated using intravenous infusion folloWed by 120 mg per day as continu ANOVA. The point estimates and corresponding 90% con? ous infusion. Systemic exposures to tipifarnib folloWing dence intervals around the least squares mean ratio of intra these intravenous regimens Were approximately 47% and venous infusion (test) versus oral administration (reference) 46% loWer, respectively, relative to the exposure folloWing a for tipifarnib Cmax and AUCO_ 10h Were calculated. The analy 200 mg oral dose. Again, no DLT Was observed in this cohort. sis Was performed on logarithmically-transformed pharma Based on these results, a tWice-daily regimen of 100 mg cokinetic parameters using the SAS version 6.12 statistical administered as a 2-hour infusion and a 200-mg/day continu ous infusion Were chosen for the intravenous to oral bridging softWare program (SAS Institute, Cary, NC.) study. Clinical Assessment Plasma Pharmacokinetics of Tipifarnib [0077] Complete patient history Was taken, and a physical examination (including vital signs), hematological tests, and [0082] As expected, the shape of the tipifarnib plasma con clinical chemistry tests Were performed at baseline and dur centration-time pro?le Was dependent on the route of admin ing treatment. To assess cardiovascular safety, tWelve-lead istration and the dosing regimen. Peak plasma concentrations E.C.G.s Were recorded at screening, during Cycle 1 and at the of tipifarnib With apparent after oral administration and the end of therapy. Although objective tumor response Was not 2-hour intravenous infusion. In contrast, continuous intrave US 2009/0042935 A1 Feb. 12, 2009
nous infusion produced relatively constant plasma concentra tration after 200 mg b.i.d. oral administration for 4 days tions during drug administration With no obvious peak. during the 10-hour dose interval is in the range of 159 ng/mL [0083] Maximum plasma concentrations Were observed at to 788 ng/mL. approximately 2 hours after oral administration of 200 mg [0090] The mean concentrations (range) of serum albumin, b.i.d. of tipifarnib for 4 consecutive days. The range of tmax al-acid glycoprotein, and total protein Were 4.1 g/100 mL Was 0.5 to 3 hours in 29 subjects; 1 subject had a maximum (3.1 to 4.7 g/mL), 131 mg/100 mL (90 to 218 mg/100 mL), concentration at 8 hours. The arithmetic mean Cmax and and 6.8 g/100 mL (4.7 to 7.9 g/mL), respectively. AUCO_lOh values (:SD, n:24), after 4 days ofb.i.d. oral dos ing Were 9941487 ng/mL and 3990:1671 ng\/h/mL, respec Metabolites of Tipifamib in Plasma tively. [0084] Higher plasma concentrations of tipifarnib Were [0091] Plasma pharmacokinetics of tipifarnib metabolites Were analyZed on Days 4, 8, and 12 folloWing 4 days admin observed When a 100 mg dose Was given as a 2-hour intrave istration as oral tablet (200 mg b.i.d.), 2-hour intravenous nous infusion relative to a 200 mg oral dose. On average, the infusion (60 and 100 mg b.i.d.), or continuous intravenous Cmax and AUCO_lOh values Were 48.0% and 19.3% higher, infusion (120 and 200 mg/ day). The major and minor metabo respectively, When tipifarnib Was administered as a 2-hour lites of tipifarnib determined in intravenous routes Were the intravenous infusion (100 mg b.i.d.) than When administered same as those in oral administration. orally (200 mg b.i.d.). The upper limit of the 90% con?dence interval fell outside the 80% to the 125% range of bioequiva [0092] In general, systemic exposure (Cmax and AUCO_lOh) to the tipifarnib-glucuronide metabolite increased With an lence. The higher exposure observed folloWing the 2-hour increase in the tipifarnib dose administered intravenously. intravenous infusion compared With that folloWing oral Comparing in parallel, the exposure to the tipifamib-glucu administration is not expected to be clinically signi?cant. ronide metabolite on Day 12 did not accumulate from previ [0085] The mean AUCO_ 10h values on Day 4 Were similar both after oral administration (200 mg b.i.d.) and continuous ous 11-day administration. The mean ratio of AUCO_ 10 h val ues for tipifarnib-glucuronide relative to tipifarnib Was 18.6 intravenous infusion (200 mg per day). The loWer limit of the for oral administration, 7.5 for 100 mg 2-hour intravenous 90% con?dence interval fell Within the 80% to 125% range; infusion, and 8.6 for the 200 mg continuous intravenous hoWever, the upper limit extended slightly beyond this range. infusion. Overall, the concentration ratio of glucuronide to In terms of total systemic exposure as measured by the AUCO_ the parent compound in plasma Was higher after oral dosing 10h, the effect of dosing by continuous infusion Was similar to of tipifarnib relative to intravenous administration. This is that of dosing by the oral route. HoWever, the shape of the probably attributable to the ?rst-pass effect through the liver pro?les Was different in that no peak tipifarnib concentration (i.e., loss of the parent compound prior to systemic absorp Was apparent folloWing the continuous infusion. tion) associated With dosing via the oral route. [0086] After dose-normalization, the mean absolute bio availability of the oral tablet formulation (oral versus 2-hour Clinical Assessment iv.) was 46.3%. Similarly, the mean absolute bioavailability (oral versus continuous intravenous infusion) of the oral tab [0093] All subjects Were evaluable for toxicity. One subject let formulation Was 40.9%. Was WithdraWn after 3 days as it Was discovered she Was not [0087] Systemic exposure to tipifarnib Was comparable fol eligible for the study; no adverse events Were reported. One loWing administration as continuous intravenous infusion subject had myelodysplastic syndrome. This subject had peri (200 mg/day) or as 2-hour intravenous infusion (100 mg ods of grade 3-4 neutropenia, managed by dose reductions b.i.d.). Again, despite the differences in the shape of the and delays. Platelet counts remained normal. No signi?cant plasma concentration-time pro?les, the mean AUCO_lOh val non-hematological toxicity Was observed. ues Were similar. The upper and loWer limits of the 90% [0094] Grade 3 or 4 drug-related hematological toxicity, con?dence interval (81.1% to 100.3%) fell Within the 80% to neutropenia, Was observed in 9/30 patients (30%0. Febrile 125% range. neutropenia Was reported in 1 subject (3%). The main drug [0088] In summary, systemic exposure to tipifarnib as mea related non-hematological toxicities, mainly grade 1, Were sured by plasma AUCO_ 1 Oh during the 10-hour interval folloW fatigue (60%), nausea (40%), anorexia (20%), vomiting ing dosing Was comparable When this compound Was admin (17%) and diarrhea (13%). Phlebitis Was observed in 3 sub istered as oral tablets (200 mg b.i.d.), by 2-hour intravenous jects, all When IV bolus Was given via a peripheral venous infusion (100 mg b.i.d.), or by continuous intravenous infu access; this Was not observed When IV bolus Was given using sion (200 mg/day). A narroW range of mean AUCO_ 10h values a central vein. Was observed across the 3 treatments (3990 to 4487 ng-h/mL). [0095] Thirty-one subjects Were evaluable for e?icacy: the The 2-hour intravenous infusion more closely resembled oral subject With MDS had a hematological improvement (du administration When pro?le shape Was considered. rable increase in hemoglobin as per International Working Group criteria for response in MDS) for 8 months. No objec Protein Binding of Tipifamib in Plasma tive tumor responses Were observed, and 14 subjects had stable disease for at least 6 months. [0089] Tipifarnib Was extensively bound to plasma proteins in all samples analyZed. The mean free (unbound) fraction DISCUSSION Was 0.62% (range 0.45 to 0.88%) in the plasma samples draWn 4 hours after the start of the continuous intravenous [0096] The objective of the “dose-determination” phase infusion. The fraction of unbound tipifarnib Was independent Was to identify intravenous dose regimens of tipifarnib that of total drug plasma concentration in the range of 21 1 ng/mL Would yield similar exposure relative to 200 mg administered to 812 ng/mL. No data are available on protein binding from orally, tWice a day. More generally said, the objective Was to subject samples taken after oral administration or after 2-hour identify an intravenous dose and schedule that Would provide intravenous infusion. HoWever, the median plasma concen adequate exposure giving similar effects as the current oral US 2009/0042935 A1 Feb. 12, 2009
administration. In the ?rst and second cohorts With loW-dose Was comparable. In contrast, the plasma concentrations of the intravenous regimen, the systemic exposures to tipifarnib glucuronidated metabolite Were approximately 2-fold higher Were considerably loWer than those of 200 mg oral adminis after oral do sing than after intravenous administration. More tration. Considered With the absence of dose limiting toxicity extensive glucuronidation during ?rst-pass metabolism in the folloWing these loW-dose regimens, the ?nal intravenous liver after oral administration is the mo st likely explanation of administration dose Was escalated to 100 mg b.i.d. as a 2-hour this route-dependent difference in the relative concentrations infusion and 200 mg/day as a continuous infusion in the of tipifamib-glucuronide. In addition, the metabolites identi “bridging” phase of the study. ?ed in this study Were independent of the administration routes. The results are also indicative a metabolite-speci?c [0097] On average, the exposures (AUCO_ 1Oh) to tipifarnib impact of ?rst-pass metabolism on the exposure to each Were comparable and Within a narroW range (3990 to 4487 metabolite. ng~h/mL) When tipifamib Was administered as an oral tablet [01 02] The value of the plasma protein binding of tipifamib (200 mg b.i.d.), 2-hour intravenous infusion (100 mg b.i.d.), from the ex vivo measurement on cancer subjects in this trial or continuous intravenous infusion (200 mg/day). When the shape of the pro?les of the 2 intravenous regimens is consid is very close to that (99.22% bound) obtained from an in vitro experiment With the plasma samples from 5 healthy men. In ered, the 2-hour infusion more closely mimicked oral admin this in-vitro study, the blank plasma samples from these istration. healthy subjects Were forti?ed With l4C-tipifarnib at 1000 [0098] The mean Cmax and AUCO_lOh values folloWing oral ng/mL and the measurement procedure Was the same as one administration of 200 mg tipifamib b.i.d. dose Was 994 ng/mL used in the current trial. The in vitro plasma protein binding of and 3990 ng-h/mL, respectively. This is in good agreement tipifamib Was also independent of the total tipifarnib concen With a previous study Where 150- and 300-mg of tipifamib trations in the range of 100 to 5000 ng/mL. Was orally administered tWice daily (mean Cmax of 443 and [0103] In conclusion, the plasma concentration-time pro 974, respectively; mean AUCO_l2h values of 2495 and 4674 ?les from the 2-hour intravenous regimen closely resembled ng~h/mL, respectively). the pro?les after oral administration. Systemic exposure to [0099] The mean oral bioavailability of tipifamib tablet tipifamib Was comparable for the ?rst 10 hours after dosing administered under fed conditions Was 46.3% (by reference When 100 mg Was given tWice daily as a 2-hour intravenous to 2-hour intravenous infusionb.i.d.) and 40.9% (by reference infusion or 200 mg Was given via the oral route. No unusual to continuous intravenous infusion). These results represent adverse events Were associated With intravenous tipifamib. approximation of absolute oral bioavailability, since plasma 1. A pharmaceutical formulation of tipifarnib suitable for samples Were collected for only 10 hours after the last drug intravenous administration. administration. HoWever, it is clear that tipifarnib has rela 2. A pharmaceutical formulation of tipifarnib according to tively good bioavailability When administered With food. claim 1, further comprising a cyclodextrine. [0100] Previous studies in humans indicted that tipifamib 3. A pharmaceutical formulation of tipifarnib according to undergoes extensive metabolism and unchanged parent com claim 1, Wherein the cyclodextrine is hydroxypropyl-[3-cy pound is a relatively small constituent in plasma. Following clodextrin. oral administration, concentrations of unchanged tipifarnib 4. A pharmaceutical formulation of tipifarnib according to Were on average 42-times loWer than total radioactivity con claim 1, Wherein the concentration of tipifamib is about 10 centrations in nonprecipitated samples and approximately mg/ml. 8-times loWer in deproteiniZed samples. No unchanged drug 5. A freeze-dried composition of tipifarnib comprising a Was excreted in the urine and less than 7% of the oral dose cyclodextrine. administered Was recovered in faces as tipifamib. Consistent 6. A freeze-dried composition according to claim 5, results Were obtained in the present study. The plasma AUCO_ Wherein the cyclodextrine is hydroxypropyl-[3-cyclodextrin. 10h values of tipifamib-glucuronide Were 3- to 30-fold higher 7. A process for preparing a pharmaceutical formulation as than that of tipifamib. Since tipifamib possesses amino and claimed in claim 1, comprising the step of mixing a freeZe keto groups in its structure, direct conjugation is to be dried composition of tipifamib With a solvent comprising expected. Importantly, in vitro studies With NIH 3T3 H-ras Water and an acid. cell line and famesyl protein transferase enZyme indicated 8. A process for preparing a pharmaceutical formulation as that the glucuronide-metabolite of tipifamib is not an inhibi claimed in claim 7, Wherein the acid is selected from tartaric tor of farnesyltransferase. acid, maleic acid, succinic acid, and citric acid. [0101] Exposure to the tWo predominate metabolites of 9. A method of treating Acute Myeloid Leukemia by tipifamib, the glucuronide conjugate and the N-dealkylated administering a pharmaceutical composition of claim 1. species, increased With an increase in the intravenous dose of 10. A method of treating breast cancer by administering a tipifamib administered. These pathWays are apparently not pharmaceutical composition of claim 1. saturated Within the dose range studied. Relative exposure to the N-dealkylated species after each route of administration * * * * *