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

`

`Office of Clinical Pharmacology Review
`
`NDA or BLA Number
`Link to EDR
`Submission Date
`Submission Type
`Brand Name
`Generic Name
`Dosage Form and Strength
`Route of Administration
`Proposed Indication
`
`Applicant
`Associated IND
`OCP Review Team
`
`OCP Final Signatory
`
`209803
`\\Cdsesub1\evsprod\NDA209803\209803.enx
`19 Dec 2016
`505 (b)(1)
`Steglatro
`Ertugliflozin
`Tablet; 5 mg and 15 mg
`Oral
`Adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes
`mellitus
`Merck Sharp & Dohme Corp
`IND 106447
`Suryanarayana Sista, PhD; Lian Ma, PhD; Yaning
`Wang, PhD; Manoj Khurana, PhD
`Chandrahas Sahajwalla, PhD
`
`1
`
`
`
`
`
`Reference ID: 4141151
`
`

`

`Table of Contents
`
`1.
`
`EXECUTIVE SUMMARY .......................................................................................................................... 9
`
`1.1
`
`1.2
`
`Recommendations ...................................................................................................................... 10
`
`Post-Marketing Requirements and Commitments ..................................................................... 10
`
`2. SUMMARY OF CLINICAL PHARMACOLOGY ASSESSMENT ....................................................................... 11
`
`2.1
`
`2.2
`
`Pharmacology and Clinical Pharmacokinetics............................................................................. 11
`
`Dosing and Therapeutic Individualization ................................................................................... 11
`
`2.2.1
`
`General dosing .................................................................................................................... 11
`
`2.2.2
`
`Therapeutic individualization .............................................................................................. 12
`
`2.3
`
`2.4
`
`Outstanding Issues ...................................................................................................................... 13
`
`Summary of Labeling Recommendations ................................................................................... 13
`
`3. COMPREHENSIVE CLINICAL PHARMACOLOGY REVIEW ...................................................................... 14
`
`3.1
`
`3.2
`
`Overview of the Product and Regulatory Background ............................................................... 14
`
`General Pharmacological and Pharmacokinetic Characteristics ................................................ 14
`
`3.2.1
`
`Mechanism of Action: ......................................................................................................... 15
`
`3.2.2
`
`Pharmacokinetics: ............................................................................................................... 15
`
`3.2.3
`
`Pharmacodynamics: ............................................................................................................ 19
`
`3.2.4
`
`QT Prolongation: ................................................................................................................. 20
`
`3.3
`
`Clinical Pharmacology Questions ................................................................................................ 22
`
`Does the clinical pharmacology information provide supportive evidence of
`3.3.1
`effectiveness? ..................................................................................................................................... 22
`
`Is the proposed general dosing regimen appropriate for the general patient population
`3.3.2
`for which the indication is being sought? ........................................................................................... 29
`
`Is an alternative dosing regimen and management strategy required for subpopulations
`3.3.3
`based on intrinsic factors? .................................................................................................................. 32
`
`Are there clinically relevant food-drug or drug-drug interactions and what is the
`3.3.4
`appropriate management strategy? ................................................................................................... 38
`
`Is the to-be-marketed formulation the same as the clinical trial formulation, and if not,
`3.3.5
`are there bioequivalence data to support the to-be-marketed formulation? ................................... 48
`
`4. APPENDICES ........................................................................................................................................ 51
`
`4.1
`
`Appendix - Summary of Bioanalytical Method Validation .......................................................... 52
`
`How are parent drug and relevant metabolites identified and what are the analytical
`4.1.1
`methods used to measure them in plasma and other matrices? ....................................................... 52
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`4.1.2 What was the performance of bioanalytical methods? ..................................................... 52
`
`4.2
`
`Appendix – Individual Study Review ........................................................................................... 56
`
`Study P036/1001 - Safety, Tolerability and PK of Single Escalating Oral Doses of
`4.2.1
`Ertugliflozin ......................................................................................................................................... 56
`
`4.2.2
`
`Study P037/1002 - Safety, Tolerability and PK of Repeated Doses of Ertugliflozin ............ 59
`
`4.2.3
`
`Study P038/1003 - PK Mass Balance, and Metabolism of 14C Ertugliflozin ........................ 62
`
`Study P040/1007 - PK and PD of 2 and 4 mg qd, and 1 mg and 2 mg bid Daily PO
`4.2.4
`Administration of Ertugliflozin in T2DM Patients .......................................................................... 64
`
`Study P035/1051 - Steady State PK and PD of 5 and 15 mg qd, and 2.5 and 7.5 mg bid
`4.2.5
`PO Administration of Ertugliflozin in Healthy Subjects ................................................................. 66
`
`4.2.6
`
`Study P010/1025 - Definitive QTc Study ........................................................................ 69
`
`Study P020/1043 - Absolute BA and Fraction Absorbed of Ertugliflozin Using a 14C
`4.2.7
`Microdose Approach ......................................................................................................................... 72
`
`4.2.8
`
`Study P023/1037 – Bioequivalence of Phase 3 and Commercial Image Tablets ......... 74
`
`4.2.9
`Tablet
`
`Study P024/1048 - Effect of Food on the PK of Ertugliflozin 15 mg Commercial Image
`76
`
`Study – P041/1009 - Safety, Tolerability, PK, and PD of Single Escalating and Multiple
`4.2.10
`Doses of Ertugliflozin in Japanese Subjects ..................................................................................... 78
`
`4.2.11
`mg
`
`Study P014/1024 - Evaluation of Hepatic Impairment on the PK of Ertugliflozin 15
`82
`
`Study P009/1023 - Evaluation of Renal Impairment on the PK and PD of Ertugliflozin
`4.2.12
`15 mg in Subjects with T2DM ........................................................................................................... 85
`
`4.2.13
`
`
`4.2.14
`mg
`
`4.2.15
`
`
`4.2.16
`mg
`
`Study P022/1033 - Two-Way DDI between Ertugliflozin 15 mg and Sitagliptin 100 mg
`89
`
`Study P019/1032 - Two-Way DDI between Ertugliflozin 15 mg and Metformin 1000
`91
`
`Study P032/1044 - Two-Way DDI between Ertugliflozin 15 mg and Glimepiride 1 mg
`94
`
`Study P030/1036 - Two-Way DDI between Ertugliflozin 15 mg and Simvastatin 40
`96
`
`Study P021/1040 - Effect of Multiple Dose Rifampin 600 mg on the PK of Ertugliflozin
`4.2.17
`15 mg 99
`
`4.3
`
`Pharmacometrics Assessment .................................................................................................. 101
`
`4.3.1
`
`Applicant’s Population PK Analysis ................................................................................... 101
`
`4.3.2
`
`Applicant’s Dose-Response Analysis ................................................................................. 109
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`4.4
`
`Applicant’s Physiological-based Pharmacokinetic (PBPK) Modeling Assessment .................... 116
`
`4.4.1
`
`Background ....................................................................................................................... 116
`
`4.4.2
`
`Methods ............................................................................................................................ 117
`
`4.4.3
`
`PBPK Model Development ................................................................................................ 118
`
`4.4.4
`
`Model Verification ............................................................................................................ 122
`
`4.4.5
`
`Model Application ............................................................................................................. 122
`
`4.4.6
`
`Results ............................................................................................................................... 123
`
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`
`
`
`
`Table 1
`
`Table 2:
`
`Table 3
`
`Table 4:
`
`Table 5
`
`Table 6
`
`Table 7
`
`Table 8
`
`Table 9
`
`Table 10
`
`Table 11
`
`Table 12
`
`Table 13
`
`Table 14
`
`Table 15
`
`Table 16
`
`Table 17
`
`List of Tables
`
`Change from Baseline in A1C(%) at Primary Timepoint by Study Full Analysis Set:
`Excluding Rescue Approach ................................................................................................................ 22
`Summary of the Statistical Analysis (ANCOVA) of Change From Baseline in HbA1c at
`Week 12(Study P016/1006) .............................................................................................................. 30
`Model-Predicted Placebo-adjusted Change from Baseline Responses for Key
`Endpoints Based on Phase 2 Studies ............................................................................................... 31
`Model-Predicted Mean (95% CI) HbA1c Response for Ertugliflozin 5 mg and 15 mg
`Doses at Week 26 for a Representative T2DM Patient ............................................................ 31
`Statistical Summary of Treatment Comparisons for Ertugliflozin Pharmacokinetic
`Parameters– Moderate Hepatic Impairment Versus Normal Hepatic Function ........... 33
`Statistical Summary of Treatment Comparisons for Ertugliflozin Pharmacokinetic
`Parameters ................................................................................................................................................. 34
`Statistical Summary of Treatment Comparisons for Plasma Ertugliflozin
`Pharmacokinetic Parameters Under Fasting and Fed Conditions ...................................... 38
`Statistical Summary of Treatment Comparisons for Plasma Ertugliflozin
`Pharmacokinetic Parameters Following a Single Oral Dose of Ertugliflozin Alone and
`Co-administered with Sitagliptin ...................................................................................................... 39
`Statistical Summary of Treatment Comparisons for Plasma Sitagliptin
`Pharmacokinetic Parameters Following a Single Oral Dose of Sitagliptin Alone and
`Co-administered with Ertugliflozin ................................................................................................. 40
`Statistical Summary of Treatment Comparisons for Plasma Ertugliflozin
`Pharmacokinetic Parameters Following a Single Oral Dose of Ertugliflozin Alone and
`Co-administered with Metformin ..................................................................................................... 41
`Statistical Summary of Treatment Comparisons for Plasma Sitagliptin
`Pharmacokinetic Parameters Following a Single Oral Dose of Sitagliptin Alone and
`Co-administered with Ertugliflozin ................................................................................................. 42
`Statistical Summary of Treatment Comparisons for Plasma Ertugliflozin
`Pharmacokinetic Parameters Following a Single Oral Dose of Ertugliflozin Alone and
`Co-administered with Glimepiride ................................................................................................... 43
`Statistical Summary of Treatment Comparisons for Plasma Glimepiride
`Pharmacokinetic Parameters Following a Single Oral Dose of Glimepiride Alone and
`Co-administered with Ertugliflozin ................................................................................................. 43
`Statistical Summary of Treatment Comparisons for Plasma Ertugliflozin
`Pharmacokinetic Parameters Following a Single Oral Dose of Ertugliflozin Alone and
`Co-administered with Simvastatin ................................................................................................... 44
`Statistical Summary of Treatment Comparisons for Plasma Simvastatin
`Pharmacokinetic Parameters Following a Single Oral Dose of Simvastatin Alone and
`Co-administered with Ertugliflozin ................................................................................................. 45
`Statistical Summary of Treatment Comparisons for Plasma Simvastatin Acid
`Pharmacokinetic Parameters Following a Single Oral Dose of Simvastatin Alone and
`Co-administered with Ertugliflozin ................................................................................................. 46
`Statistical Summary of Treatment Comparisons for Plasma Ertugliflozin
`Pharmacokinetic Parameters Following a Single Oral Dose of Ertugliflozin Alone and
`Co-administered with Simvastatin ................................................................................................... 47
`
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`Table 18
`
`Statistical Summary of Treatment Comparisons for Plasma Ertugliflozin
`Pharmacokinetic Parameters ............................................................................................................. 49
`
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`Reference ID: 4141151
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`

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`Figure 1
`Figure 2
`Figure 3
`Figure 4
`Figure 5
`
`Figure 6
`
`Figure 7
`Figure 8
`
`Figure 9
`
`Figure 10
`
`Figure 11
`
`Figure 12
`
`Figure 13
`
`Figure 14
`
`Figure 15
`
`Figure 16
`
`Figure 17
`
`Figure 18
`
`Figure 19
`Figure 20
`Figure 21
`
`Figure 22
`
`Figure 23
`
`Figure 24
`
`List of Figures
`
`Schematic of the mechanism of Action of Ertugliflozin ........................................................... 15
`Proposed Metabolic Pathway for Ertugliflozin ........................................................................... 16
`Drug-Drug Interactions Between Ertugliflozin and Concomitant Medications ............. 18
`UGE versus Ertugliflozin Dose in T2DM Subjects ...................................................................... 20
`Plot of Estimated Mean Differences of QTcF With 90% Confidence Intervals Between
`Ertugliflozin and Placebo, and Moxifloxacin and Placebo ...................................................... 21
`Least Squares Mean Change from Baseline in A1C (%) at Week 52 in Study
`P002/1013, FAS (constrained longitudinal data analysis); Excluding Rescue
`Approach ..................................................................................................................................................... 23
`Schematic for Studies P003/1022, P007/1017 and P006/1015 ........................................ 25
`Mean (±SD) Trough Plasma Ertugliflozin Concentrations Following 5 mg and 15 mg
`Doses ............................................................................................................................................................. 25
`LS Mean Change From Baseline Over Time for HbA1c (Study P003, Full Analysis Set:
`Excluding Rescue Approach) .............................................................................................................. 26
`LS Mean Change From Baseline Over Time for HbA1c (Study P007, Full Analysis Set:
`Excluding Rescue Approach) .............................................................................................................. 27
`LS Mean Change From Baseline Over Time for HbA1c (Study P006, Full Analysis Set:
`Excluding Rescue Approach) .............................................................................................................. 28
`LS Mean Change From Baseline Over Time for HbA1c (Study P001, Full Analysis Set:
`Excluding Rescue Approach) .............................................................................................................. 29
`Dose-Response Analysis (3-Parameter Emax) of Percent Change From Baseline in
`HbA1c at Week 12 ................................................................................................................................... 30
`Observed and Final Model-Predicted Mean HbA1c Response versus Ertugliflozin
`Dose by Study at Week 26 .................................................................................................................... 32
`Regression and 90% CI of Ln AUCinf After Oral Administration of Ertugliflozin Versus
`BSA-Normalized eGFR in Subjects with Varying Degrees of Renal Function ................. 33
`Individual and Geometric Mean Plasma Ertugliflozin AUCinf (Left Panel) and Cmax
`(Lower Panel) Values by Renal Function Group ......................................................................... 34
`Regression and 90% CI of Ln Change from Baseline in 24-Hour UGE After Oral
`Administration of Ertugliflozin Versus BSA-Normalized eGFR in Subjects with
`Varying Degrees of Renal Function .................................................................................................. 35
`Dose-Normalized Ertugliflozin Exposure Comparison Among Dose Levels by Ethnic
`Groups .......................................................................................................................................................... 36
`Cumulative Urinary Glucose Excretion Over 0-24 Hours by Dose and Population ..... 36
`UGT1A9 Genotype Effects on Ertugliflozin AUC ......................................................................... 37
`Individual and Geometric Mean Plasma Ertugliflozin AUCinf (Left Panel) and Cmax
`(Right Panel) Values by Treatment .................................................................................................. 38
`Individual and Geometric Mean Plasma Ertugliflozin AUCinf (Left Panel) and Cmax
`(Right Panel) Values Following a Single Oral Dose of Ertugliflozin Alone and Co-
`administered with Sitagliptin ............................................................................................................. 39
`Individual and Geometric Mean Plasma Sitagliptin AUCinf (Left Panel) and Cmax (Right
`Panel) Values Following a Single Oral Dose of Sitagliptin Alone and Co-administered
`with Ertugliflozin ..................................................................................................................................... 40
`Individual and Geometric Mean Plasma Ertugliflozin AUCinf (Left Panel) and Cmax
`(Right Panel) Values Following a Single Oral Dose of Ertugliflozin Alone and Co-
`administered with Metformin ............................................................................................................ 41
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`Figure 25
`
`Figure 26
`
`Figure 27
`
`Figure 28
`
`Figure 29
`
`Figure 30
`
`Figure 31
`
`Figure 32
`
`Figure 33
`
`Individual and Geometric Mean Plasma Metformin AUCinf (Left Panel) and Cmax (Right
`Panel) Values Following a Single Oral Dose of Metformin Alone and Co-administered
`with Ertugliflozin ..................................................................................................................................... 42
`Individual and Geometric Mean Plasma Ertugliflozin AUCinf (Left Panel) and Cmax
`(Right Panel) Values Following a Single Oral Dose of Ertugliflozin Alone and Co-
`administered with Glimepiride .......................................................................................................... 43
`Individual and Geometric Mean Plasma Glimepiride AUCinf (Left Panel) and Cmax
`(Right Panel) Values Following a Single Oral Dose of Glimepiride Alone and Co-
`administered with Ertugliflozin ........................................................................................................ 44
`Individual and Geometric Mean Plasma Ertugliflozin AUCinf (Left Panel) and Cmax
`(Right Panel) Values Following a Single Oral Dose of Ertugliflozin Alone and Co-
`administered with Simvastatin .......................................................................................................... 45
`Individual and Geometric Mean Plasma Simvastatin AUCinf (Left Panel) and Cmax
`(Right Panel) Values Following a Single Oral Dose of Simvastatin Alone and Co-
`administered with Ertugliflozin ........................................................................................................ 46
`Individual and Geometric Mean Plasma Simvastatin Acid AUCinf (Left Panel) and Cmax
`(Right Panel) Values Following a Single Oral Dose of Simvastatin Alone and Co-
`administered with Ertugliflozin ........................................................................................................ 47
`Individual and Geometric Mean Plasma Ertugliflozin AUCinf (Left Panel) and Cmax
`(Right Panel) Values Following a Single Oral Dose of Ertugliflozin Alone and Co-
`administered with Multiple Doses of Rifampin .......................................................................... 48
`Mean (±SD) Plasma Ertugliflozin Concentrations Following Administration of 15 mg
`Phase 3 Formulation and 15 mg Commercial image Formulation (inset shows profile
`up to 12 hours) ......................................................................................................................................... 49
`Individual and Geometric Mean Plasma Ertugliflozin AUCinf (Left Panel) and Cmax
`(Right Panel) Values Following 15 mg Phase 3 Formulation and 15 mg Commercial
`image Formulation .................................................................................................................................. 50
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`Reference ID: 4141151
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`

`

`1. EXECUTIVE SUMMARY
`
`
`This is an original NDA submitted by Merck Sharp & Dohme Corporation on 19 December 2016, seeking
`marketing approval for Ertugliflozin as an adjunct to diet and exercise to improve glycemic control in
`adults with type 2 diabetes mellitus. Currently 3 other approved therapies in this class (Canagliflozin,
`Dapagliflozin and Empagliflozin) are available in the US for this indication. Ertugliflozin is an oral,
`selective inhibitor of sodium glucose co-transporter-2 (SGLT2) which inhibits renal glucose reabsorption
`and results in urinary glucose excretion (UGE) and reductions in plasma glucose and hemoglobin A1c
`(HbA1c) in patients with type 2 diabetes mellitus (T2DM). In vitro, ertugliflozin has been shown to be a
`highly selective SGLT2 inhibitor with greater than 2000x selectivity for SGLT2 (50% inhibitory
`concentration [IC50] = 0.877 nM) compared to SGLT1 (IC50 = 1960 nM). Ertugliflozin is included in the
`drug product as a co-crystal with L-pyroglutamic acid (L-PGA), known as ertugliflozin L-PGA.
`
`The proposed dosing regimen is to start with a dose of ertugliflozin 5 mg once daily, taken in the
`morning, with or without food. In patients tolerating ertugliflozin 5 mg once daily, the dose may be
`increased to 15 mg once daily if additional glycemic control is needed. Ertugliflozin is proposed to be
`marketed under the tradename Steglatro, and will be available in 5 mg and 15 mg strengths as oral tablets.
`
`The efficacy and safety of ertugliflozin in T2DM patients was supported by data from 4 Phase 3 studies
`(P001/1016, P007/1017, P005/1019, P003/1022) conducted in T2DM patients. A total of 24 studies (19
`Phase 1, 2 Phase 2, and 4 Phase 3) conducted in healthy subjects and in T2 DM patients, assessed the
`pharmacokinetics (PK) and pharmacodynamics (PD) of ertugliflozin. The proposed 5 mg and 15 mg
`commercial tablets are made from
`and use the same composition as the Phase 3
`formulation
`. The pink and red film coating used for the 5 mg and 15 mg commercial
`tablets are the same as the white film coating used in Phase 3 tablets except for the addition of iron oxide
`. The commercial tablets were scientifically
`bridged to the formulation used in Phase 3 studies in a dedicated bridging study (P023/1037).
`
`From a clinical pharmacology perspective, the proposed dosing regimen of ertugliflozin 5 mg once daily,
`followed by an increase to 15 mg once daily if additional glycemic control is needed, is appropriate. The
`PK and PD of ertugliflozin in T2DM patients were evaluated in pivotal Phase 3 studies. The PK in
`T2DM patients were comparable to that in healthy subjects. Ertugliflozin steady state exposure was
`equivalent when administered as 2.5 mg BID vs. 5 mg QD and as 7.5 mg BID vs. 15 mg QD. In addition,
`UGE during a 24-hour interval at steady state was similar when administered as 2.5 mg BID vs. 5 mg QD
`and as 7.5 mg BID vs. 15 mg QD. This information facilitated to develop fixed-dose combination (FDC)
`products in combination with Metformin and with Sitagliptin. Along with the current NDA, two separate
`NDAs for the FDCs, ertugliflozin/sitagliptin FDC tablets (
` 5 mg/100 mg,
` 15
`mg/100 mg) (NDA 209805), ertugliflozin/metformin FDC tablets (2.5mg/500mg, 2.5mg/1000mg,
`7.5mg/500mg, 7.5mg/1000mg) (NDA 209806) for the treatment of type 2 diabetes mellitus (T2DM) as
`adjunct to diet and exercise therapy, were submitted. Please see Clinical Pharmacology reviews by Dr.
`Lei He in DARRTS for NDAs 209805 and 209806.
`
`The Clinical Pharmacology review of NDA 209803 focused on the dose selection for Phase 3 studies, and
`confirming the PK/PD results from dose-response and population pharmacokinetics (PopPK) analyses of
`ertugliflozin.
`
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`Reference ID: 4141151
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`9
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`1.1 Recommendations
`
`The Office of Clinical Pharmacology has reviewed the information contained in NDA 209803 and found
`it acceptable to support approval of Ertugliflozin in the T2DM population Key review issues with
`specific recommendations and comments are summarized below:
`
`Supportive evidence of
`effectiveness
`
`The reduction in I-IbAlc from baseline at week 26 in pivotal Phase 3
`studies provides primary evidence of effectiveness.
`
`in Phase 3 efficacy trials are bioequivalent.
`
`General dosing
`instructions
`
`Dosing in patient
`subgroups
`
`Bridge between the “to- be-
`marketed" and clinical trial
`formulations
`
`The PK and PD (UGE) of ertugliflozin in healthy volunteers and T2DM
`patients provide supportive evidence for effectiveness.
`
`From a Clinical Pharmacology perspective, the proposed treatment
`regimen of starting ertugliflozin at a dose of 5 mg once daily, followed
`by an increase to 15 mg once daily ifadditional glycemic control is
`needed, is acceptable.
`
`No separate dosing/dosing regimen is recommended in any patient
`subgroups due to intrinsic (e. g., age and body weight) and extrinsic
`factors. Ertugliflozin is not recommended for use in patients with
`eGFR <60 mL/min/1.73m2, or in patients with severe hepatic
`impairment.
`
`A dedicated bridging study (POZ3/1037) provided evidence that the “to-
`be-marketed” (commercial image) formulation and the formulation used
`
`1.2
`
`Post-Marketing Requirements and Commitments
`
`None.
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`Reference ID: 4141151
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`

`2. SUMMARY OF CLINICAL PHARMACOLOGY ASSESSMENT
`
`2.1
`
`Pharmacology and Clinical Pharmacokinetics
`
`Ertugliflozin is an oral, selective inhibitor of sodium glucose co-transporter-Z (SGLT2) which inhibits
`renal glucose reabsorption and results in urinary glucose excretion (UGE) and reductions in plasma
`glucose and hemoglobin Alc (HbAlc) in patients with type 2 diabetes mellitus (T2DM). In vitro,
`ertugliflozin has been shown to be a highly selective SGLT2 inhibitor with greater than 2000x selectivity
`for SGLT2 (50% inhibitory concentration [ICso] = 0.877 nM) compared to SGLTl (ICso = 1960 nM).
`
`The following is a summary of the clinical pharmacokinetics of ertugliflozin:
`
`Absorption:
`
`0 Following single-dose oral administration of 5 mg and 15 mg of ertugliflozin, under fasted
`conditions, time to peak plasma concentrations (TI.m) of ertugliflozin occur at 1 hour postdose.
`O A dose-proportional increase in plasma ertugliflozin Cm and AUC was observed following
`single doses from 0.5 mg to 300 mg and following multiple doses from 1 mg to 100 mg.
`0 The absolute oral bioavailability of ertugliflon'n following administration of a 15 mg dose is
`approximately 100%.
`
`Ertugliflozin C...x is reduced by 29% and Tm prolonged by 1 hour following administration of
`ertugliflozin with a high-fat and high-calorie meal compared to the fasted state, however AUC
`was unaifected.
`
`Distribution:
`
`The mean steady-state volume of distribution of ertugliflozin is approximately 86 L following
`an intravenous dose.
`
`
`
`Elimination:
`
`Metabolism:
`
`Plasma protein binding of ertugliflozin is independent of ertugliflozin plasma concentrations,
`and18 approximately 94%. In patients with renal or hepatic impairment. plasma protein binding
`is not meanin u
`.
`. lasma concentration ratio of -
`-
`
`The mean systemic plasma ertugliflozin clearance following an intravenous microdose of 100
`11g dose was 11.2 W. Based on PopPK analysis, the mean elimination half-life in T2DM
`patients with normal renal function was estimated to be approximately 16.6 hours.
`Approximately 41% and 50% of the drug-related radioactivity was eliminated in feces and
`urine, respectively, following administration of an oral [“C]—ertugliflozin solution to healthy
`subjects. Only 1. 5% of the administered dose was excreted as unchanged ertugliflozin in urine
`and approximately 34% as unchanged ertugliflozin1n feces, which may likely be due to biliary
`
`The primary clearance mechanism for ertugliflozinis by metabolism. The major metabolic
`pathway for ertugliflozin is UGT1A9 and UGT2B7-mediated O-glucuronidation (86%) to two
`glucuronides that are pharmacologically inactive at clinically relevant concentrations. Thereis
`minimal CYP-mediated oxidative metabolism of ertugliflozin (12%).
`
`2.2 Dosing and Therapeutic lndividualization
`
`2.2.1 General dosing
`
`The proposed staning dose of Steglatro is 5 mg once daily, taken in the morning, with or without food. In
`patients tolerating Steglatro 5 mg once daily, the dose may be increased to 15 mg once daily if additional
`glycemic control is needed.
`
`Reference ID: 4141151
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`11
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`In patients with volume depletion, correcting this condition prior to initiation of Steglatro is
`recommended.
`
` A
`
` longitudinal dose-response model was fitted to the data for the primary evaluation of HbA1c lowering
`effect of ertugliflozin. Since exposures of ertugliflozin increased in a dose-proportional manner and PK
`variability of ertugliflozin was low, dose was considered to be a good surrogate for ertugliflozin exposure.
`A longitudinal exposure-response model was therefore also fitted to the HbA1c data. The longitudinal
`exposure-response model did not provide any additional predictive performance benefit over the dose-
`response model. Therefore, the dose-response model was considered the final model for evaluation of
`HbA1c lowering effect of ertugliflozin. Based on the final model parameter estimates, the 5 mg and 15
`mg doses elicited HbA1c responses (-0.617% and -0.698%, respectively) that were >80% and >90% of
`the model-estimated Emax (-0.745%) and consistent with the results on the dose-response model using data
`from Phase 2 studies.
`
`The proposed dosing regimen is supported by a dose-response analysis. For further details, see section
`Section 4.3.2.
`
`2.2.1.1 QD Dosing vs. BID Dosing
`
`The equivalence of ertugliflozin exposure at steady-state (AUC24) following daily dosing of 5 mg QD vs.
`2.5 mg BID, and following 15 mg QD vs. 7.5 mg BID were evaluated in Study P035/1051. To
`demonstrate bioequivalence, the 90% CI for the ratio (BID/QD) of geometric means for AUC24 would
`have to be within the 80% - 125% limits. This study also evaluated the similarity of PD effect (UGE24)
`following 5 mg QD vs. 2.5 mg BID, and following 15 mg QD vs. 7.5 mg BID dosing. To demonstrate
`bioequivalence, the the 90% CI for the ratio (BID/QD) of geometric means for UGE24 would have to be
`within 70% - 143% limits.
`
`For the 5 mg QD vs. 2.5 mg BID comparison, the 90% CI for the ratio of geometric means for AUC24 was
`98.76% - 102.83%, and for the 15 mg QD vs. 7.5 mg BID comparison, the 90% CI for the ratio of
`geometric means for AUC24 was 97.08% - 102.45%, demonstrating PK bioequivalence f