CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`203214Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`
`

`

`CLINICAL PHARMACOLOGY REVIEW
`
`
`
`
`203214
`NDA
`Submission Date
`10/21/2011
`TBD
`Brand Name
`Tofacitinib
`Generic Name
`Clinical Pharmacology Reviewer Lokesh Jain, Ph.D.
`Pharmacometrics Reviewer
`Lokesh Jain, Ph.D. and Atul Bhattaram, Ph.D.
`Pharmacogenomics Reviewer
`Jeffrey Kraft, Ph.D.
`Pharmacometrics Team Leader
`Atul Bhattaram, Ph.D.
`Pharmacogenomics Team Leader Michael Pacanowski, Pharm.D., M.P.H.
`Clinical Pharmacology Team
`Suresh Doddapaneni, Ph.D.
`Leader
`OCP Division
`OND Division
`
`Sponsor/Authorized Applicant
`Submission Type; Code
`Formulation; Strength(s)
`Indication
`Dosage Regimen
`
`Clinical Pharmacology II
`Division of Pulmonary, Allergy, and
`Rheumatology Products
`Pfizer, Inc.
`505(b)(1); standard review
`Tablet ; 5 mg and 10 mg
`Rheumatoid Arthritis
`5 mg BID; some patients may benefit from an
`increase to 10 mg BID based on clinical response
`
`
`
`Executive Summary ..............................................................................4
`1.
`Recommendations........................................................................................................................ 4
`1.1
`Phase IV Commitments ............................................................................................................... 4
`1.2
`Summary of Clinical Pharmacology and Biopharmaceutics Findings ..................................... 4
`1.3
`2. Question Based Review ........................................................................8
`2.1 List the in vitro and in vivo Clinical Pharmacology and Biopharmaceutics studies and the clinical
`studies with PK and/or PD information submitted in the NDA or BLA....................................... 8
`General Attributes of the Drug ............................................................................................... 10
`2.2.1 What are the highlights of the chemistry and physical-chemical properties of the drug
`substance and the formulation of the drug product? ............................................................... 10
`2.2.2 What are the proposed mechanism of action and therapeutic indications?............................. 11
`2.2.3 What are the proposed dosages and routes of administration?................................................ 12
`2.2.4 What drugs (substances, products) indicated for the same indication are approved in the US?
`................................................................................................................................................ 12
`General Clinical Pharmacology............................................................................................... 13
`
`2.2
`
`2.3
`
`Reference ID: 3149379
`
`

`

`2.4
`
`2.5
`
`2.3.1 What are the design features of the clinical pharmacology and biopharmaceutics studies and
`the clinical studies used to support dosing or claims?............................................................. 13
`2.3.2 What is the basis for selecting the response endpoints and how are they measured in clinical
`pharmacology studies?............................................................................................................ 13
`2.3.3 Are the active moieties in plasma and clinically relevant tissues appropriately identified and
`measured to assess pharmacokinetic parameters and exposure response relationships?......... 13
`Exposure-Response................................................................................................................... 13
`2.4.1 What are the characteristics of the exposure-response relationship for effectiveness?........... 13
`2.4.2 What are the characteristics of the exposure-response relationships for safety?................... 14
`2.4.3 Does this drug prolong QT/QTc Interval? .............................................................................. 14
`2.4.4 Is the dose and dosing regimen selected consistent with the known E-R relationship?.......... 14
` What are the PK characteristics of the drug?...................................................................... 14
`2.5.1 What are the single and multiple dose PK parameters of parent drug and relevant metabolites
`in healthy adults? .................................................................................................................... 14
`2.5.2 How does the PK of the drug and its relevant metabolites in healthy adults compare to that in
`patients with the target disease?.............................................................................................. 17
`2.5.3 What is the inter- and intra-subject variability of the PK parameters in volunteers and patients
`with the target disease? ........................................................................................................... 17
`2.5.4 What are the characteristics of drug absorption? .................................................................... 18
`2.5.5 What are the characteristics of drug distribution?................................................................... 18
`2.5.6 Does the mass balance study suggest renal or hepatic as the major route of elimination?...... 18
`2.5.7 What is the percentage of total radioactivity in plasma identified as parent drug and
`metabolites? ............................................................................................................................ 19
`2.5.8 What are the characteristics of drug metabolism?................................................................... 20
`2.5.9 Is there evidence for excretion of parent drug and/or metabolites into bile? .......................... 21
`2.5.10 Is there evidence for enterohepatic recirculation for parent and/or metabolites?.................... 22
`2.5.11 What are the characteristics of drug excretion in urine? ......................................................... 22
`2.5.12 Based on PK parameters, what is the degree of the proportionality of the dose-concentration
`relationship?............................................................................................................................ 22
`2.5.13 How do the PK parameters change with time following chronic dosing? .............................. 23
`2.5.14 Is there evidence for a circadian rhythm of the PK?............................................................... 24
`Intrinsic Factors........................................................................................................................ 24
`2.6.1 What are the major intrinsic factors responsible for the inter-subject variability in exposure
`(AUC, Cmax, Cmin) in patients with the target disease and how much of the variability is
`explained by the identified covariates? ................................................................................... 24
`2.6.2 Based upon what is known about E-R relationships in the target population and their
`variability, what dosage regimen adjustments are recommended for each group? ................. 24
`2.6.3 Does genetic variation impact exposure and/or response?...................................................... 31
` Extrinsic Factors...................................................................................................................... 31
`2.7.1 Is there an in vitro basis to suspect in vivo drug-drug interactions? ....................................... 31
`2.7.2 Is the drug a substrate of CYP enzymes?................................................................................ 31
`2.7.3 Is the drug an inhibitor and/or an inducer of enzymes? ........................................................... 31
`2.7.4 Is the drug a substrate, an inhibitor and/or an inducer of transporter processes?.................... 32
`2.7.5 Are there other metabolic/transporter pathways that may be important?................................ 33
`2.7.6 What extrinsic factors influence exposure and/or response, and what is the impact of any
`differences in exposure on effectiveness or safety responses?................................................ 33
`2.7.7 What are the drug-drug interactions?...................................................................................... 33
`2.7.8 Does the label specify coadministration of another drug? ...................................................... 37
`2.7.9 What other co-medications are likely to be administered to the target population?................ 37
`2.7.10 Is there a known mechanistic basis for pharmacodynamic drug-drug interactions? ............... 38
`2.8 General Biopharmaceutics....................................................................................................... 38
`2.8.1 Based on the biopharmaceutic classification system principles, in what class is this drug and
`formulation? What solubility, permeability and dissolution data support this classification? 38
`2.8.2 How is the proposed to-be-marketed formulation linked to the clinical service formulation?
`................................................................................................................................................ 38
`2.8.3 What is the effect of food on the bioavailability of the drug when administered as solution or
`
`2.6
`
`2.7
`
`NDA203214
`Clinical Pharmacology Review_NDA203214.doc
`
`Page 2 of 158
`
`Reference ID: 3149379
`
`

`

`2.9
`
`2.8.4 Was the bioequivalence of the different strengths of the to be marketed formulation tested? If
`so were they bioequivalent or not?.......................................................................................... 41
`Analytical Section ..................................................................................................................... 41
`2.9.1 How are parent drug and relevant metabolites identified and what are the analytical methods
`used to measure them in plasma and other matrices?.............................................................. 41
`2.9.2 Which mtabolites have been selected for analysis and why?.................................................. 42
`2.9.3 For all moieties measured, is free, bound, or total measured? ................................................ 42
`2.9.4 What bioanalytical methods are used to assess concentrations of the measured moieties? .... 43
`2.9.5 What is the range of the standard curve? How does it relate to the requirements for clinical
`studies? What curve fitting techniques were used?................................................................. 43
`Detailed Labeling Recommendations...................................................................................... 45
`2.9
`PHARMACOMETRIC REVIEW................................................................................................................ 46
`1.
`SUMMARY OF FINDINGS...................................................................................................... 46
`1.1.
`Key Review Questions ............................................................................................................... 46
`The purpose of this review is to address the following key questions.......................................................... 46
`1.1.1.
`Are the proposed labeling statements based on population pharmacokinetic analysis acceptable?
`
`46
`1.1.2.
`What are the characteristics of the exposure-response relationship for effectiveness?............... 46
`1.1.3.
`What are the characteristics of the exposure-response relationship for safety?.......................... 48
`1.1.4.
`Is the dose and dosing regimen selected consistent with the known Exposure- Response
`relationship? ................................................................................................................................................. 53
`1.1.5.
`What are the characteristics of the exposure-response relationship for pharmacodynamic
`markers? 59
`1.2.
`Recommendations ...................................................................................................................... 68
`1.3.
`Label Statements......................................................................................................................... 68
`2.
`PERTINENT REGULATORY BACKGROUND ..................................................................... 71
`3.
`RESULTS OF SPONSOR’S ANALYSIS.................................................................................. 71
`4.
`REVIEWER’S ANALYSIS ....................................................................................................... 85
`4.1.
`Introduction ................................................................................................................................ 85
`4.2.
`Objectives................................................................................................................................... 85
`4.3.
`Methods ...................................................................................................................................... 86
`4.3.1.
`Data Sets..................................................................................................................................... 86
`4.3.2.
`Software...................................................................................................................................... 86
`4.3.3.
`Models........................................................................................................................................ 86
`4.4.
`Results ........................................................................................................................................ 86
`LISTING OF ANALYSES CODES AND OUTPUT FILES....................................................................... 88
`GENOMICS REVIEW................................................................................................................................. 95
`INDIVIDUAL STUDY REVIEW................................................................................................................ 98
`
`
`
`
`
`
`
`
`
`
`
`NDA203214
`Clinical Pharmacology Review_NDA203214.doc
`
`Page 3 of 158
`
`Reference ID: 3149379
`
`

`

`1. Executive Summary
`
`1.1 Recommendations
`
`The Office of Clinical Pharmacology finds NDA 203214 acceptable
`
`1.2 Phase IV Commitments
`
`None
`1.3 Summary of Clinical Pharmacology and Biopharmaceutics
`Findings
`
`Pfizer, Inc. has submitted NDA 203214 seeking marketing approval for tofacitinib.
`Tofacitinib is an orally administered Janus kinase (JAK) inhibitor with preferential
`activity against JAK1 and/or JAK3 over JAK2. If approved, it will be the first JAK
`inhibitor for treatment of rheumatoid arthritis.
`
`Sponsor supported this NDA submission with 21 phase 1 studies, 5 phase 2 studies, 5
`phase 3 studies (to support efficacy and safety), and 12 population based modeling
`analyses.
`
`
`Pre-Clinical Support for Dose Selection
`Data from mouse collagen-induced arthritis (CIA) model demonstrated that effective
`modulation of the inflammatory response through JAK1/3 inhibition may not require
`continuous coverage of tofacitinib (i.e., plasma tofacitinib concentrations in excess of
`IC50). ED50 in animal models for BID vs. QD dosing regimen were 6-12.8 mg/kg and
`33.5-40.5 mg/kg, respectively, and BID was anticipated to inhibit JAK1/3 signaling
`for longer duration than QD. Based on results from preclinical studies, sponsor
`designed the clinical program to optimize the BID dosing regimen.
`
`Dose-Response
` A trend of increase in ACR20, ACR70, ACR90 and DAS28-3 response at week 12
`was observed with increase in dose from 1 to 15 mg for treatment with tofacitinib
`monotherapy. When tofacitinib (from 3 mg BID to 15 mg BID and 20 mg QD) was
`administered in background of methotrexate, dose related changes in ACR 20,
`ACR50, ACR70 and DAS 28 were not observed.
` A trend of decrease in neutrophil counts and increase in LDLC, HDLC, total
`cholesterol and serum creatinine was observed with increase in dose for tofacitinib
`monotherapy. A similar dose-response relationship for lipid endpoints was also
`observed when tofacitinib was administered in background of methotrexate
` A trend of increase in hemoglobin was seen for lower doses up to 5 mg following
`which a decline was observed (i.e., an inverted U-shape relationship) with tofacitinib
`monotherapy. A similar dose-response relationship for hemoglobin was also observed
`when tofacitinib was administered in background of methotrexate
`
`NDA203214
`Clinical Pharmacology Review_NDA203214.doc
`
`Page 4 of 158
`
`Reference ID: 3149379
`
`

`

`
`
` Selection of dose was based on probability of achieving the target effect with respect
`to both efficacy (defined as placebo-adjusted response rate of at least 20% for
`ACR20, 20% for ACR50, and 15% for ACR70 at week 12) and safety (no more than
`5% placebo-adjusted incidences of anemia through 24 weeks). 5 and 10 mg bid doses
`had approximately 50% probability of achieving the target effect
` ACR20, ACR50 and ACR90 responses observed in Phase 3 clinical trials were in
`similar range as observed in Phase 2 studies
` Trends for safety endpoints between 5 and 10 mg dose in Phase 3 trials were similar
`to that observed in Phase 2 studies
` Changes in CD3+, CD4+ and CD8+ cell counts were not dose dependent following
`tofacitinib treatment up to 24 weeks
` There was a trend of increase in Natural Killer cell (CD16+/56+ cell) counts with
`increase in dose
` There was a trend of decline in B cell (CD19+ cell) counts with increase in dose
` A decline was observed in IgG, IgM, and IgA levels following treatment with
`tofacitinib for 24 weeks compared to placebo; however, these changes were small and
`not dose-dependent
`
`Pharmacokinetics
`Rheumatoid Arthritis vs. Healthy
` Population PK analysis showed 43% lower apparent clearance (CL/F) in a typical RA
`patient relative to a healthy adult
`
`Absorption
` The absolute bioavailability of tofacitinb at 10 mg dose was 74%
` Systemic exposure (AUC0-∞) and peak plasma concentration (Cmax) increased in
`proportion to the dose in the dose range of 1 to 100 mg.
` Tmax was reached by approximately 0.5-1 hours following oral administration
` Coadministration with food had no significant effect on the extent of absorption
`(AUC0-∞) but rate of absorption (Cmax) was reduced by 32%.
` Upon multiple dosing, steady-state was reached by 24-48 hours with negligible
`accumulation
` Tofacitinib is a substrate of P-gp transporter
`
`Distribution
` Tofacitinib has a total plasma protein binding of approximately 39%. Tofacitinib
`binds moderately to albumin and does not bind to alpha-1 acid glycoprotein.
` Steady-state volume of distribution (Vdss) for tofacitinib following iv infusion
`administration was 87 L, suggesting distribution into tissues.
`
`Metabolism and Transporters
` Tofacitinib was extensively metabolized, primarily by CYP3A4 enzyme with minor
`contribution from CYP2C19
` All metabolites have less than <8% of total drug exposure and their potency was
`reported to be 10% of the potency of tofacitinib for JAK1/3 inhibition.
`
`NDA203214
`Clinical Pharmacology Review_NDA203214.doc
`
`Page 5 of 158
`
`Reference ID: 3149379
`
`

`

` Based on in vitro studies, tofacitinib is not a substrate of BCRP transporter.
` Based on in vitro studies, at therapeutic concentrations, tofacitinib has low potential
`for induction or inhibition of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4 metabolic
`enzymes and low potential of inhibition for P-gp, OCT2, OATP1B1, OATP1B3
`
`Elimination
` Of the 94% drug recovered following oral administration in a mass balance study,
`approximately 29% and 51% was recovered in urine as parent drug and metabolites,
`respectively. In feces, proportion of parent and metabolites recovered was
`approximately 1% and 13%.
` The terminal elimination half-life of tofacitinb was approximately 3 hours after
`single- or multiple-dose
`
`
`
`Population Pharmacokinetic Analysis
` Age
`Elderly patients age 70 years or 80 years were estimated to have less than 10% difference
`in AUC and Cmax relative to the mean age of 55 years, after accounting for differences in
`renal function (i.e., creatinine clearance)
`
` 
`
` Weight
`Patients with extreme body weight 40 kg and 140 kg were estimated to have less than 5%
`difference in AUC relative to the mean weight of 70 kg, after accounting for differences
`in renal function (i.e., creatinine clearance)
`
` 
`
` Gender
`Women were estimated to have less than 7% difference in AUC and Cmax compared to
`men, after accounting for differences in renal function (i.e., creatinine clearance)
` Race
`Based on available data are no major differences were seen in tofacitinib AUC and Cmax
`between White, Black and Asian patients, after accounting for differences in renal
`function (i.e., creatinine clearance)
`
`Special Population
`
`
` Renal Impairment
` Mean percentage change in AUC (90%CI), for subjects with mild, moderate, and
`severe renal impairment compared to normal renal function were respectively: 41% (-
`5%, 109%), 71% (14%, 157%), and 156% (69%, 287%). Mean percentage changes in
`Cmax (90% CI) for these cases were respectively: 1% (-31%, 49%), 2% (-31%,
`52%), and 21% (-19%, 81%). At this point in time, additional safety analysis is
`ongoing and a final decision on the dosing regimen to be approved is pending. If
`both 5 and 10 mg BID doses are approved, tofacitinib dose should not exceed 5 mg
`BID in subjects with moderate and severe renal impairment. However, if only 5 mg
`BID is approved, a reduced tofacitinib dose of 5 mg QD is recommended in these
`subjects.
`
`NDA203214
`Clinical Pharmacology Review_NDA203214.doc
`
`Page 6 of 158
`
`Reference ID: 3149379
`
`

`

` A 14 days study was conducted to assess the impact of tofacitinib on renal function
`by measuring the glomerular filtration rate (iohexol serum clearance), effective renal
`plasma flow (by p-amino hippuric acid (PAH) clearance), and measured creatinine
`clearance (CLCr, based on 24-hour urine collection) on day 1 and day 15. No
`significant change in iohexol serum clearance, PAH clearance, and CLCr were
`observed with mean change of less than 10% for comparison of Day 15 vs. Day 1.
`Renal function is not affected at least following 14 days of treatment.
`
` 
`
` Hepatic Impairment
` Mean percentage change in AUC (90%CI) for subjects with mild and moderate
`hepatic impairment vs. normal hepatic function were respectively: 3% (-22%, 36%)
`and 65% (25%, 117%). Mean percentage change in Cmax (90% CI) for these cases
`were respectively: -1% (-25%, 32%) and 49% (12%, 97%). If both 5 and 10 mg BID
`doses are approved, tofacitinib dose should not exceed 5 mg BID in subjects with
`moderate hepatic impairment. However, if only 5 mg BID is approved, a reduced
`tofacitinib dose of 5 mg QD is recommended in these subjects.
` Tofacitinib was not evaluated in patients with severe hepatic impairment because of
`the risk of immunosuppression in patients who are already at risk of infection from
`their hepatic disease (for the reason that a significant portion of tofacitinib is cleared
`through hepatic metabolism). Therefore, tofacitinib is not recommended in patients
`with severe hepatic impairment
`
`
`
`Drug-Drug Interaction (DDI)
` Effect of coadministered drugs on tofacitinib exposure
` Tofacitinib coadministration with a strong CYP3A inhibitor, ketoconazole, increased
`the mean tofacitinib AUC (90%CI) by 103% (91%, 116%) and Cmax by 16% (5%,
`29%). If both 5 and 10 mg BID doses are approved, tofacitinib dose should not
`exceed 5 mg BID when it is coadministered with strong CYP3A4 inhibitors.
`However, if only 5 mg BID is approved, a reduced tofacitinib dose of 5 mg QD is
`recommended when coadministered with strong CYP3A4 inhibitors
` Coadministration with a moderate CYP3A4 and strong CYP2C19 inhibitor,
`fluconazole, increased mean tofacitinib AUC (90%CI) by 79% (64%, 96%) and Cmax
`by 27% (12%, 44%). If both 5 and 10 mg BID doses are approved, tofacitinib dose
`should not exceed 5 mg BID when it is coadministered with moderate CYP3A4 and
`strong CYP2C19 inhibitors. However, if only 5 mg BID is approved, a reduced
`tofacitinib dose of 5 mg QD is recommended for coadministration with moderate
`CYP3A4 and strong CYP2C19 inhibitors
` Tofacitinib coadministration with a strong CYP3A inducer, rifampin, resulted in
`substantial decreases in mean tofacitinib AUC (90%CI) by -84% (-86%, -82%) and in
`Cmax by -74% (-77%, -69%). Coadministration with rifampin is not recommended
`because that will result in inefficacious concentrations of tofacitinib
` Coadministration with tacrolimus, a CYP3A substrate with narrow therapeutic index,
`increased mean (90%CI) tofacitinib AUC (90%CI) by 21% (13%, 30%) and
`decreased Cmax by -9% (-17%, -1%). However, because of potential for
`pharmacodynamic drug interaction (immunosuppressive drug effects from both
`drugs), tofacitinib coadministration with tacrolimus is not recommended
`
`NDA203214
`Clinical Pharmacology Review_NDA203214.doc
`
`Page 7 of 158
`
`Reference ID: 3149379
`
`

`

` Coadministration with cyclosporine, a CYP3A substrate with narrow therapeutic
`index and also an inhibitor of P-gp increased mean (90%CI) tofacitinib AUC
`(90%CI) by 73% (62%, 85%) and decreased Cmax by -17% (-29%, -3%). However,
`because of potential for pharmacodynamic drug interaction (immunosuppressive drug
`effects from both drugs), tofacitinib coadministration with cyclosporine is not
`recommended
` Coadministration with methotrexate, had no significant effect on mean (90%CI)
`tofacitinib exposure with geometric mean ratio and 90% CI for AUC of 103% (99%,
`107%) and for Cmax of 103% (94%, 112%). No dose adjustment recommended for
`tofacitinib when coadministered with methotrexate
`
`
`
` Effect of tofacitinib on exposure of coadministered drugs
` Concomitant use of oral contraceptives (OC) with tofacitinib did not have any
`significant effect on plasma levels of ethinyloestradiol with geometric mean ratio
`(90%CI) for comparison with vs. without tofacitinib were, for AUC, 107% (99%,
`115%), and for Cmax, 90% (82%, 98%), and on plasma levels of levonorgestrel with
`geometric mean ratio (90%CI) for comparison of with vs. without tofacitinib were for
`AUC of 101% (95%, 107%) and for Cmax of 112% (105%, 120%). No dose
`adjustment recommended for OC when coadministered with tofacitinib
` Concomitant use with tofacitinib had no substantial effect on the exposure of
`midazolam, a sensitive CYP3A substrate, with geometric mean ratio (90%CI) with
`vs. without tofacitinib were for AUC of 104% (96%, 113%) and for Cmax of 102%
`(96%, 109%). No dose adjustment recommended for CYP3A substrates when
`coadministered with tofacitinib
` Concomitant use of tofacitinib and methotrexate, decreases mean (90% CI)
`methotrexate AUC by -10% (-23%, 4%) and Cmax by -13% (-24%, 0%). No dose
`adjustment recommended for methotrexate when coadministered with tofacitinib
`
`
`
`2. Question Based Review
`
`
`2.1 List the in vitro and in vivo Clinical Pharmacology and
`Biopharmaceutics studies and the clinical studies with PK and/or PD
`information submitted in the NDA or BLA
`
`
`Thirteen in vitro studies using human biomaterials were conducted and are listed Table 1.
`
`
`
`
`
`
`
`
`
`
`NDA203214
`Clinical Pharmacology Review_NDA203214.doc
`
`Page 8 of 158
`
`Reference ID: 3149379
`
`

`

`
`Table 1: Tofacitinib (CF-690,550) In Vitro Studies Using Human Biomaterials
`
`Objective
`Study Number
`Plasma Protein Binding of CP-690,550 in Mouse, Rat, Dog, Monkey and
`DMZOOl-690550-018
`Human
`
`Protein Binding of CP-690,550 in Human Serum Albumin and til-Acid
`Glycoprotein
`Blood to Plasma Concentration Ratio of CP-690550 in Rat, Monkey and
`Human Whole Blood
`Identification of In Vitro Metabolites of CP—690,550 in Human Liver
`Micmsomes and Recombinant CYP450 isofonns
`
`DM2002-690550-025
`
`(JP-69055 0_18Feb11_055956
`
`DMZOO4-690550—046
`
`DM2007-690550-067
`
`Identification of Human CYP450 Isoforms Responsible for In Vitro
`Metabolism of (JP-690,550
`Effect of CP-690,550 on Human Drug Metabolizing Enzymes In Vitro
`Potential for CP—690,550 to induce CYP3A4 And CYP1A2 In Human
`Hep atocytes
`Evaluation of CP-690,5 50 as Substrate for P-Glycoprotein
`"mi 0/170ct.08/060532
`Potential for CP-690,550 to Inhibit P-Glycoprotein
`CP-69055 0_150ct10_l 75 813
`Evaluation of CP-690,550 as Substrate for BCRP
`CP-690,550f09Ju110811353 23
`Potential for CP-690,55 O to Inhibit OCT2
`Potential for CP-690,55 0 to Inhibit OATP 1B1
`CP-69055 0728Ju1107192119
`
`Potential for CP-690,550 to Inhibit OATP 1B3
`CP-690550 02Aug10 095440
`BCRP 7 Breast cancer resistance protein; OATP 7 Organic Anion Transport Protein; OCT 7 Organic Cation
`Transp orter
`(Source -Table 1. Section 2.7.2. Summary of Clinical Pharmacology Studies)
`
`DMZOOI -690550-020
`DMZOO7-
`(“"9001
`(b) (4)
`
`XT088024
`
`Studies in Healthy Subjects
`Nine Phase 1 studies characterized the single and/or multiple-dose PK of tofacitinib.
`o
`Single—dose escalation (First-in-Human) for tofacitinib was studied in healthy
`volunteers in Study A3921002.
`o Multiple—dose escalation and tolerability was evaluated in Study A3921003 in
`subjects with medically stable psoriasis.
`
`0
`
`Study A3921005 was conducted in healthy volunteers to evaluate the bioavailability
`of a tablet formulation of tofacitinib relative to the OPC formulation.
`
`0 The effect of food on tofacitinib PK was assessed in Study A3921005 and later
`repeated with the proposed commercial tablet in Study A3921076.
`
`0
`
`0
`
`0
`
`0
`
`0
`
`Study A3921010 evaluated the metabolic profile and routes of excretion of
`radiolabeled tofacitinib (i.e., [14C]CP-690,550) in healthy male subjects.
`Study A3921077 was conducted in healthy volimteers to determine the absolute
`bioavailability of tofacitinib.
`Study A3921075 was conducted to establish bioequivalence between the Phase 2B,
`Phase 3 and the commercial tablet formulations.
`
`Study A3921036 evaluated the PK of tofacitinib in Japanese and Western subjects
`
`Study A3921065 examined the PK of tofacitinib in Chinese subjects.
`
`Studies Evaluating the Impact of Change Renal and Hepatic Function or Impact on
`Renal Function
`
`Three clinical studies evaluated the PK of tofacitinib in subjects with renal or hepatic
`impairment.
`0 The PK and dialyzability of tofacitinib were evaluated in subjects with End Stage
`Renal Disease (ESRD) in Study A3921004.
`
`NDA203214
`Clinical Pharmacology Review_NDA203214.doc
`
`Page 9 of 158
`
`Reference ID: 3149379
`
`

`

` Study A3921006 investigated the PK of tofacitinib in subjects with mild, moderate
`and severe renal impairment.
` Study A3921033 evaluated the effect of 14 days treatment with tofacitinib on renal
`function (glomerular filtration rate (GFR)) in healthy volunteers
` Study A3921015 examined the PK of tofacitinib in subjects with mild and moderate
`hepatic impairment. Subjects with severe hepatic impairment were not evaluated.
`
`
`Studies of Drug-Drug Interactions
`Seven clinical studies evaluated drug-drug interactions with tofacitinib.
` The effect of other drugs on the PK of tofacitinib was evaluated in the following
`studies: methotrexate (A3921013), fluconazole (A3921014), tacrolimus and
`cyclosporine (A3921020), ketoconazole (A3921054) and rifampin (A3921056).
` The effect of tofacitinib on the PK of other drugs was evaluated in the following
`studies: midazolam (A3921059), oral contraceptives (A3921071) and methotrexate
`(A3921013).
`
`
`Phase 2 Dose-Ranging Studies
`Five dose ranging studies evaluated more than one dose levels of tofacitinib.
`Global studies
` Study A3921019 was a 6-week, double-blind, placebo-controlled, parallel group,
`monotherapy study
` Study A3921025 was a 24-week, double-blind, placebo-controlled, parallel group
`study in patients receiving background methotrexate
` Study A3921035 was a 24-week, double-blind, placebo- and active-controlled,
`parallel group, monotherapy study
`Studies in Japanese Patients
` Study A3921039 was a 12-week, double-blind, placebo-controlled, parallel group,
`study in Japanese patients receiving background methotrexate
` Study A3921040 was a 12-week, double-blind, placebo-controlled, parallel group,
`monotherapy study in Japanese patients
`
`
`Population Pharmacokinetic Studies
`Population pharmacokinetic analysis used tofacitinib plasma concentration-time data
`from five Phase 2 studies in RA patients.
`
`Phase 3 Study
`Trough concentrations were collected over 12 months in the Phase 3 study A3921064
`
`2.2 General Attributes of the Drug
`2.2.1 What are the highlights of the chemistry and physical-chemical
`properties of the drug substance a