CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`
`APPLICATION NUMBER:
`202343Orig1s000
`
`
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`
`
`

`

`ADDENDUM
`CLINICAL PHARMACOLOGY REVIEW
`
`202343
`December 3, 2010
`
`
`
`NDA
`Submission
`Date(s)
`Brand Name
`Generic Name
`Reviewers
`Team Leader
`OCP Division
`OND Division
`
`Sponsor
`Submission Type
`Formulation
`Strength(s)
`Indication
`Dosage &
`Administration
`
`Juvisync ™, MK-0431D
`Sitagliptin phosphate+simvastatin tablet
`Sang M. Chung, Ph.D.
`Jayabharathi Vaidyanathan, Ph.D. (Acting)
`Clinical Pharmacology II
`Metabolism and Endocrinology Products
`(DMEP)
`Merck
`505(b)(1), Standard
`100/10, 100/20, and 100/40 (mg sitagliptin / mg
`simvastatin)
`Treatment with both sitagliptin and simvastatin
`Patients switching from co-administered sitagliptin (100
`mg) and simvastatin (10, 20, or 40 mg) can initiate
`JUVISYNC at the doses of sitagliptin and simvastatin
`already being taken. JUVISYNC can be taken with or
`without food in the evening.
`
`
`
`
`This addendum is to finalize the pending recommendation in the original Clinical
`Pharmacology review upon the availability of the Office of Scientific Investigations
`(OSI) inspection review issued on September 7, 2011. Also provided is the comments on
`the development of fixed-dose combination with sitagliptin 50 mg from the clinical
`pharmacology perspective.
`
`
`Pending Recommendation in the Original Review dated September 1, 2011:
`The Office of Clinical Pharmacology / Division of Clinical Pharmacology 2 (OCP/DCP-
`™ and finds it acceptable provided that 1) the
`2) has reviewed NDA 202343 for
`Agency and the sponsor agree on the labeling and 2) there is no significant issue from the
`review of Office of Scientific Investigation.
`
`
`
`
`Reference ID: 3016071
`
`(b) (4)
`
`

`

`Final Recommendation:
`The Office of Clinical Pharmacology / Division of Clinical Pharmacology II (OCP/DCP-
`II) has reviewed NDA 202343 for Juvisync™. Data presented in the submission and the
`analysis of data indicates that the proposed FDC formulations meet the bioequivalence
`criteria and the results are acceptable. However, the findings of OSI inspection indicate
`that there were compliance issues at the clinical study site related to the authenticity of
`the test and reference formulations. The issues identified are not related to the validity of
`analytical methods or data presented in the NDA but may be legal or regulatory in nature
`and are being addressed by the OSI.
`
`Phase IV Commitments:
`The sponsor has agreed to develop the FDC with sitagliptin 50 mg to permit dosing of
`patients with moderate renal impairment. The new strengths needs to be developed and
`data to support its approval (e.g., in vivo and/or in vitro study) should be submitted to the
`Agency per the schedule specified in the approval letter.
`
`
`Reviewer’s Comment:
`
`Comments on the OSI recommendation from the clinical pharmacology perspective
`The main issue raised by the OSI was that drug product was not randomly chosen to be
`administered to the volunteers, but pre-specified by the sponsor, which raised the
`authenticity question (refer the OSI memo in Attachment 1). To evaluate the impact of
`this issue, this reviewer looked at additional information available in the NDA as follows:
`
`1. All pivotal studies were open-label and not blinded. Further, reference drug was 2
`tablets and test product was 1 tablet. Therefore, it would be obvious if authenticity
`was being compromised, i.e., the person administering the treatment to volunteers
`would have known if the treatment is test or a reference.
`
`
`2. In the NDA, additional pilot BE study (Study 153, Part I, n=24) study had been
`submitted. The product used in this study was manufactured from the same bulk lot as
`the pivotal BE study (Study 153, Part II) but different packaging lot (refer the
`detailed information in Attachment 2). The results from pilot BE study indicated that
`among the 3 components, sitagliptin and simvastatin acid met the BE criteria. On the
`other hand, while simvastatin AUC met the BE criteria, its Cmax was marginally
`outside the BE limits (i.e., upper bound 1.26 instead of 1.25). Therefore both the
`studies, pilot and pivotal, showed similar results, i.e., the products are BE. The above
`conclusions are also supported by the following analysis conducted by this reviewer;
`• Means of pharmacokinetic parameters of sitagliptin, simvastatin, and
`simvastatin acid from Part I are not significantly different (p>0.05) compared to
`those of Part II according to the ANOVA test using SAS 9.2. In addition,
`variances of those pharmacokinetic parameters from Part I are not significantly
`different (p>0.05) from those of Part II according to Levene's test for
`homogeneity (equality) of variances using SAS 9.2.
`
`
`
`Reference ID: 3016071
`
`

`

`3. All the pharmacokinetic parameters met the BE criteria with tight confidence interval
`(CI) even though there was significant variability in simvastatin and simvastatin
`exposure (Table 1 and 2). Therefore, potential difference among kits/packaging lots
`of the test formulation may not affect the BE conclusion
`4. During the drug development, site, equipment and scale changes for the to-be-
`marketed product was bridged to the biobatch using dissolution comparison data. The
`difference among packaging lots/kits within the same bulk lot of biobatch would be
`smaller than the difference between biobatch and to-be-marketed.
`
`
`
`
`
`Table 1 Summary Statistics and Statistical Comparisons for the Plasma PK Parameters of Sitagliptin,
`Simvastatin and Simvastatin Acid
`P153, Part I
`
`MK-0431D
`AM*
`SD (CV%)
`
`7395
`7296
`951
`
`105.89
`20.34
`
`52.07
`4.88
`
`1295 (17)
`1236 (17)
`321 (31)
`
`53.59 (73)
`15.30 (81)
`
`27.11 (58)
`2.81 (58)
`
`Simvastatin + Sitagliptin
`N
`AM*
`SD (CV%)
`24
`24
`24
`
`7625
`7532
`913
`
`24
`24
`
`24
`24
`
`102.45
`19.84
`
`57.46
`5.66
`
`1419 (18)
`1389 (17)
`261 (27)
`
`44.72 (55)
`15.97 (81)
`
`39.08 (61)
`5.17 (73)
`
`Pharmacokinetic Parameter
`Sitagliptin
`AUC0-∞ ‡ (nM*hr)
`AUC0-last ‡ (nM*hr)
`Cmax ‡ (nM)
`Simvastatin
`AUC0-last ‡ (ng/mL*hr)
`Cmax ‡ (ng/mL)
`Simvastatin Acid
`AUC0-last ‡ (ng/mL*hr)
`Cmax ‡ (ng/mL)
`AM = Arithmetic Mean
`SD: Standard Deviation
`CV% = 100 x sqrt( exp(s2) - 1), where s2 is the observed variance on the natural log-scale
`P153, Part II
`
`N
`
`24
`24
`24
`
`24
`24
`
`24
`24
`
`N
`
`99
`99
`99
`
`99
`99
`
`99
`99
`
`
`
`
`
`Reference ID: 3016071
`
`MK-0431D
`AM*
`SD (CV%)
`
`Simvastatin + Sitagliptin
`N
`AM*
`SD (CV%)
`
`Pharmacokinetic Parameter
`Sitagliptin
`AUC0-∞ ‡ (nM*hr)
`AUC0-last ‡ (nM*hr)
`Cmax ‡ (nM)
`Simvastatin
`AUC0-last ‡ (ng/mL*hr)
`Cmax ‡ (ng/mL)
`Simvastatin Acid
`AUC0-last ‡ (ng/mL*hr)
`Cmax ‡ (ng/mL)
`AM = Arithmetic Mean
`SD: Standard Deviation
`CV% = 100 x sqrt( exp(s2) - 1), where s2 is the observed variance on the natural log-scale
`
`7994
`7907
`948
`
`1469 (18)
`1455 (18)
`268 (28)
`
`123.11
`17.46
`
`70.13 (59)
`10.94 (60)
`
`60.70
`4.86
`
`39.59 (66)
`3.14 (65)
`
`99
`99
`99
`
`99
`99
`
`99
`99
`
`8128
`8036
`975
`
`124.7
`18.41
`
`55.54
`5.16
`
`1451 (17)
`1431 (17)
`287 (30)
`
`68.31 (57)
`12.45 (68)
`
`40.61 (69)
`3.38 (66)
`
`

`

`Table 2 Summary of statistical analysis on the BE.
`
`Stren h
`
`100/80
`
`90% CI
`
`100/10
`
`90% CI
`
`
`
`PK Parameter
`
`AUCO—last (nM*hr)
`Cmax
`.
`Simvastatin
`
`Cmax nu"mL
`Simvastatin Acid
`
`AUCO-last (nghnL‘hr)
`uhnL
`
`0.99
`0.98
`
`0.98
`
`(0.98. 1.00)
`0.94. 1.02
`
`0.92. 1.06
`
`.
`
`.
`
`.
`
`1.01
`1.03
`
`1.13
`
`(0.99. 1.02)
`0.98. 1.07
`
`1.05. 1.21
`
`*: geometric mean ratio (FDC u’ (Simvastatin + Sitagliptin»
`
`Comments on the develo ment
`
`to am for FDC with sita i tin 50 m from the clinical
`
`pharmacology perspective
`
`The development of the FDC strengths of sitagliptin/simvastatin 50/10, 50/20 and 50/40
`to permit dosing in patients with moderate renal impairment was raised by the FDA in
`Type C meting on September 30, 2010 (refer the meeting minute in Attachment 3). The
`sponsor agreed to develop those strengths as Phase IV commitment.
`00(4)
`
`The above data indicate that a BE study may not be
`needed and possible biowaiver request may be submitted as discussed during the Type C
`meeting. However,
`if substantial changes need to be made to develop FDC with
`sitagliptin 50 mg, a BE may be needed.
`
`In conclusion, the new strengths needs to be developed and data to support its approval
`(e.g., in vivo and/or in vitro study) should be submitted to the Agency per the schedule in
`the approval letter.
`
`Table 3 Summary of amount per tablet
`
`Inn-m
`—_—m-m-
`400
`400
`100/40*
`800
`
`Strength
`
`Total
`
`Sitagliptin
`layer
`
`Simvastatin
`layer
`
`r0 1 - sed develo ment
`
`*: biowaiver was granted by the ONDQA-Biophalmaceutics review team.
`
`20 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`Reference ID: 3016071
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SANG M CHUNG
`09/16/2011
`
`JAYABHARATHI VAIDYANATHAN
`09/16/2011
`
`CHANDRAHAS G G SAHAJWALLA
`09/16/2011
`
`Reference ID: 3016071
`
`

`

`
`
`CLINICAL PHARMACOLOGY REVIEW
`
`
`NDA
`Submission
`Date(s)
`Brand Name
`Generic Name
`Reviewers
`Team Leader
`OCP Division
`OND Division
`
`Sponsor
`Submission Type
`Formulation
`Strength(s)
`Indication
`Dosage &
`Administration
`
`202343
`December 3, 2010
`
`™, MK-0431D
`Sitagliptin phosphate+simvastatin tablet
`Sang M. Chung, Ph.D.
`Jayabharathi Vaidyanathan, Ph.D. (Acting)
`Clinical Pharmacology II
`Metabolism and Endocrinology Products
`(DMEP)
`Merck
`505(b)(1), Standard
`100/10, 100/20, and 100/40 (mg sitagliptin / mg
`simvastatin)
`Treatment with both sitagliptin and simvastatin
`Patients switching from co-administered sitagliptin (100
`mg) and simvastatin (10, 20, or 40 mg) can initiate
` at the doses of sitagliptin and simvastatin
`already being taken.
` can be taken with or
`without food in the evening.
`
`
`
`Table of Contents
`1 Executive Summary ................................................................................................................................ 2
`1.1 Recommendation.............................................................................................................................. 2
`1.2 Phase IV Commitments.................................................................................................................... 2
`1.3 Summary of Important Clinical Pharmacology Findings................................................................. 2
`2 Question-Based Review (QBR) .............................................................................................................. 4
`2.1 General Attributes of the Drug and Drug Product............................................................................ 4
`2.2 Extrinsic Factors............................................................................................................................... 8
`2.2.1 What extrinsic factors influence exposure and/or response, and what is the impact of any
`differences in exposure on efficacy or safety responses?...........................................................8
`2.3 General Biopharmaceutics ............................................................................................................. 15
`2.3.1
`Is the proposed to-be-marketed fixed dose formulation bioequivalent to the co-
`administration of sitagliptin and simvastatin formulations? ....................................................15
`2.4 Analytical....................................................................................................................................... 23
`2.4.1 Are bioanalytical studies acceptable? ......................................................................................23
`3 Labeling Comments (Major comments)................................................................................................ 26
`4 Appendix............................................................................................................................................... 29
`4.1 Components and composition of final market image of MK-0431D ............................................. 29
`4.2 Pivotal Study Synopsis (P153 and P255)....................................................................................... 32
`
`
`
`NDA 202343
`
`
`
`1
`
`Reference ID: 3009851
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`1 Executive Summary
`
`1.1 Recommendation
`
`The Office of Clinical Pharmacology / Division of Clinical Pharmacology 2 (OCP/DCP-
`™ and finds it acceptable provided that 1) the
`2) has reviewed NDA 202343 for
`Agency and the sponsor agree on the labeling and 2) there is no significant issue from the
`review of Office of Scientific Investigation.
`
`
`1.2 Phase IV Commitments
`
`None
`
`1.3 Summary of Important Clinical Pharmacology Findings
`
`™, fixed-dose combination (FDC)
`The sponsor has submitted the NDA 202343 for
`tablets of sitagliptin and simvastatin as a 505(b)(1), with the indication for whom
`treatment with both sitagliptin and simvastatin is needed. Sitagliptin and simvastatin have
`been approved for the treatment of Type 2 diabetes as Januvia™ since October 16, 2006
`and for the treatment of dyslipidemia as Zocor™ since December 23, 1991, respectively.
`The goal of development program is to demonstrate bioequivalence (BE) of sitagliptin,
`™ administration compared
`simvastatin and simvastatin acid exposure following
`to those of co-administration of sitagliptin and simvastatin (simvastatin+sitagliptin).
`Simvastatin is an inactive pro-drug and converted to its active form, simvastatin acid,
`after administration. Therefore, pharmacokinetic (PK) parameters of simvastatin acid
`should be considered as a primary endpoint for the BE assessment of simvastatin in
`™ from clinical safety and
`addition to those of simvastatin. The BE is to bridge to
`efficacy data of 1) sitagliptin, 2) simvastatin and 3) sitagliptin+simvastatin. The sponsor
`™ or sitagliptin+simvastatin.
`has not conducted a Phase 3 trial following
`The proposed strengths are 100/10, 100/20 and 100/40 mg (mg sitagliptin / mg
`simvastatin). The tablet strengths containing 50 mg sitagliptin (i.e., 50/10, 50/20 and
`50/40 mg) are currently in development and the sponsor agreed to submit the data by
`December 2011. Januvia™ has been approved for 100 mg once daily with the dose
`adjustment to 50 mg for patients with the moderate renal impairment and 25 mg with the
`severe renal impairment and end stage renal disease. Simvastatin™ dosing range is 5 to 40
`mg once daily in the evening and 5 mg/day is recommended as the starting dose for
`™ is not
`patients with severe renal impairment. The sponsor proposes that
`recommended in patients with moderate or severe renal impairment or ESRD because
`FDC strengths are not available for the specific populations at this time.
`
` A
`
`™ as follows:
` total of eight clinical pharmacology trials were conducted for
`•
`two BE trials - one using the lowest strength (100/10 mg) and the other one using the
`highest strength (100/80 mg)
`
`NDA 202343
`
`
`
`2
`
`Reference ID: 3009851
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`™ using the highest strength (100/80 mg)
`• one trial for the food effect on
`•
`two relative bioavailability trials to explore preliminary formulations
`•
`two trials for the drug-drug interaction assessment
`
`Biowaiver was requested for middle strengths (100/20, 100/40) and has been granted by
`the ONDQA-Biopharmaceutic review team (refer Dr. John Z. Duan’s review).
`The BE of FDC was concluded referencing Januvia™+Zocor™ because the primary PK
`parameters (AUC and Cmax) of sitagliptin, simvastatin and simvastatin acid following
`the FDC met the regulatory BE goal post of 90% confidence interval (90% CI) (Table 1).
`
`Table 1 Summary of statistical analysis on the BE.
`
`
`Tablet Strength
`
` A
`
`™ (Table 2).
` high-fat breakfast did not affect sitagliptin exposure following
`Meanwhile, simvastatin AUC decreased by 24% and its Cmax increased by 20% with the
`high-fat breakfast. In addition, simvastatin acid AUC and Cmax increased by 37% and
`116%, respectively, with the breakfast (Table 2). While, the clinical significance of the
`™ is
`above exposure change in simvastatin and simvastatin acid is not known,
`recommended to be taken in the evening as indicated in the simvastatin labeling.
`
`Table 2 Summary of statistical analysis for the effect of food on the exposure of sitagliptin,
`™
`simvastatin, and simvastatin acid after administration of
`
`GMR*
`
`Fed/Fasted
`90% CI
`
`(0.98, 1.02)
`(0.87, 1.03)
`
`(0.64, 0.90)
`(0.97, 1.48)
`
`(1.16, 1.63)
`(1.84, 2.55)
`
`1.00
`0.94
`
`0.76
`1.20
`
`1.37
`2.16
`
`
`
`3
`
`
`
`Pharmacokinetic Parameter
`Sitagliptin
`AUC0-last
`Cmax
`Simvastatin
`AUC0-last
`Cmax
`Simvastatin acid
`AUC0-last
`Cmax
`*: geometric mean ratio
`
`
`
`NDA 202343
`
`Reference ID: 3009851
`
`100/80
`90% CI
`
`GMR*
`
`0.99
`0.98
`
`0.99
`0.98
`
`PK Parameter
`Sitagliptin
`AUC0-last (nM*hr)
`Cmax (nM)
`Simvastatin
`AUC0-last (ng/mL*hr)
`Cmax (ng/mL)
`Simvastatin Acid
`(0.87, 0.98)
`0.93
`AUC0-last (ng/mL*hr)
`(0.88, 1.02)
`0.95
`Cmax (ng/mL)
`*: geometric mean ratio (FDC / (Simvastatin + Sitagliptin))
`
`(0.98, 1.00)
`(0.94, 1.02)
`
`(0.93, 1.05)
`(0.92, 1.06)
`
`100/10
`90% CI
`
`(0.99, 1.02)
`(0.98, 1.07)
`
`(0.99, 1.16)
`(1.05, 1.21)
`
`(0.96, 1.11)
`(0.97, 1.12)
`
`GMR
`
`1.01
`1.03
`
`1.07
`1.13
`
`1.03
`1.04
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`There was no significant drug interaction between sitagliptin and simvastatin Digoxin
`exposure was significantly increased b
`sitagliptin-i-simvastatin. Patients receiving
`digoxin should be monitored when
`0’(4)
`is co—administered.
`
`The sponsor decided not to market the highest strength (100/80 mg) because simvastatin
`80 mg dosing is limited only for patients who are currently taking 80 mg because of
`significantly higher rhabdomyolysis incidence compared to that of lower doses.
`
`The sponsor submitted a full waiver for the pediatric assessment for the following
`aspects:
`
`0 The product fails to represent a meaningful therapeutic benefit over existing
`therapies for pediatric patients and is unlikely to be used in a substantial number
`of all pediatric age groups or the pediatric age group(s) for which a waiver is
`being requested,
`0 DMEP has not required sponsors of lipid—lowering medications to evaluate drugs’
`efi'ectiveness in the general pediatric population to satisfy the requirements of
`PREA
`(5X4)
`
`0 Pediatric studies with sitagliptin are ongoing.
`
`PeRC meeting was held on August 17, 2011 and the committee agreed on the above
`assessments.
`
`Review of the Office of Scientific Investigation (081) on the pivotal BE studies is
`pending at this time.
`
`In conclusion. the clinical pharmacology information of NDA 202343 is acceptable
`provided that review of 081 finds no significant issue on the pivotal BE studies.
`
`2 Question—Based Review (QBR)
`
`2.1 General Attributes of the Drug and Drug Product
`
`(”"0" is
`(m4):- is a bi-layer, film coated FDC tablets of sitagliptin and simvastatin.
`indicated for patients switching from sitagliptin+simvastatin.
`(mom is expected to improve
`compliance. The proposed strengths are 100/10, 100/20 and 100/40 (sitagliptin—
`mg/simvastatin—mg) and will submit the developmental tablets data containing 50 mg
`sitagliptin by December 2011 as agreed at the pre-NDA meeting.
`
`NDA 202343
`
`4
`
`Reference ID: 3009851
`
`

`

`General attributes of drugs
`
`to the clinical pharmacology are
`Properties of sitagliptin and simva-statin relevant
`summarizedinTable3 from Januvia
`and Zocor
`labeling.
`
`Table 3 Summary of labeling information related to properties of sitagliptin and simvastatin
`
`— Sita 14'
`Structural formula
`
`simvastaun
`
`Solubility /
`Dissolution
`
`Soluble in water
`285% dissolution at 15 minutes for all
`tablet strengths at all pHs with or without
`
`0 Practically insoluble in water
`0 Over
`60 minutes
`to be
`dissolved more than 90%
`
`Mode of action
`
`'
`
`‘
`
`'
`
`'
`
`'
`
`'
`
`3-hydroxy—3-methylglutaryl—
`coenzyme A (HIVIG—CoA)
`reductase inhibitor
`
`
`
`Indication
`
`Pharmacokinetics
`
`to diet and exercise to improve Adjunctive therapy to diet to l)
`Adjunct
`glycemic control in adults with type 2 diabetes
`dyslipidemias except Types I
`mellitus
`and V and 2) reduction the risk
`of heart disease mortali
`
`Absolute bioavailability=87%
`No food efled
`Volume of distribution=l98 L
`Proteinbinding = 38%
`79% excreted unchanged in the mine
`Terminal half-life=12_4 hours
`Reml clearance=350 mIJmin
`
`0
`0
`
`Availability to the general
`circulation is low (<5%)
`Protein binding=95%
`13% and 60% oftotal
`radioactivity administered in
`mine and feces, respectively
`
`FDC formulation development
`
`(”"0“
`A bilayer tablet was selected for
`sitagliptin and simvastatin. Two exploratory
`D2) were developed
`
`“"0 between
`"'""’_ formulations (MK-0431B D1 and
`0”“)
`
`the final market composition. Clinical pharmacology trials related to the formulation
`development for MK-0431D are summarized in Table 4.
`
`MK-0431D D2 led
`
`NDA 202343
`
`5
`
`Reference ID: 3009851
`
`

`

`
`
`Table 4 Summary of clinical pharmacology trials related to formulation development for MK-0431D
`
`
`Study Type
`MK-0431D Tablet Probe Formulation Study
`• Part I: D1 vs. Januvia+generic simvastatin
`• Part II: D2 vs. Januvia+generic simvastatin
`
`Protocol Number
`P154
`
`
`
`In addition, the sponsor submitted results of three drug-drug interaction trials as follows:
`
`
`P153
`
`P155
`
`P255
`
`P025
`P168
`P169
`
`MK-0431D Tablet Definitive Bioequivalence Study
` Part I: probe formulation vs. Januvia™+Zocor™
` Part II: definitive bioequivalence study for 100-mg/80-mg vs.
`Januvia™+Zocor™
`
`MK-0431D Tablet Food Effect Study
`MK-0431D Tablet Definitive Bioequivalence Study for 100-mg/10-mg
`vs. Januvia™+Zocor™
`
`Effect of sitagliptin 200 mg QD for 5 days on simvastatin 20 mg†
`Effect of simvastatin 80 mg QD for 7 days on sitagliptin 100 mg
`Effect of co-administration of sitagliptin and simvastatin on digoxin
`†: Component of filing with the original sitagliptin (Januvia™) in Dec-2005
`
`
`
`
`Formulations used to support MK-0431D programs are summarized in Table 5.
`Components and composition of the final market image of MK-0431D are summarized in
`Appendix 4.1.
`
`NDA 202343
`
`
`
`6
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`Reference ID: 3009851
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`

`

`
`
`Table 5 Summary of formulations used to support MK-0431D program
`
`
`
`
`
`
`NDA 202343
`
`
`
`7
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`Reference ID: 3009851
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`

`

`
`
`2.2 Extrinsic Factors
`
`2.2.1 What extrinsic factors influence exposure and/or response, and what is the
`impact of any differences in exposure on efficacy or safety responses?
`
`2.2.1.1 Drug-Drug Interaction
`
`Effect of simvastatin on sitagliptin
`
`The effect of simvastatin 80 mg QD for 7 days on sitagliptin 100 mg was evaluated in an
`open-label, randomized, 2-period, 2-treatment, crossover study design in healthy male
`(n=5) and female (n=5) subjects (Study P168). The following two treatments were
`administered after an overnight fasting condition with a minimum 5-day washout:
`• Treatment A: sitagliptin 100 mg
`• Treatment B: simvastatin 80 mg once daily in the morning Days 1 through 7 and
`sitagliptin 100 mg on Day 5
`
`
`Formulations used for the study are as follows:
`
`
`Dosage Form
`Tablet
`Tablet
`
`Expiration
`Date
`Sep-2011
`Sep-2010
`
`Potency
`Drug
` 100-mg
`Sitagliptin†
` 80-mg
`Simvastatin‡
`† JANUVIA™ is manufactured by Merck
`‡ ZOCOR® is manufactured by Merck
`
`Lot Number
`Y1909
`X5768
`
`
`The primary endpoints were sitagliptin AUC0-∞, AUC0-last, and Cmax. The effect of
`simvastatin on sitagliptin was evaluated using the BE approach for the comparability
`between Treatment A and B. sitagliptin PK parameters and results of statistical analysis
`are summarized in Table 6. Sitagliptin plasma concentration-time profiles and individual
`ratios of PK parameters are shown in Figure 1. The results indicate that there is no
`significant impact of simvastatin 80 mg QD for 7 days on sitagliptin 100 mg.
`
`Table 6 Summary statistics for plasma sitagliptin PK parameters and statistical analysis (P168)
`
`
`Sitagliptin
`
`Simvastatin + Sitagliptin
`
`(Simvastatin + Sitagliptin) /
`Pharmacokinetic
`Sitagliptin
`Parameter
`90% CI
`GMR
`95% CI
`GM
`N
`95% CI
`GM
`N
`1.01
`(0 97, 1 05)
`(6351, 8201)
`7217
`10
`(6426, 8297)
`7302
`10
`AUC0-∞ ‡ (nM hr)
`AUC0-last ‡ (nM hr)
`(0 97, 1 05)
`(6269, 8119)
`7134
`10
`(6346, 8219)
`7222
`10
`1.01
`(1 00, 1 26)
`(704, 946)
`816
`10
`(787, 1059)
`913
`10
`Cmax ‡ (nM)
`1.12
`
`
`Tmax ║ (hr)
`(0 5, 5 0)
`2 0
`10
`(0 5, 5 0)
`2 5
`10
`
`
`Apparent t1/2 § (hr)
`1 2
`11 5
`10
`1 6
`10 4
`10
`‡ Back-transformed least-squares mean and CI from linear mixed effects model performed on natural log-transformed values;
`GMR = Geometric least-squares mean ratio ([Simvastatin + Sitagliptin]/Sitagliptin)
`║ Median (min, max) reported for Tmax
`§ Harmonic mean, jack-knife standard deviation reported for apparent t1/2
`GM = Geometric Least-Squares Mean;
`CI: Confidence Interval
`
`
`
`NDA 202343
`
`
`
`8
`
`Reference ID: 3009851
`
`

`

`
`
`
`
`
`Figure 1
`
`Mean plasma concentration-time profiles (left) and individual GMR of PK
`parameters (right)
`
`
`
`
`
`Effect of sitagliptin+simvastatin on digoxin
`
`The effect of sitagliptin 100 mg + simvastatin 80 mg QD for 9 days on digoxin 0.5 mg
`was evaluated in an open-label, randomized, 2-period, 2-treatment, crossover study
`design in healthy male (n=8) and female (n=6) subjects (Study P169). The following two
`treatments were administered after an overnight fasting condition with a minimum 5-day
`washout:
`• Treatment A: digoxin 0.5 mg
`• Treatment B: sitagliptin 100 mg + simvastatin 80 mg once daily in the morning
`Days 1 through 9 and digoxin 0.5 mg on Day 5
`
`100-mg
`
`Tablet
`
`1-Sep-2011
`
`Y1911
`
`Merck & Co Inc
`
`0 25-mg
`
`Tablet
`
`1-May-2011
`
`A38580
`
`GlaxoSmithKline
`
`
`
`The primary endpoints were digoxin AUC0-∞, AUC0-last, and Cmax. The effect of
`simvastatin+sitagliptin on digoxin was evaluated using the BE approach for the digoxin
`exposure comparability between Treatment A and B. Digoxin PK parameters and results
`of statistical analysis are summarized in Table 7. Digoxin plasma concentration-time
`profiles and individual ratios of digoxin PK parameters are shown in Figure 2. The results
`indicate that sitagliptin 100 mg + simvastatin 80 mg increase digoxin AUC by 26% and
`Cmax by 41% compared to those of digoxin alone.
`
`NDA 202343
`
`
`
`9
`
`Reference ID: 3009851
`
`
`Formulations used for the study are as follows:
`
`
`Potency
`
`80-mg
`
`Dosage
`Form
`Tablet
`
`Expiration
`Date
`1-Apr-2011
`
`Lot Number
`
`Manufacturer
`
`Y2107
`
`Merck & Co Inc
`
`Drug
`
`Simvastatin
`(ZOCOR®)
`Sitagliptin
`(JANUVIA
`Digoxin
`(Lanoxin®)
`
`

`

`
`
`The impact of co-administration of sitagliptin and simvastatin on digoxin is greater than
`that of sitagliptin alone (refer the following Januvia™ labeling on digoxin).
`
`
`Digoxin: Sitagliptin had a minimal effect on the pharmacokinetics of digoxin. Following
`administration of 0.25 mg digoxin concomitantly with 100 mg of JANUVIA daily for 10
`days, the plasma AUC of digoxin was increased by 11%, and the plasma Cmax by 18%.
`
`
`Therefore, the co-administration should be done with caution in patients with digoxin
`therapy.
`
`
`Table 7 Summary statistics for plasma digoxin PK parameters and statistical analysis (P169)
`
`
`Digoxin
`
`(Digoxin + Simvastatin +
`Digoxin + Simvastatin +
`Sitagliptin
`Sitagliptin) /
`Sitagliptin
`90% CI
`GMR
`95% CI
`GM
`N
`GM
`95% CI
`N
`
`
`
`
`
`
`
`
`
`AUC0-last ‡ (nM hr)
`(1 13, 1 41)
`(28 18, 35 79)
`31 76
`13
`40 10
`(35 47, 45 33)
`12
`1.26
`(1 20, 1 66)
`(2 15, 2 96)
`2 52
`13
`3 57
`(3 03, 4 21)
`12
`Cmax ‡ (nM)
`1.41
`
`
`Tmax ║ (hr)
`(1 0, 2 0)
`1 0
`13
`1 0
`(0 5, 2 0)
`12
`
`
`Apparent t1/2 § (hr)
`19 2
`44 9
`13
`34 4
`13 5
`12
`‡ Back-transformed least-squares mean and CI from linear mixed effects model performed on natural log-transformed values;
`GMR = Geometric least-squares mean ratio ([Simvastatin + Sitagliptin]/Sitagliptin)
`║ Median (min, max) reported for Tmax
`§ Harmonic mean, jack-knife standard deviation reported for apparent t1/2
`GM = Geometric Least-Squares Mean;
`CI: Confidence Interval
`rMSE: Root mean square error on log-scale from linear mixed effect model When multiplied by 100, provides estimate of the
`pooled within-subject coefficient of variation
`
`Pharmacokinetic
`Parameter
`
`
`
`
`
`Figure 2 Mean digoxin plasma concentration-time profiles (left) and individual GMR of PK
`parameters (right)
`
`
`
`
`
`
`NDA 202343
`
`
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`
`
`10
`
`Reference ID: 3009851
`
`BEST AVAILABLE
`COPY
`
`

`

`Reviewer’s Comment: The minimum 5 days may not be sufficient washout period
`considered up to 45 hours digoxin half-life (Table 7). Therefore, the results of statistical
`analysis may not be reliable. However. labeling on cautions based on the relative digoxin
`exposure change between treatments seems acceptable.
`
`Effect of sitagliptin on simvastatin
`
`information because those were
`The study results were provided as supplemental
`submitted with the sitagliptin original NDA and JanuviaTM already had labeling on
`simvastatin as follows:
`
`Simvastatin: Single—dose pharmacokinetics of simvastatin, a CYP3A4 substrate, was not
`meaningfully altered in subjects receiving nmltiple daily doses of sitagliptin. Therefore,
`sitagliptin is not an inhibitor of CYP3A4—mediated metabolism
`
`In brief. the effect of sitagliptin 200 mg as 2x100 mg QD for 5 days on simvastatin 20
`mg was estimated in healthy subjects (n=12) (Study P025) and primary results are shown
`in Table 8. Refer the clinical pharmacology review for the original NDA for the details of
`study results.
`
`Table 8 Summary statistics for simvastatin PK parameters (N=12) (1’025)
`
`Geometric Meant
`simvastatin +
`Pharmacokinetic Parameters Sita ' tin
`Active HMG-CoA Reductase Inhibitors
`
`GMRt 90% C or n Value
`simvastatin + Sitagliptin/
`simvastatin
`
`simvastatin
`
`61 .14
`AUthg) (ng—eq hr/mL)
`12.23
`Cu (ng—eq lmL)
`1.8x
`Tun .
`Total HMG£0A Reductase Inhibitors
`
`AUths0(ng—eq hr/mL)
`Cm(ng-eq lmL)
`T... (hr)
`Simvastatin Acid
`
`161.6
`46.78
`1.8:
`
`.
`
`.
`
`AUC(o-hs¢) (ng-hr/mL)
`Cm(nglmL)
`T... (hr)
`
`_
`
`_
`
`1.06 (0.88, 1.26)
`0.94 (0.66, 1.34)
`06635
`
`1.01(0.80, 1.28)
`0.88 (0.59, 1.31)
`0.6305
`
`1.12 (0.93, 1.35)
`1.06 (0.86, 1.32)
`0.290s
`
`
`
`AUCaun) (ng-hr/mL)
`Cm(nglmL)
`.
`Tun (hr)
`1‘ Back-transformed from the log scale.
`: Median.
`sp—Value: p—Value of between treatment comparison using rank analysis.
`GMR=Geometric Mean Ratio;
`CI=Confidence Interval.
`
`.
`
`0.85 (0.60, 1.22)
`0.80 (0.51, 1.26)
`0.6395
`
`NDA 202343
`
`11
`
`Reference ID: 3009851
`
`

`

`
`
`2.2.1.2 Food Effect
`
`The effect of food on the final market composition (FMC) of fixed-dose combination
`tablet was evaluated using an open-label, randomized, 2-period, 2-treatment, single-dose,
`crossover study in healthy subjects (n=18 male and 14 female) (Study P155). The
`following two treatments were administered with a minimum 5-day washout:
`• Treatment A: MK-0431D 100/80 mg administration under fasted condition
`• Treatment B: MK-0431D 100/80 mg administration under a standard high-fat
`breakfast
`
`
`Formulations used for the study are as follows:
`
`
`
`Drug
`MK-0431D
`(sitagliptin/simvastatin)
`
`
`Potency
`100-mg
`/ 80-mg
`
`Formulation
`Number
`WL00033417
`
`Dosage
`Form
`Tablet
`
`Control
`Number
`WL00037796
`
`Assay Potency
`Mean % of Claim (n=2)
`Sitagliptin
`Simvastatin
`95 8
`100 2
`
`
`The primary endpoints were sitagliptin, simvastatin, and simvastatin acid AUC0-∞, AUC0-
`last, and Cmax. The effect of food was evaluated using the BE approach for the
`comparability of exposure between Treatment A and B. Plasma concentration-time
`profiles of sitagliptin, simvastatin, and simvastatin acid are shown in Figure 3 and their
`PK parameters with statistical analysis are summarized in Table 9. Individual GMR are
`shown in Figure 4. The results indicate that there is no significant impact of food on
`sitagliptin. However, simvastatin AUC decreased by 24% and its Cmax increased by 20%
`with the high-fat breakfast. In addition, simvastatin acid AUC and Cmax increased by
`37% and 116%, respectively, with the breakfast (Table 9). While, the clinical significance
`™
`of the above exposure change in simvastatin and simvastatin acid is not known,
`is recommended to be taken in the evening as indicated in simvastatin labeling.
`
`
`
`NDA 202343
`
`
`