CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`
`
`APPLICATION NUMBER:
`202343Orig1s000
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`PHARMACOLOGY REVIEW(S)
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Application Number:
`Supporting Document/s:
`Applicant’s Letter Date
`CDER Stamp Date:
`Product:
`Indication:
`Applicant:
`Review Division:
`
`Reviewer:
`Supervisor/Team Leader:
`Division Director:
`Project Manager:
`
`202343
`SDN
`7 Dec 2010
`7 Dec 2010
`(MK-0431D)
`Type 2 diabetes mellitus (T2DM) and hyperlipedemia
`Merck
`Division of Metabolism and Endocrinology Products
`(HFD-510)
`Patricia Brundage, Ph.D.
`Todd Bourcier, Ph.D.
`Mary Parks, M.D.
`Raymond Chiang
`
`
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and necessary for
`approval of NDA 202343 are owned by Merck or are data for which Merck has obtained a
`written right of reference. Any information or data necessary for approval of NDA 202343 that
`Merck does not own or have a written right to reference constitutes one of the following:
`(1) published literature, or (2) a prior FDA finding of safety or effectiveness for a listed drug, as
`described in the drug’s approved labeling. Any data or information described or referenced
`below from a previously approved application that Merck does not own (or from FDA reviews or
`summaries of a previously approved application) is for descriptive purposes only and is not
`relied upon for approval of NDA 202343.
`.
`
`Reference ID: 2974927
`
`1
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`

`

`NDA 202343
`
`
`
`Patricia Brundage
`
`TABLE OF CONTENTS
`1 EXECUTIVE SUMMARY ......................................................................................... 3
`1.1
`INTRODUCTION.................................................................................................... 3
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 3
`1.3 RECOMMENDATIONS............................................................................................ 4
`2 DRUG INFORMATION ............................................................................................ 5
`2.1 DRUG................................................................................................................. 5
`2.2 RELEVANT NDAS AND DMFS............................................................................... 6
`2.3 DRUG FORMULATION ........................................................................................... 6
`2.4 COMMENTS ON NOVEL EXCIPIENTS....................................................................... 7
`2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ......................................... 8
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN .................................... 10
`2.6
`2.7 REGULATORY BACKGROUND .............................................................................. 10
`3 STUDIES SUBMITTED.......................................................................................... 11
`
`4 PHARMACOLOGY................................................................................................ 11
`
`5 PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 12
`
`6 GENERAL TOXICOLOGY..................................................................................... 14
`THREE-MONTH ORAL TOXICITY STUDY IN RATS (TT #09-1239) ...................................... 14
`7 GENETIC TOXICOLOGY ...................................................................................... 25
`
`8 CARCINOGENICITY ............................................................................................. 26
`
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY ................................ 27
`
`INTEGRATED SUMMARY AND SAFETY EVALUATION................................. 29
`
`11
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`Reference ID: 2974927
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`

`NDA 202343
`
`
`
`Patricia Brundage
`
`1
`
`Executive Summary
`
`Introduction
`1.1
`This is a 505(b)(1) application for the fixed dose combination (FDC) drug product of sitagliptin
`phosphate and simvastatin (MK-0431D) for the treatment of patients with Type 2 diabetes
`mellitus (T2DM) and hyperlipidemia. Sitagliptin (Januvia®; Merck; NDA 21-995) was approved
`by the FDA as an oral anti-hyperglycemic agent, and simvastatin (Zocor®; Merck; NDA 19-766)
`was approved as an oral anti-hypercholesterolemic agent. Both drug products are approved for
`chronic use.
`
`This 505(b)(1) application relies primarily on the Agency’s findings of safety and efficacy for
`Januvia® (sitagliptin) and Zocor® (simvastatin). As the sponsor is the primary NDA holder for
`sitagliptin and simvastatin, all nonclinical information for both components of the FDC were
`available for review.
`
`The sponsor conducted clinical pharmacology studies to assess the pharmacokinetics of the
`drug combination as well as possible drug-drug interactions between sitagliptin and simvastatin.
`
`Brief Discussion of Nonclinical Findings
`1.2
`The nonclinical pharmacology, pharmacokinetics/ADME properties, and toxicity of sitagliptin and
`simvastatin have been established individually under NDA 21-995 (sitagliptin) and NDA 19-766
`(simvastatin).
`
`Due to the concern of possible toxicologic interactions between sitagliptin and simvastatin,
`especially regarding adverse effects on the skeletal muscle, the sponsor conducted a 3-month
`co-administration toxicology study in rats to assess the potential toxicity due to co-administration
`of sitagliptin and simvastatin. There was no mortality or significant adverse clinical effects
`associated with the co-administration of sitagliptin and simvastatin at exposures greater than
`20 times those at the maximum clinical dose of either drug in the FDC. Although there were no
`adverse muscle or pancreas effects associated with either drug administered alone or in
`combination, co-administration of sitagliptin and simvastatin did cause an increase in adverse
`liver effects.
`
`Administration of the simvastatin high dose (60 mg/kg; ~47-114X MHRD; based on AUC)
`caused an increase in liver weight, hepatocellular hypertrophy, and an increase in ALT levels
`(~2-3X ↑ compared to controls). Although these effects were not observed in animals
`administered sitagliptin alone, the co-administration of sitagliptin (180 mg/kg; ~20X MHRD;
`based on AUC) and simvastatin caused a slightly greater dose-related increase in liver weight
`(females only) and ALT levels with both the low (30 mg/kg; ~20-66X MHRD; based on AUC)
`and high (60 mg/kg; ~47-114X MHRD; based on AUC) simvastatin doses suggesting a possible
`drug-drug interaction between sitagliptin and simvastatin with regards to liver toxicity. Although
`the sponsor did not establish a NOAEL for the additional increases in liver weight and ALT
`levels, these adverse liver effects are clinically monitorable. Co-administration of the simvastatin
`high dose (60 mg/kg; ~47X MHRD; based on AUC) and sitagliptin (180 mg/kg; ~20X MHRD;
`based on AUC) also caused bile duct hyperplasia. Given that there were no similar findings in
`animals administered the simvastatin high dose or sitagliptin alone and that bile duct
`proliferation/hyperplasia was previously observed in rats in studies conducted under
`NDA 21-995 (sitagliptin) and NDA 19-766 (simvastatin), this finding suggests a potential
`
`Reference ID: 2974927
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`3
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`

`

`NDA 202343
`
`Patricia Brundage
`
`drug-drug interaction. However, as a NOEL (30 mg simvastatin/180 mg sitagliptin) was
`established for this finding at approximately 20 times the human exposure at the MRHD, this is
`of minimal concern clinically.
`
`Simvastatin treatment was associated with adverse effects in the nonglandular stomach and
`thyroid. These findings were not markedly affected by the co-administration of sitagliptin.
`Moreover, they are consistent with those observed in the rat in toxicology studies conducted in
`support of NDA 19—766 (simvastatin) and are not considered to be clinically relevant.
`
`Information from the genotoxicity, carcinogenicity, and reproductive studies conducted under
`NDA 21-995 (sitagliptin) and NDA 19-766 (simvastatin) support the chronic administration of
`MK—0431A XR. Pregnancy category X is recommended for the FDC drug product given that
`simvastatin is classified in pregnancy category X because lipid lowering drugs offer no benefit
`during pregnancy when cholesterol and cholesterol derivatives are needed for normal fetal
`development.
`
`1 .3
`
`Recommendations
`
`1 .3.1
`
`Approvability
`
`Pharmacology and Toxicology recommends the approval of MK-0431A XR for the proposed
`indication in adults.
`
`1.3.2
`
`Additional Non Clinical Recommendations
`
`No additional nonclinical studies are required.
`
`1 .3.3
`
`Labeling
`
`The nonclinical labeling information for the FDC drug product of sitagliptin and simvastatin
`(MK—0431 D) is similar to the language used in the labels for which the sponsor is the primary
`NDA holder for both drug products. The safety margin for simvastatin regarding the
`teratogenicity studies (under Section 8.1 ) will need to be corrected to account for the maximum
`simvastatin dose of 40 mg/day; change to the proposed label is underlined. Additionally, the
`paragraph discussing the results of the 3-month rat co-administration study should be deleted
`as it does not contain nonclinical data pertinent to the safe/effective use of the drug.
`
`8.1
`
`Pregnancy
`
`Simvastatin
`
`Simvastatin was not teratogenic in rats or rabbits at doses (25, 10 mg/kg/day,
`
`respectively) that resulted in 6 times the human exposure based on mg/m2 surface area.
`However, in studies with another structurally-related statin, skeletal malformations were
`observed in rats and mice.
`
`13.2 Animal Toxicology and/or Pharmacology
`(hm
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`Reference ID: 2974927
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`NDA 202343
`
`Patricia Brundage
`
`(II) (4)
`
`2
`
`Drug Information
`
`2.1
`
`Drug
`
`CAS Registry Number
`
`Sitagliptin Phosphate: 16676-29-2
`
`Simvastatin: 79902-63-9
`
`Code Name
`
`Sitagliptin Phosphate: MK—0431, L-000224715
`
`Simvastatin: MK—0733
`
`Chemical Name
`
`Sitagliptin Phosphate:
`-
`7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8- tetrahydro-[3-
`(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate
`
`Simvastatin:
`
`-
`
`[1 S-[1 a,3a,7B,8[3(28*,4S*),8aB]]-1 ,2,3,7,8,8a—Hexahydro—3,7—dimethyl-8—[2—
`(tetrahydro—4—hydroxy-6—oxo—2H-pyran—2—yl )ethyl]-1 -naphthalenyl—2,2—
`dimethylbutanoate
`- Butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a,hexahydro-3,7-dimethyl-8-[2—
`(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1 -naphthalenyl ester,[1 S-
`[1a,3a,7|3,8[5(28*,4$*), -8aB]] (USP)
`2,2-dimethylbutyric acid, 8-ester with (4R,6R)-6-[2-[(1S,2$,6R,8$,8aR)—
`1 ,2,6,7,8,8a-hexahydro-8-hydroxy-2,6-dimethyl-1-napthyl]ethyl]tetrahydro-4-
`hydroxy—ZH-pyran—Z—one
`(1S,3R,7S,BS,8aR)—8—[2—[(2R,4R)—4-hydroxy—6-oxotetrahydro—2H-pyran-2—
`yl]ethyl]—3,7—dimethyl—1 ,2,3,7,8,8ahexahydronaphthalen—1-y| 2,2,-
`dimethylbutanoate (Ph. Eur.)
`
`-
`
`-
`
`Molecular Formula/Molecular Weight
`
`Sitagliptin Phosphate: C15H15F6N5O . H304P - H20/523.32
`
`Simvastatin: C25H3805/418.57
`
`Reference ID: 2974927
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`

`

`NDA 202343
`
`
`
`Patricia Brundage
`
`Structure or Biochemical Description
`Sitagliptin Phosphate:
`
`Simvastatin:
`
`
`
`
`
`
`Pharmacologic Class
`Sitagliptin is dipeptidyl peptidase 4 inhibitor (DPP4 inhibitor); an anti-hyperglycemic
`agent.
`Simvastatin is a competitive inhibitor of hydroxymethyl glutaryl coenzyme A (HMG-CoA)
`reductase.
`
`2.2
`
`Relevant NDAs and DMFs
`NDA 21-995 (Januvia®; sitagliptin phosphate; Merck)
`NDA 19-766 (Zocor®; simvastatin; Merck)
`Drug Formulation
`2.3
`The FDC tablets consist of a bilayer configuration in which each layer is an immediate-release
`(IR) formulation of each drug. For initial registration, three tablet strengths of the FDC drug
`product have been developed:
`• Sitagliptin/simvastatin 100 mg/10 mg
`• Sitagliptin/simvastatin 100 mg/20 mg
`• Sitagliptin/simvastatin 100 mg/40 mg
`
`
`Each drug substance is an active ingredient of an approved drug product and is manufactured
`using the same chemistry, manufacturing, and controls as for its respective approved
`single-entity drug. The bilayer tablet is coated with an
`film coat.
`
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`Reference ID: 2974927
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`NDA 202343
`
`Patricia Brundage
`
`Unit Sumgth (mg)
`SI '_
`I- #51111an
`
`Dihasu: eukhnn phosphate
`Mucuystalline cellulose
`Croscarmellose sodium
`
`Sodium steam mum
`
`2.4
`Comments on Novel Excipients
`All excipients are compendial grade with the exception ofthe—
`
`
`
`Dflnsic calcium phosphate
`Nfieroctystalline cellulose
`Cmnnellme sodium
`
`Sodium swuyl
`
`Butylated hydroxyuisole (BI-IA)
`Ascoubic acid
`
`Citric acid monohydnh
`Lactose monohydnte
`Pre- - dammed com starch
`
`
`CPR 73.1200 E172
`
`S nonsor’s Table
`
`polyvinyl alcohol
`polyethylene glycol
`talc
`titanium dioxide
`iron oxide yellow
`iron oxide red.
`iron oxide black
`
`USP-NF, Ph. Eur.
`USP-NF, Ph. Eur.
`USP-NF, Ph. Eur.
`USP-NF, Ph. Eur.
`USP-NF, CPR 73.1200, E172
`USP—NF, CFR 73.1200, El72
`
`Reference ID: 2974927
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`

`

`NDA 202343
`
`Patricia Brundage
`
`2.5
`
`Comments on Impurities/Degradants of Concern
`
`Impurities
`Information on the characterization of impurities for sitagliptin and simvastatin are provided in
`NBA 21-995 and NBA 29—766, respectively.
`
`Degradants
`Acceptance criteria were established for individual and total degradates of sitagliptin and
`simvastatin in MK-0431 D FDC tablets based on potential contributions from the drug substance,
`manufacture of drug product, and predicted increase given the 12-month formal stability studies
`(FSS) results of the drug product.
`
`Sitagliptin
`A limit of NMT W" was established for individual unspecified degradates of sitagliptin in
`MK-0431 D FDC tablets, which meets the ICH Q3B(R2) identification threshold based on the
`maximum daily clinical dose of sitagliptin (100 mg sitagliptin). Although not observed in the FSS
`(through 52 weeks at the long term storage condition of 25°C/60% RH and through 26 weeks at
`the accelerated storage condition of 40°CI75% RH), a
`"M"
`
`was identified as a potential
`“M" is proposed, there is no notable
`degradant. While no limit for this
`toxicological concern regarding this potential degradant.
`
`(b) (4)
`
`Simvastatin
`
`Release and shelf life criteria were established for the simvastatin degradation products. The
`main mode of degradation for simvastatin is oxidation and hydrolysis. The identified degradates
`include
`(”"9
`
`NMT
`
`Single unspecified degradation products are specified at
`“M" (release and end of shelf life criteria), which is in accordance with the ICH Q3B(R2).
`
`Reference ID: 2974927
`
`

`

`NDA 202343
`
`Patricia Brundage
`
`Simvastatin Degradation Products: Proposed Release and Shelf Specifications
`
`
`
`sed release and shelf life limits for the degradanlW
`The ro
`andm meetthe ICH Q
`qua I ca Ion
`res o
`ased
`
`on t e maXImum aI y c Inlca ose o Slmvastatin (40 mg Simvastatin).
`
`ro e
`
`when the drug product was stored at accelerated temperature and humidi
`
`conditions.
`
`e
`
`the highest sitagliptin/Simvastatin table 5 rength of 100 mg/4O mg, when repo e against a
`
`e onna non of theTF
`urlng ormu a non eve opmen revea e
`s u Ies pe orrne
`I
`s a I
`proposed release specification is NMT
`. According tothe sponsor, ah level for
`Simvastatin reference standard, corresponds tofl. Relative to the combined amount of
`sitagliptin and Simvastatin, a! level in these a ets corresponds to an actual degradate
`level of-; see sponsor's ca cu ation adjustment for the
`level below. The proposed
`
`
`shelf-life speCIfication for th
`which is the
`
`
`growth anticipated over the propos
`e an a ows or me od variabili
`. At
`
`the proposed shelf life specification 0
`the sponsor calculated the actual
`level
`
`
`
`for the highest sitagliptin/Simvastatin tablet s rength of 100 mg/40 mg to be! base on the
`tin and Simvastatin . Thus, the actual de rada e evels of the
`sum of both activities (sitagli
`-, which are less than
`do not
`exceed the ICH Q3B(R2) qual Ica Ion
`
`.
`
`.
`
`res o o
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`Reference ID: 2974927
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`

`

`NDA 202343
`
`
`
`Patricia Brundage
`
`Sponsor’s Calculation Adjustment for
`(Release Specification)
`• Mass of
` based on simvastatin working standard (100% label claim = 40 mg) =
`
` * 40 mg =
`• Actual level of
` based on sum of both actives (sitagliptin + simvastatin) =
`
`/(100+40) mg =
`
` Level at NMT
`
`
`
`
`
`2.6
`Proposed Clinical Population and Dosing Regimen
`The MK-0431D is intended for the treatment of patients with T2DM and hypercholesterolemia.
`Doses of 100 mg/10 mg, 100 mg/20 mg, and 100 mg/40 mg (sitagliptin/simvastatin) should be
`taken as a single daily dose in the evening, with or without food.
`2.7
`Regulatory Background
`Sitagliptin was approved in 2006 as an oral anti-hyperglycemic agent to improve glycemic
`control in adults with T2DM. The recommended dose is 100 mg once daily.
`
`Simvastatin was approved in 1991 as oral hypocholesterolemic agent. It is currently indicated to
`reduce cardiovascular (CV) events/deaths in patients at high risk of CV events (e.g., diabetes,
`CHD, etc) and to reduce high cholesterol associated with a variety of conditions. Simvastatin is
`available at doses of 5 mg (starting dose for patients with severe renal impairment and patients
`on cyclosporine or danazol), 10 mg, 20 mg, 40 mg, and 80 mg. For adults, the recommended
`starting dose is 20-40 mg/day. In adolescents (10-17 years of age) with heterozygous familial
`hypercholesterolemia, the recommended dosing range is 10-40 mg/day.
`
`Extensive clinical experience exists for both drugs.
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`Reference ID: 2974927
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`10
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`NDA 202343
`
`
`
`Patricia Brundage
`
`Studies Submitted
`
`
`
` 3
`
`Studies Reviewed
`3.1
`The nonclinical safety and efficacy of sitagliptin and simvastatin, individually, has been fully
`evaluated for chronic administration under NDA 21-995 (Januvia®; sitagliptin; Merck) and
`NDA 19-766 (Zocor®; simvastatin; Merck). The sponsor conducted a 3-month oral toxicity study
`in the rat with co-administration of sitagliptin and simvastatin to determine (1) the potential
`toxicity and toxicologic interaction and toxicokinetic profile of co-administration of sitagliptin and
`simvastatin, and (2) the toxicokinetic profile of L-654969 (an active metabolite of simvastatin
`[simvastatin acid]).
`
`No a priori safety concern stemming from the combined mechanisms of action for sitagliptin and
`simvastatin.
`
`Possible drug-drug interactions addressed in clinical studies.
`
`No preclinical reproductive studies with the FDC were required as simvastatin carries pregnancy
`category X labeling, which will be applied to the FDC product.
`
`Sponsor conducted a 3-month oral toxicity study in the rat with the co-administration of
`sitagliptin and simvastatin to determine (1) the potential toxicity and toxicologic interaction and
`toxicokinetic profile of co-administration of sitagliptin and simvastatin, and (2) the toxicokinetic
`profile of L-654969 (an active metabolite of simvastatin [simvastatin acid]).
`3.2
`Studies Not Reviewed
`None.
`3.3
`None.
`4
`
`Previous Reviews Referenced
`
`Pharmacology
`
`Primary Pharmacology
`4.1
`No pharmacology studies were conducted for this submission for MK-0431D. The pharmacology
`of sitagliptin and simvastatin were previously established individually under NDA 21-995
`(sitagliptin) and NDA 19-766 (simvastatin). For the FDC product MK-0431D, there were no
`a priori safety concerns stemming from the combined mechanisms of action for sitagliptin and
`simvastatin.
`Mechanism of Action
`Sitagliptin
`According to the approved label for Januvia™ (sitagliptin):
`
`
`Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with
`type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the
`active intact hormones are increased by sitagliptin, thereby increasing and prolonging
`the action of these hormones. Incretin hormones, including glucagon-like peptide-1
`(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the
`
`Reference ID: 2974927
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`NDA 202343
`
`
`
`Patricia Brundage
`
`intestine throughout the day, and levels are increased in response to a meal. These
`hormones are rapidly inactivated by the enzyme DPP-4. The incretins are part of an
`endogenous system involved in the physiologic regulation of glucose homeostasis.
`When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase
`insulin synthesis and release from pancreatic beta cells by intracellular signaling
`pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic
`alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging
`active incretin levels, sitagliptin increases insulin release and decreases glucagon levels
`in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for
`DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations
`approximating those from therapeutic doses.
`
`
`Simvastatin
`Simvastatin is a competitive inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A
`(HMG-CoA). This enzyme is the rate limiting step in cholesterol synthesis which catalyzes the
`conversion of HMG-CoA to mevalonic acid. Simvastatin treatment significantly reduces plasma
`levels of low-density lipoprotein cholesterol (LDL-C), and has beneficial effects on a variety of
`other lipid parameters, including triglycerides, high-density lipoprotein cholesterol (HDL-C),
`non-HDL-C, and apolipoproteins B and A-I.
`4.2
`Secondary Pharmacology
`No nonclinical secondary pharmacology studies were conducted for this submission for
`MK-0431D.
`
`Safety Pharmacology
`4.3
`No nonclinical safety pharmacology studies were conducted for this submission for MK-0431D.
`The safety pharmacology of sitagliptin and simvastatin were previously established individually
`under NDA 21-995 (sitagliptin) and NDA 19-766 (simvastatin).
`
`Sitagliptin
`Safety assessment of neurological, renal, pulmonary, and gastrointestinal effects of sitagliptin
`did not identify any significant liability. Although sitagliptin clearly inhibits hERG potassium
`current in vitro at concentrations that markedly exceed human exposure, it does represents a
`potential cardiac conduction liability. No treatment-related changes in QT or other ECG interval
`were identified in telemetered dogs at doses up to 50 mg/kg.
`
`Simvastatin
`Simvastatin and its metabolite simvastatin acid are well tolerated in the human cardiovascular,
`respiratory and gastrointestinal systems in humans.
`5
`Pharmacokinetics/ADME/Toxicokinetics
`
`PK/ADME
`5.1
`The pharmacokinetics/ADME of sitagliptin and simvastatin were previously established
`individually under NDA 21-995 (sitagliptin) and NDA 19-766 (simvastatin).
`
`Sitagliptin
`An oral dose of sitagliptin is rapidly absorbed. Sitagliptin is widely distributed in tissues with
`tissue concentration of the drug generally exceeding that in plasma except in the brain, eyes,
`
`Reference ID: 2974927
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`NDA 202343
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`
`Patricia Brundage
`
`and bone. Sitagliptin is predominantly eliminated by renal mechanisms, but is also excreted in
`the feces via biliary secretion. Metabolism is minimal with unchanged material accounting for
`the major compound-related component in the plasma, urine and bile. Oxidative conversion is
`mediated primarily by CYP3A4 and secondarily by CYP2C8. No active human metabolites of
`sitagliptin have been identified. Sitagliptin does not appear to inhibit CYP450 enzymes nor
`induce CYP3A4. Sitagliptin is a p-glycoprotein and hOAT3 substrate, but does not interfere in
`the shuttling of other substrates via these transporters in vitro. Plasma protein binding is
`moderate (30%) and does not differ between species.
`
`Simvastatin
`Simvastatin is rapidly absorbed in rats, dogs and humans. Simvastatin is administered as the
`inactive lactone prodrug and is hydrolyzed in the plasma and liver to the ß-hydroxy acid form
`(simvastatin acid) for pharmacological activity. Simvastatin has low systemic bioavailability due
`to the extensive first-pass hepatic extraction and extensive biliary excretion. In rats, dogs, and
`humans, biliary excretion is the major route of elimination. Tissue distribution studies in mice,
`rats, and dogs indicate that simvastatin achieves relatively high concentrations in the liver.
`Simvastatin is extensively metabolized. At least eight metabolites are identified in the dog, rat
`and human. The simvastatin metabolites 6'-hydroxy, 3"-hydroxy, 6'-hydroxymethyl and
`6'-carboxylic acid were active, and contribute to the pharmacological activity of simvastatin.
`CYP3A is the major enzyme responsible for simvastatin metabolism. Simvastatin and its active
`acid form are highly bound to plasma proteins, primarily to albumin (~95%). Protein binding is
`comparable in dog and man.
`
`Nonclinical Co-administration of Sitagliptin and Simvastatin
`The nonclinical toxicokinetics (AUC, Cmax, and Tmax) of sitagliptin, simvastatin, and
`simvastatin acid (L-654969; active simvastatin metabolite) were assessed in rats
`co-administered sitagliptin (180 mg/kg) and simvastatin (30 and 60 mg/kg) for 3 months as part
`of a toxicology study. Toxicokinetic findings are discussed in the General Toxicology section
`under the study.
`
`3-Month Rat TK at Week 13 (Sponsor’s Table)
`
`
`The sponsor also conducted clinical studies to assess the pharmacokinetics and possible
`drug-drug interaction of the co-administration of sitagliptin and simvastatin.
`
`
`
`Reference ID: 2974927
`
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`Patricia Brundage
`
`General Toxicology
`6
`The nonclinical toxicology of sitagliptin and simvastatin were previously established individually
`under NDA 21-995 (sitagliptin) and NDA 19-766 (simvastatin). Sitagliptin-related toxicities in the
`mouse (kidney), rat (kidney, liver, heart, teeth, bone marrow, and lymph nodes), and dog
`occurred at very large multiples of clinical exposure; NOAELs with large safety factors were
`established for all toxicities. Simvastatin-related toxicities occurred in the liver (rat, rabbit and
`dog), skeletal muscle, nonglandular forestomach (rat only), CNS (dog only), and testes (dog
`only). Hepatotoxicity and skeletal muscle degeneration in nonclinical species occurred at doses
`similar to or moderately above clinical exposure. Simvastatin-related hepatotoxicity is
`characterized by morphologic changes in rats and rabbits, and transaminase elevations in dogs
`without a morphologic correlate. Simvastatin achieves relatively higher concentrations in liver,
`the target organ, relative to other tissues. The liver also is the site where interconversion
`between simvastatin (inactive lactone) and simvastatin acid occurs.
`
`Due to the concern of possible toxicologic interactions between sitagliptin and simvastatin,
`especially regarding adverse effects on the skeletal muscle, the sponsor conducted a 3-month
`nonclinical study in rats co-administered sitagliptin and simvastatin to rule out possible
`interactions on the skeletal muscle or other potential interactions.
`Three-Month Oral Toxicity Study in Rats (TT #09-1239)
`
`
`Study #
`TT #09-1083
`Study Report Location EDR
`Conducting Laboratory
`Merck Research Laboratories
`and Location
`West Point, PA
`Date of Study Initiation 25 March 2009
`GLP Compliance Yes
`QA Statement Yes
`Drug, Lot #, and % Purity MK-0733, L-000644128-000U222, 99.3%
`MK-0431, L-000224715-010X023, 100%
`
`
`Key Study Findings
`(cid:131) Systemic exposure (AUC) for sitagliptin (180 mg/kg; 163-193 µM·h [AUC]) in this study
`provided ~20X safety margin over the AUC at the clinical dose of 100 mg/day (8.5 µM•hr
`[AUC]).
`(cid:131) The combined systemic exposure (AUC) simvastatin and simvastatin acid (active
`metabolite; L-654969) provided safety margins of ~20-66X (3-10 µM·h [AUC]) and
`~47-114X (7-17 µM·h [AUC]) at doses of 30 mg/kg and 60 mg/kg simvastatin,
`respectively, based on a maximum clinical dose of 40 mg/day (0.15 µM•hr [AUC]).
`(cid:131) No adverse muscle or pancreas effects were observed in animals co-administered
`sitagliptin and simvastatin.
`(cid:131) Adverse liver effects (↑ ALT, ↑ liver weight [females], hepatocellular hypertrophy
`[females], and bile duct hyperplasia [males]) were associated with the high dose (HD) of
`simvastatin (60 mg/kg; 7-17 µM·h; ~47-113X MHRD). An increase in ALT levels and liver
`weight were also observed at both doses of simvastatin (≥30 mg/kg; 3-10 µM·h; ~33X
`MHRD) when co-administered with sitagliptin (180 mg/kg; 163-193 µM·h ~20X MHRD)
`suggesting a possible drug-drug interaction between sitagliptin and simvastatin with
`regards to liver toxicity.
`(cid:131) Treatment-related adverse nonglandular stomach effects (↑ wall thickness, acanthosis
`and/or hyperkeratosis of the mucosa, and inflammation) and thyroid effects (↑ thyroid
`
`Reference ID: 2974927
`
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`NDA 202343
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`
`Patricia Brundage
`
`weight and follicular epithelial hypertrophy) were associated with the simvastatin HD
`(60 mg/kg; 7-17 µM·h; ~47-113X MHRD) and were not markedly affected by the
`co-administration of sitagliptin.
`(cid:131) Transient salivation was attributable to sitagliptin treatment. Excess salivation, which
`was previously associated with sitagliptin treatment in rats, was attributed to poor
`palatability of the drug.
`(cid:131) Sitagliptin systemic exposure was not affected co-administration of simvastatin.
`Interestingly, simvastatin (~3-6X ↓) and L-654969 (~2-4X ↓) exposures were lower in the
`animals co-administered the simvastatin low dose (LD; 30 mg/kg) and sitagliptin
`compared to those administered only the simvastatin LD. A similar effect was not
`observed with the HD of simvastatin.
`
`
`Reviewer’s Comments
`(cid:131) Although a NOAEL was not established for the treatment-related liver effects (↑ ALT and
`liver weight) associated with the co-administration of simvastatin and sitagliptin, potential
`treatment-related adverse liver effects are clinically monitorable. Additionally, the
`sponsor administered doses of sitagliptin and simvastatin that provided exposures
`≥20 times the maximum clinical exposure, so it is possible that adverse liver effects may
`not occur at clinical exposures.
`(cid:131) The bile duct hyperplasia in males co-administered sitagliptin (180 mg/kg) and the
`simvastatin HD (60 mg/kg) is possibly due to the co-administration of the drugs as bile
`duct hyperplasia was previously observed in rats in studies conducted under
`NDA 21-995 (sitagliptin; 2-year study) and NDA 19-766 (simvastatin; 14-week study).
`However, the sponsor has established a NOEAL for the bile duct hyperplasia
`(30/180 mg/kg) with an adequate margin of safety (~20-66X MHRD; based on AUC).
`(cid:131) The following was the rationale for dose selection by the sponsor: The HD of simvastatin
`(60 mg/kg) was anticipated to produce very slight or no skeletal muscle degeneration in
`rats following 3-month oral administration. The sitagliptin dose of 180 mg/kg was a
`NOEL when orally administered to rats for up to 6 months and was expected to provide
`~20-fold exposure margin based on exposure at the clinical dose (100 mg; 8.5 µM•hr).
`While the study results suggest that exacerbation of simvastatin-related skeletal muscle
`toxicity by sitagliptin is unlikely, administration of a higher simvastatin dose closer to that
`previously found to produce skeletal muscle degeneration (e.g., 180 mg/kg in the
`14-week rat study) would have been optimal to better examine possible interactions of
`the two drugs on with regard to myotoxicity.
`
`
`
`Reference ID: 2974927
`
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`NDA 202343
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`Patricia Brundage
`
`Formulation/Vehicle
`
`Unique Study Design
`
`Doses 0, 30/0, 60/0, 0/180, 30/180, and 60/180 mg/kg
`(simvastatin[MK-0733]/sitagliptin[MK-0431])
`Frequency of Dosing Daily
`Route of Administration Oral gavage
`Dose Volume 2.5 mL/kg
`MK-0733 vehicle: 0.5% methylcellulose in
`deionized water
`MK-0431 vehicle: 0.5% methylcellulose with
`5 mM HCl in deionized water
`Species/Strain Rat, Sprague-Dawley, Crl:CD(SD)
`Number/Sex/Group 10/sex/group
`Age 5 weeks
`Weight Females: 109-141 g
`Males: 129-163 g
`MK-0733 (or MK-0733 vehicle) was dosed
`first, followed immediately by administration of
`MK-0431 (or MK-0431 vehicle); control
`animals were dosed with MK-0733 vehicle
`immediately followed by administration of
`MK-0431 vehicle.
`Deviation from Study
`Protocol None
`
`Observations Times and Results
`Mortality
`Daily observations with less frequent examinations on weekends and holidays.
`
`All animals survived to scheduled termination.
`
`Clinical Signs
`Daily observations with less frequent examinations on weekends and holidays.
`
`The