CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`209803Orig1s000
`209805Orig1s000
`209806Orig1s000
`NON-CLINICAL REVIEW(S)
`
`
`
`
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY NDA/BLA REVIEW AND EVALUATION
`
`209805
`Application number:
`SDN 1
`Supporting document/s:
`12/19/2016
`Applicant’s letter date:
`12/19/2016
`CDER stamp date:
`Ertugliflozin and Sitagliptin
`Product:
`Type 2 Diabetes Mellitus
`Indication:
`Merck Sharp and Dohme Corp
`Applicant:
`DMEP
`Review Division:
`Jessica J. Hawes, Ph.D.
`Reviewer:
`Ronald Wange, Ph.D.
`Supervisor/Team Leader:
`Jean-Marc Guettier, M.D.
`Division Director:
`Elizabeth Godwin
`Project Manager:
`Template Version: September 1, 2010
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 209805 are owned by Merck Sharp and Dohme Corp
`are data for which Merck Sharpe and Dohme Corp has obtained a written right of
`reference.
`Any information or data necessary for approval of NDA 209805 that Merck Sharp and
`Dohme Corp 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 reflected in the drug’s approved labeling. Any data or information
`described or referenced below from reviews or publicly available summaries of a
`previously approved application is for descriptive purposes only and is not relied upon
`for approval of NDA 209805.
`
`Reference ID: 4195727
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`NDA #209805
`
`Jessica Hawes, Ph.D.
`
`TABLE OF CONTENTS
`
`1 EXECUTIVE SUMMARY ......................................................................................... 3
`1.1
`INTRODUCTION.................................................................................................... 3
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 4
`1.3 RECOMMENDATIONS............................................................................................ 4
`2 DRUG INFORMATION ............................................................................................ 5
`2.1 DRUG................................................................................................................. 5
`2.2 RELEVANT INDS, NDAS, BLAS AND DMFS........................................................... 6
`2.3 DRUG FORMULATION ........................................................................................... 6
`2.4 COMMENTS ON NOVEL EXCIPIENTS....................................................................... 8
`2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ......................................... 8
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN ...................................... 8
`2.7 REGULATORY BACKGROUND ................................................................................ 8
`3 STUDIES SUBMITTED............................................................................................ 9
`3.1
`STUDIES REVIEWED............................................................................................. 9
`3.2
`STUDIES NOT REVIEWED ..................................................................................... 9
`3.3
`PREVIOUS REVIEWS REFERENCED........................................................................ 9
`4 PHARMACOLOGY................................................................................................ 10
`4.1
`PRIMARY PHARMACOLOGY................................................................................. 10
`4.2
`SECONDARY PHARMACOLOGY............................................................................ 10
`4.3
`SAFETY PHARMACOLOGY................................................................................... 11
`5 PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 13
`5.1
`PK/ADME........................................................................................................ 13
`5.2
`TOXICOKINETICS ............................................................................................... 15
`6 GENERAL TOXICOLOGY..................................................................................... 16
`6.1 ERTUGLIFLOZIN ..................................................................................................... 16
`6.2 SITAGLIPTIN .......................................................................................................... 17
`6.3 FDC ERTUGLIFLOZIN/SITAGLIPTIN .......................................................................... 17
`7 GENETIC TOXICOLOGY ...................................................................................... 37
`8 CARCINOGENICITY ............................................................................................. 38
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY ................................ 39
`10
`SPECIAL TOXICOLOGY STUDIES................................................................... 39
`11
`LABELING REVIEW .......................................................................................... 39
`SECTION 8 USE IN SPECIFIC POPULATIONS .................................................................... 39
`SECTION 12 CLINICAL PHARMACOLOGY ......................................................................... 42
`SECTION 13 NONCLINICAL TOXICOLOGY ........................................................................ 44
`11
`INTEGRATED SUMMARY AND SAFETY EVALUATION................................. 46
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`NDA #209805
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`Jessica Hawes, Ph.D.
`
`FDC TOXICOLOGY SUMMARY TABLE ............................................................................. 48
`
`Table of Tables
`Table 1: Summaries of Pivotal Previously-Reviewed Nonclinical Studies....................... 9
`Table 2: Ertugliflozin Summary of Pivotal General Toxicology Studies ......................... 16
`Table 3: Body Weights - 13-week Rat Study #14GR162............................................... 25
`Table 4: Food Consumption - 13-week Rat Study #14GR162 ...................................... 27
`Table 5: Hematology Parameters - 13-week Rat Study #14GR162 .............................. 28
`Table 6: Clinical Chemistry Parameters - 13-week Rat Study #14GR162..................... 29
`Table 7: Clinical Chemistry Parameters Continued - 13-week Rat Study #14GR162 ... 30
`Table 8: Urine Parameters - 13-week Rat Study #14GR162......................................... 30
`Table 9: Ertugliflozin + Sitagliptin Coadministration Human Safety Margins ................. 48
`
`Table of Sponsor’s Tables
`Sponsor's Table 1: Ertugliflozin/Sitagliptin FDC Tablet Formulation Composition........... 7
`Sponsor's Table 2: Summary of Ertugliflozin PK Parameters with Coadministration in
`Humans – Study #P022/1033 ....................................................................................... 15
`Sponsor's Table 3: Summary of Sitagliptin PK Parameters with Coadministration in
`Humans – Study #P022/1033 ....................................................................................... 16
`Sponsor's Table 11: Macroscopic Findings - 13-week Rat Study #14GR162 ............... 33
`Sponsor's Table 12: Organ Weights - 13-week Rat Study #14GR162 .......................... 34
`Sponsor's Table 13: Histopathology - 13-week Rat Study #14GR162 .......................... 35
`Sponsor's Table 14: PF-04971729 Toxicokinetics - 13-week Rat Study #14GR162..... 36
`Sponsor's Table 15: Sitagliptin Toxicokinetics - 13-week Rat Study #14GR162........... 37
`
`Table of Figures
`Figure 1: Male Ketone Urinalysis - 13-week Rat Study #14GR162............................... 31
`Figure 2: Female Ketone Urinalysis - 13-week Rat Study #14GR162........................... 32
`
`Executive Summary
`1
`Introduction
`1.1
`Merck Sharp and Dohme Corp. has submitted NDA application packages for the new
`molecular entity (NME) Ertugliflozin (PF-04971729, MK-8835) alone (NDA #209803,
`IND #106447) and as fixed dose combination (FDC) products with the marketed drugs
`Metformin (MK-8835B, NDA #209806, IND #122329) and Sitagliptin (MK-8835A, NDA
`#209805, IND #122330) for the treatment of type 2 diabetes mellitus (T2DM).
`
`The nonclinical profile for the NME, ertugliflozin, was fully evaluated in the Pharm/Tox
`review under NDA #209803. This review focuses on evaluation of additional
`information pertinent to the ertugliflozin + sitagliptin hydrochloride FDC product.
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`Reference ID: 4195727
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`NDA #209805
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`
`1.2
`
`Brief Discussion of Nonclinical Findings
`
`Coadministration of ertugliflozin and sitagliptin in rats for 13-weeks was generally well-
`tolerated with sufficient margins of safety and was not associated with significant
`adverse systemic toxicities. Furthermore, no new clinically relevant or synergistic
`adverse toxicities due to coadministration of PF-04971729 and sitagliptin were
`observed. Thus, the rat combination toxicology study adequately bridges the proposed
`FDC product to the ertugliflozin nonclinical safety profile under NDA #209803, with
`sufficient safety margins based on AUC exposures at the maximum recommended high
`doses (MRHDAUC) of 15 mg/day ertugliflozin (89x MRHDAuc) and 100 mg/day sitagliptin
`(9x MRHDAUC). Overall, the nonclinical data were considered to be sufficient and
`support clinical dosing of the FDC product at ertugliflozin doses up 15 mg/day
`ertugliflozin and sitagliptin doses up to 100 mglday.
`
`1.3 Recommendations
`
`1.3.1 Approvability
`
`The nonclinical data support market approval of the ertugliflozin/sitagliptin FDC
`
`1.3.2 Additional Non Clinical Recommendations
`
`None
`
`1 .3.3 Labeling
`
`Nonclinical labeling recommendations are below. See Section 11 Labeling Review for a
`full discussion of proposed changes. Only labeling specific to the FDC or the sitagliptin
`component are captured in this review. Please see the NDA review under #209803 for
`labeling recommendations regarding the ertugliflozin component.
`
`Only one minor edit specific for sitagliptin was recommended (Section 8.1 ).
`
`Section: 8 USE IN SPECIFIC POPULATIONS
`
`Section 8.1 Pregnancy
`
`Sitagligtin
`Sitagliptin administered to pregnant female rats and rabbits from gestation day 6 to 20
`(organogenesis) did not adversely affect developmental outcomes at oral doses up to 250 mg/kg (rats)
`and 125 mg/kg (rabbits), or approximately 30- and 20-times human exposure at the maximum
`recommended human dose (MRHD) of 100 mg/day based on AUC comparisons. Higher doses increased
`the incidence of rib malformations in offspring at 1,000 mg/kg, or approximately 100 times human
`exposure at the MRHD.
`
`(m4)
`
`Sitagliptin administered to female rats from gestation day 6 to lactation day 21 decreased body
`weight in male and female offspring at 1,000 mg/kg. No functional or behavioral toxicity was observed in
`offspring of rats.
`Placental transfer of sitagliptin administered to pregnant rats was approximately 45% at 2 hours
`and 80% at 24 hours postdose. Placental transfer of sitagliptin administered to pregnant rabbits was
`approximately 66% at 2 hours and 30% at 24 hours.
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`Reference ID: 4195727
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`NDA #209805
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`Jessica Hawes, Ph.D.
`
`Drug Information
`2
`2.1 Drug
`CAS Registry Number
`Ertugliflozin: 1210344-57-2
`Sitagliptin: 654671-77-9
`
`Generic Name
`Ertugliflozin + sitagliptin
`
`Code Name
`Ertugliflozin + sitagliptin FDC: MK-8835A
`
`Ertugliflozin: PF-04971729, MK-8835
`Ertugliflozin L-pyroglutamic acid (L-PGA) co-crystal form: PF-04971729
`It is noted that the neutral amorphous form was used for most exploratory toxicology studies,
`whereas the L-PGA co-crystalline form intended for marketing was used in pivotal toxicology and
`safety pharmacology studies.
`
`Sitagliptin:
`
`MK-0431, L-000224715-010X, sitagliptin phosphate
`
`Chemical Name
`PF-04971729:
`
`PF-04971729
`
`Sitagliptin:
`
`(1S,2S,3S,4R,5S)-5-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-1-
`hydroxymethyl-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol
`
`(1S,2S,3S,4R,5S)-5-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-1-
`hydroxymethyl-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol L-pyroglutamic
`acid
`
`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-(cid:68)]pyrazine
`phosphate (1:1) monohydrate
`
`Molecular Formula/Molecular Weight
`PF-04971729:
`C22H25ClO7 / 436.88 g/mol
`PF-04971729
`C27H32ClNO10 / 566.00 g/mol
`
`C16H15F6N5O / 407.32 g/mol
`Sitagliptin:
`Sitagliptin phosphate monohydrate salt: C16H15F6N5(cid:50) (cid:404) H3PO4 (cid:404) H2O / 523.32 g/mol
`
`Reference ID: 4195727
`
`5
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
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`

`

`NDA #209805
`
`Jessica Hawes, Ph.D.
`
`Structure or Biochemical Description
`Ertugliflozin L-PGA
`
`L-pyroglutamic acid
`
`PF-0497l 729
`
`Sitagliptin
`
`N
`
`N
`
`/ \U N
`
`' H3p04
`
`- H20
`
`Pharmacologic Class
`Ertugliflozin: Sodium glucose co-transporter 2 (SGLT2) Inhibitor
`Sitagliptin:
`Dipeptidyl peptidase-4 (DPP-4) inhibitor
`
`2.2 Relevant INDs, NDAs, BLAs and DMFs
`
`CF;
`
`NDA #209803 (IND #106447): MK-8836 Ertugliflozin, Merck Sharp and Dohme Corp
`
`NDA #209806 (IND #122329): MK-8835A (Ertugliflozin + metformin FDC), Merck
`Sharp and Dohme Corp
`
`NDA #21995:
`
`Januvia (Sitagliptin), Merck Sharp and Dohme Corp
`
`2.3 Drug Formulation
`
`@(4)
`
`The ertugliflozin/sitagliptin FDC will be formulated as film coated tablet in 4 strengths:
`"m 5 mg ertugliflozin + 100 mg sitagliptin,
`“m"
`and 15 mg ertugliflozin + 100 mg sitagliptin. The
`following two tables are representative of the formulations for all 4 strengths.
`
`Reference ID: 4195727
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`

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`NDA #209805
`
`Jessica Hawes, Ph.D.
`
`Sponsor's Table 1: ErtugliflozinISitagliptin FDC Tablet Formulation Composition
`
`Table l
`
`Ertugliflo ' .
`
`Tablet Composition
`
`
`
`
`
`
`Core Tablet
`
`—_m
`——“
`
`
`
`
`
`
`
`
`Core nun Weight
`
`'
`
`
`
`(Tables excerpted from sponsor’s package)
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`NDA #209805
`
`Jessica Hawes, Ph.D.
`
`2.4 Comments on Novel Excipients
`All excipients are compendial and controlled at acceptable levels.
`2.5 Comments on Impurities/Degradants of Concern
`Ertugliflozin-related impurities and degradants were qualified under NDA #209803.
`2.6
`Proposed Clinical Population and Dosing Regimen
`The proposed clinical population is adults with T2DM.
`
`The sponsor’s recommended starting dose is 5 mg ertugliflozin/100 mg sitagliptin once
`daily with or without food. The sponsor recommends that the dose may be increased to
`a maximum dose of 15 mg ertugliflozin/100 mg sitagliptin once daily if additional
`glycemic control is needed.
`Sponsor’s Maximum Recommended Human Dose:
`FDC: Once daily dose of 15 mg ertugliflozin and 100 mg sitagliptin
`(cid:190) Total: 15 mg/day ertugliflozin + 100 mg/day sitagliptin
`(cid:16) Ertugliflozin: * AUC = 1.38 (cid:80)g(cid:194)h/mL, Cmax = 266 ng/mL (cid:167) 0.6 (cid:80)M
`*Based on the clinical population pharmacokinetic (PK) analysis
`(cid:16) Sitagliptin: **AUC0-24 = 6.9 (cid:80)M(cid:194)h = 2.81 (cid:80)g(cid:194)h/mL, Cmax = 805 nM
`** Based on study #PB022/1033 (CSR, Table 12)
`
`Ertugliflozin: The proposed MRHD under NDA #209803 for the NME alone is also 15
`mg/day.
`
`Sitagliptin: Approved maximum daily dose of Sitagliptin is 100 mg once daily
`2.7 Regulatory Background
`(cid:120) An IND for Ertugliflozin was originally submitted as PF04971729 in September
`2009.
`(cid:120) On 4/14/2014, the sponsor submitted a Type B meeting request and a pre-IND
`package for the FDC Ertugliflozin + Sitagliptin product. On 4/22/2014, a Pre-
`IND/Type B meeting was granted with written responses sent to the sponsor on
`6/12/2014. Within the pre-IND package, the sponsor submitted 3 clinical
`questions, but no non-clinical questions.
`(cid:120) On 7/30/2014, the sponsor submitted and cross-referenced the new IND
`#122330 for the FDC product MK-8835A containing ertugliflozin and sitagliptin for
`the treatment of T2DM.
`(cid:120) On 3/25/2015, the sponsor submitted a meeting request to discuss a revised
`clinical pharmacology and biopharmaceutics plan and written responses were
`sent on 6/8/2015
`(cid:120) Pediatric study plan (PSP) written responses were provided on 7/2/2015 and a
`PSP initial agreement was provided on 8/20/2015.
`(cid:120) On 7/6/2016, the sponsor submitted a Type-B Pre-NDA meeting request. A pre-
`NDA meeting was held on 9/6/2016. Two nonclinical questions were submitted,
`
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`NDA #209805
`
`Jessica Hawes, Ph.D.
`
`but not discussed at the meeting. The sponsors was informed via written
`responses that the nonclinical safety package was adequate to support filing of
`the NDA, but that conclusions regarding the carcinogenicity findings were a
`matter of review. A total of 13 additional questions were discussed and/or
`addressed, but were not nonclinical.
`
`Ertugliflozin
`
`o Ertugliflozin was originally submitted as PF04971729 under IND #106447 in
`September 2009.
`0 And NDA package for ertugliflozin as an NME alone (non-FDC) drug formulation
`was submitted at the same time as the ertugliflozin/metformin FDC NDA on
`12/19/2016.
`
`Sitagliptin
`
`Sitagliptin was approved under NDA #21995 as Januvia® (Merck & Co., Inc.) on
`10/16/2006 as an adjunct to diet and exercise to improve glycemic control in adults with
`T2DM with a maximum approved adult dose set at 100 mg/day. Sitagliptin has been
`prescribed for treatment of type II diabetes in patients worldwide for 11 years. The label
`for Sitagliptin was updated in January 2017.
`
`3
`
`Studies Submitted
`
`3.1
`
`Studies Reviewed
`
`All nonclinical studies for ertugliflozin were submitted and reviewed under NDA#209803
`and IND #106447. All nonclinical coadministration studies have been previously
`reviewed under IND #106447 and #122330.
`
`3.2
`
`Studies Not Reviewed
`
`None
`
`3.3
`
`Previous Reviews Referenced
`
`A preliminary 2-week combination toxicology study studies was reviewed in
`Pharmacology and Toxicology (Pharmeox) review #1 under IND #122330 by Dr. David
`Carlson. A pivotal 13-week combination toxicology studies was reviewed in detail in
`Pharm/Tox review #7 under IND #106447 by Dr. Jessica Hawes. Summaries of these
`studies are included in this review.
`
`Table 1: Summaries of Pivotal Previously-Reviewed Nonclinical Studies
`
`Combination Toxicology
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`NDA #209805
`
`Jessica Hawes, Ph.D.
`
`Study #
`
`Brief Title
`
`Primary Review
`
`2—Week Oral Gavage Toxicity and Toxicokinetic Study
`With PF-04971729 and Sitagliptin In Rats
`
`:23at:$33; ngggqox
`8/28/2014
`
`T141333?#8294467
`Pfizer #13GR342)
`TT147808
`
`“(4) #8300338,
`(
`Pfizer #14GR162)
`
`35301:; D" Hawes’
`
`13-Week Oral Gavage Toxicity and Toxicokinetic Study
`with PF-04971729 and Sitagliptin in Rats (GLP)
`
`IND #106447 Pharm/Tox
`
`Brief summaries of nonclinical studies for sitagliptin were based on the Pharmfrox
`review by Dr. Bourcier for Januvia under NDA #21995.
`
`4
`
`Pharmacology
`
`4.1
`
`Primary Pharmacology
`
`Ertugliflozin is an inhibitor of SGLT2, thereby blocking the transport of glucose from the
`pro-urine across the apical membrane of the proximal epithelial cells and resulting in
`significant glucosuria. Ertugliflozin is highly selective for SGLT2 over SGLT1 and other
`glucose transporters (GLUT1-4).
`
`Sitagliptin is a competitive inhibitor of the DPP-4 enzyme that functions to digest the
`gastrointestinal hormone incretins GLP-1 and GIP, which are released in response to a
`meal. Thus, sitagliptin inhibits inactivation of GLP-1 and GIP, thereby resulting in
`increases the secretion of insulin and suppressed glucagon release by pancreatic alpha
`cells.
`
`Drug activity related to proposed indication:
`Ertugliflozin administration in rats results in concentration-dependent glucosuria, which
`is directly related to the pharmacodynamic (PD) activity of SGLT2 inhibition.
`Ertugliflozin administration in rats is associated with concomitant decreases in plasma
`glucose levels despite compensatory increases in food consumption. Glucosuria has
`also been reported in humans.
`
`Sitagliptin suppresses glucagon release and increases insulin secretion; leading to
`normalization of blood glucose levels. Sitagliptin has also been shown to lower HbA1c
`levels in human.
`
`4.2
`
`Secondary Pharmacology
`
`Ertugliflozin
`
`Nonclinical secondary pharmacology studies for ertugliflozin were fully evaluated in the
`Pharmeox review by Dr. Hawes under NDA #209803.
`
`Briefly, significant drug-drug interactions (DDI) with ertugliflozin administration and
`drugs metabolized by cytochrome P450 (CYP) enzymes or transported by organic anion
`transporters (OATs), organic cation transporters (OCTs) or organic anion transporting
`polypeptides (OATPs) are not likely at clinical exposures. Significant DDI with
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`diphosphate-glucuronosyltransferase (UGT) enzyme inhibition is also unlikely at clinical
`concentrations.
`
`Sitagliptin
`Sitagliptin is metabolized by CYP3A4 and CYP2C8 enzymes; thus, concomitant use of
`sitagliptin with drugs that interfere with CYP3A4 and/or CYP2C8 may lead to increases
`in systemic sitagliptin exposures.
`Ertugliflozin/Sitagliptin FDC
`Drug-drug interactions between ertugliflozin and sitagliptin are not anticipated.
`
`Ertugliflozin and sitagliptin are predominantly eliminated by different mechanisms and
`are not expected to affect each other’s elimination pathways. Ertugliflozin is
`predominantly metabolized by UGT1A9 and UGT2By, with minor contributions by
`CYP3A4, and even less by CYP3A5 and CYP2C8. Sitagliptin is predominantly
`eliminated via filtration at the glomerulus and excreted in the urine unchanged,
`accounting for 79% of the dose, with the remaining being eliminated via hepatic
`metabolism by CYP3A4 and CYP2C8. Although both drugs are partially metabolized
`by CYP2C8, the role of CYP2C8 metabolism for sitagliptin is minor and very minor for
`ertugliflozin; thus, competition for CYP2C8-mediated metabolism is unlikely to occur or
`lead to changes in PK parameters of either drug.
`
`Ertugliflozin does not exhibit reversible or time-dependent inhibition of CYP3A4 or
`CYP2C8 in human liver microsomes (HLMs) in vitro, with IC50 values of >30 (cid:80)M, which
`is at least 50-fold higher than clinical ertugliflozin Cmax concentrations (0.6 (cid:80)M). The
`ertugliflozin metabolites M5a and M5c also do not inhibit CYP3A4 or CYP2C8 enzymes.
`Thus, ertugliflozin and its disproportional metabolites are not likely to interfere with
`sitagliptin metabolism at clinical exposure levels.
`
`Sitagliptin does not inhibit or induce metabolizing enzymes involved in ertugliflozin
`metabolism; thus sitagliptin is not anticipated to affect ertugliflozin exposures.
`Furthermore, since sitagliptin plasma protein binding is relatively low (38%), it is less
`likely to interact with highly protein-bound drugs, such as ertugliflozin.
`4.3
`Safety Pharmacology
`Both ertugliflozin and sitagliptin may be associated with some concern for
`cardiovascular (CV) effects at high doses, but are associated with sufficient margins of
`safety at therapeutic doses. Given that the margins of safety for cardiovascular effects
`are sufficient for each drug alone and a DDI is not likely, the margins of safety for the
`FDC product is considered to be sufficient as well.
`Ertugliflozin
`Standard CV, neurological and pulmonary safety pharmacology studies were completed
`for ertugliflozin under IND #106447 and NDA #209803.
`
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`NDA #209805
`
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`
`Central Nervous System (CNS): At 500 mg/kg ertugliflozin in male rats, drug-related
`decreases in average body temperature of 0.4°C, and 30-40% decreases in locomotor
`activity, were observed at Cmax exposures approximately 339-fold higher than clinical
`Cmax exposure at the maximum recommended high dose (MRHDCmax) of 15 mg/day.
`The no observed adverse effect level (NOAEL) for CNS effects in rats was set at 25
`mg/kg, which is associated with a safety margin of ~36x MRHDCmax.
`
`Cardiovascular System: Ertugliflozin weakly inhibited the human ether-a-go-go-
`related gene (hERG) potassium channel in vitro with an IC50 of 59 (cid:80)M and an IC20 of
`8.11 (cid:80)M in CHO cells, but was a poor inhibitor in human embryonic kidney (HEK293)
`cells with an IC50 (cid:89)(cid:68)(cid:79)(cid:88)(cid:72) (cid:82)(cid:73) (cid:33)(cid:22)(cid:19)(cid:19) (cid:541)(cid:48)(cid:17) Ertugliflozin also weakly inhibited Nav1.5 currents
`with an IC50 of 188 (cid:80)M. Although significant inhibition of hERG and Nav1.5 currents
`were reported at concentrations (cid:149)(cid:22)(cid:19) (cid:151)(cid:48) (50x MRHDCmax), significant hERG or Nav1.5
`inhibition is not anticipated at biologically relevant exposure levels. In dogs, single
`doses of 50 mg/kg ertugliflozin (163x MRHDCmax) were associated with moderate
`decreases in the QTc interval, cardiac contractility, and heart rate corresponding with
`Tmax, as well as increases in systolic blood pressure (sBP) and lengthening of the PR
`interval, with a NOAEL of 5 mg/kg and a safety margin of ~13x MRHDCmax. In the 27-
`day pair-fed study #PD001 in spontaneous hypertensive rats (SHR), ertugliflozin-related
`decreases in blood pressures and heart rate were associated with treatment-related
`diuresis and activation of the renin-angiotensin-aldosterone-system (RAAS) at 36
`mg/kg/day (11x MRHDCmax). Furthermore, based on similar effects observed with a
`diuretic positive control anti-hypertensive, it’s likely that ertugliflozin-related CV effects in
`the SHR model are, at least in part, secondary to PD-related diuresis.
`Respiratory System: In rats, dose-dependent increases in respiratory rate (cid:11)(cid:313)(cid:21)(cid:28)-40%)
`(cid:68)(cid:81)(cid:71) (cid:80)(cid:76)(cid:81)(cid:88)(cid:87)(cid:72) (cid:89)(cid:82)(cid:79)(cid:88)(cid:80)(cid:72) (cid:11)(cid:313)(cid:21)(cid:24)-23%) were observed for up to 120 minutes post-dose and
`correlated with Cmax at doses of (cid:149)(cid:21)(cid:24) (cid:80)(cid:74)(cid:18)(cid:78)(cid:74) (cid:11)~36x MRHDCmax), with a NOAEL of 5 mg/kg
`(9x MRHDCmax).
`
`Supplemental
`
`Renal/Urinary System: No specific renal safety pharmacology studies were
`performed. However, repeat-dose toxicology studies indicate that ertugliflozin causes
`increased urinary glucose excretion and kidney alterations in rats and dogs at clinical
`exposure levels.
`
`Gastrointestinal System: No GI-specific safety studies were performed. However,
`repeat-dose toxicology studies indicate that ertugliflozin causes changes in stool quality,
`vomiting and ulceration of the tongue in rats and dogs.
`
`Immunotoxicity: There were no indications of immunotoxicity or antigenicity in repeat-
`dose toxicology studies.
`
`Sitagliptin
`
`Reference ID: 4195727
`
`12
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`

`NDA #209805
`
`Jessica Hawes, Ph.D.
`
`Standard CV, neurological and pulmonary safety pharmacology studies for sitagliptin
`were reviewed under NDA #21995, and are summarized below.
`
`Neurological: No drug-related CNS effects were identified in rat or mouse CNS safety
`pharmacology studies with functional observational battery (FOB) assessments of CNS
`activity at doses up to 180 mg/kg in rats and 100 mg/kg in mice. The no observed effect
`level (NOEL) for neurological effects is >180 mg/kg in rats and >100 mg/kg in mice.
`
`Cardiovascular: Sitagliptin inhibits hERG activity with an IC50 of 147 (cid:80)M, an IC20 of
`~50 (cid:80)M, and complete inhibition at 1000 (cid:80)M, with 80% reversibility. In anesthetized
`(cid:71)(cid:82)(cid:74)(cid:86)(cid:15) (cid:71)(cid:72)(cid:70)(cid:85)(cid:72)(cid:68)(cid:86)(cid:72)(cid:86) (cid:76)(cid:81) (cid:69)(cid:79)(cid:82)(cid:82)(cid:71) (cid:83)(cid:85)(cid:72)(cid:86)(cid:86)(cid:88)(cid:85)(cid:72) (cid:11)(cid:315)(cid:24)(cid:25) (cid:80)(cid:80) (cid:43)(cid:74)(cid:12) (cid:68)(cid:81)(cid:71) (cid:75)(cid:72)(cid:68)(cid:85)(cid:87) (cid:85)(cid:68)(cid:87)(cid:72) (cid:11)(cid:315)(cid:23)(cid:19) (cid:69)(cid:83)(cid:80)(cid:12) (cid:90)(cid:72)(cid:85)(cid:72)
`observed with IV infusions of 30 mg/kg and plasma concentrations of 202 (cid:80)M (253x
`MRHDCmax), which is associated with a NOAEL of 10 mg/kg (plasma levels (cid:148)(cid:24)(cid:28) (cid:80)M =
`74x MRHDCmax). In conscious telemetered dogs, an oral dose of 50 mg/kg (1-hour
`postdose plasma level of 34 (cid:80)M = 43x MRHDCmax) was associated with an increase in
`(cid:75)(cid:72)(cid:68)(cid:85)(cid:87) (cid:85)(cid:68)(cid:87)(cid:72) (cid:11)(cid:313)(cid:22)(cid:19) (cid:69)(cid:83)(cid:80)(cid:12) (cid:68)(cid:81)(cid:71) (cid:86)(cid:75)(cid:82)(cid:85)(cid:87)(cid:72)(cid:81)(cid:76)(cid:81)(cid:74) (cid:76)(cid:81) (cid:51)(cid:53) (cid:76)(cid:81)(cid:87)(cid:72)(cid:85)(cid:89)(cid:68)(cid:79) (cid:76)(cid:81) (cid:26)(cid:24)(cid:8) (cid:82)(cid:73) (cid:68)(cid:81)(cid:76)(cid:80)(cid:68)(cid:79)(cid:86)(cid:15) (cid:90)(cid:76)(cid:87)(cid:75) (cid:68) (cid:49)(cid:50)(cid:36)(cid:40)(cid:47) (cid:82)(cid:73)
`10 mg/kg (1-hour postdose plasma levels of 7 (cid:80)M = 9x MRHDCmax). No drug-related
`changes in QT or other ECG interval were reported. Sitagliptin-related CV risks were
`evaluated in the CV outcome trial TECOS, wherein the sponsor reported that there was
`not a drug-related increase in risk of major adverse CV events or the risk of
`hospitalization for heart failure.
`
`Pulmonary: No meaningful effects on pulmonary parameters were reported in rats at
`oral doses up to 180 mg/kg. In anesthetized dogs, no changes in respiratory parameters
`were observed at an IV dose of 10 mg/kg; however, decreases in blood pressure and
`(cid:76)(cid:81)(cid:70)(cid:85)(cid:72)(cid:68)(cid:86)(cid:72)(cid:86) (cid:76)(cid:81) (cid:75)(cid:72)(cid:68)(cid:85)(cid:87) (cid:85)(cid:68)(cid:87)(cid:72) (cid:82)(cid:73) (cid:148)(cid:20)(cid:24) (cid:80)(cid:76)(cid:81)(cid:88)(cid:87)(cid:72)(cid:86) (cid:90)(cid:72)(cid:85)(cid:72) (cid:82)(cid:69)(cid:86)(cid:72)(cid:85)(cid:89)(cid:72)(cid:71)(cid:17)
`
`Renal: No consistent changes in renal function parameters including glomerular
`filtration rate, effective renal plasma flow, electrolyte excretion, plasma electrolyte
`concentrations, and filtration fraction were reported in dogs at oral doses up to 10
`mg/kg.
`
`Gastrointestinal: No significant effects on GI motility, basal gastric acid secretion, or
`gastrin-stimulated gastric acid output were reported in dogs at 10 mg/kg.
`5
`Pharmacokinetics/ADME/Toxicokinetics
`5.1
`PK/ADME
`Ertugliflozin
`Ertugliflozin PK parameters were characterized in human, dog, rat, and mouse species.
`Ertugliflozin protein binding is high in all 4 species, ranging from 92 to 97%. Significant
`species differences in absorption were associated with oral bioavailability ranging from
`moderate to high across species and oral absorption ranges of 75-87% in mice, 56-88%
`in rats, 94-97% in dogs, and up to 100% in humans. Tmax is achieved within 30 minutes
`in mice, 0.7 to 2.3 hours in rats, and 0.8 to 1.5 hours in dogs. In humans, Tmax is
`
`Reference ID: 4195727
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`13
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`NDA #209805
`
`Jessica Hawes, Ph.D.
`
`achieved after 1 hour in humans (fasted), but after 2 hours in humans in the fed state,
`indicating absorption delays in the presence of food. Systemic exposures follow linear
`pharmacokinetics with a trend for slight increases in female exposures over time at high
`doses in rodents, indicating a potential gender effect which is likely related to gender
`differences in metabolism in rodents. Ertugliflozin has a moderate half-life (t1/2) of 3 to 4
`hours in rodents and 8 hours in dogs, but is 1.5 to 4 times longer in humans ranging
`from 12 to 18 hours.
`
`Ertugliflozin may be a substrate for the efflux transporter permeability glycoprotein
`1/multidrug resistance protein 1 (P-gp/MDR1), but is not affected by P-gp/MDR1
`inhibitors; thus, P-gp/MDR1 is unlikely to be a limiting factor in Ertugliflozin absorption.
`Ertugliflozin has a moderate volume of distribution in rats with preferential distribution
`into plasma relative to red blood cells. The highest distribution is primarily to organs
`responsible for drug metabolism and elimination, such as the bladder, liver, and kidney.
`Ertugliflozin is also highly distributed to rat adrenal gland, Harderian gland, and
`pancreas. Ertugliflozin crosses the adult blood:brain barrier, but only reaches
`concentrations 3 to 63-fold lower than that of blood; whereas distribution to the choroid
`plexus and pituitary gland is 2-fold greater than blood. In fetal rats, ertugliflozin more
`readily crosses the blood:brain barrier, resulting in significantly more drug exposure to
`fetal CNS tissues and eyes than in corresponding adult tissues relative to plasma levels.
`Ertugliflozin is excreted in rat milk at exposures comparable to maternal plasma levels.
`Ertugliflozin also readily crosses the rat placental barrier, but with fetal exposures
`remaining lower than maternal plasma levels.
`
`In rats, elim