CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`206073Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`
`

`

`BIOPHARMACEUTICS REVIEW ADDENDUM
`Office of New Drug Quality Assessment
`NDA 206-073
`1/30/14; 6/3/14
`DMEP
`Boehringer Ingelheim Pharmaceuticals,
`Inc.
`Glyxambi
`empagliflozin/linagliptin fixed-dose
`combination tablets
`adjunct to diet and exercise to improve
`glycemic control in adults with type 2
`diabetes mellitus
`IR Tablet; 10 mg/5 mg and 25 mg/5mg
`
`Application No.:
`Submission Date(s):
`Division:
`Applicant:
`
`Trade Name:
`
`Generic Name:
`
`Indication:
`
`Formulation/strengths:
`Route of
`Administration:
`
`Oral
`
`Reviewer: Kareen Riviere, Ph.D.
`
`Secondary Signature: Tapash Ghosh, Ph.D.
`Supervisor: Paul Seo, Ph.D.
`Date
`Assigned:
`Date of
`10/15/14
`Review:
`Type of Submission: 505(b)(1) New Drug
`Application
`
`1/30/14
`
`that Glyxambi
`the Biopharmaceutics review dated September 16, 2014, Dr. Kareen Riviere stated
`In
`(empagliflozin/linagliptin) 10 mg/5 mg and 25 mg/5mg immediate release tablets are recommended for approval from
`a Biopharmaceutics standpoint pending the OSI inspection results for the pivotal BE Study 1275.3. In the OSI
`inspection report for Study 1275.3 dated October 3, 2014, Drs. Seongeun (Julia) Cho and Sripal R. Mada stated:
`
`Based on the inspectional outcomes, these reviewers conclude that the clinical and analytical portions of
`the Study 1275.003 are acceptable for further Agency review.
`
`Thus, NDA 206-073 for Glyxambi (empagliflozin/linagliptin) 10 mg/5 mg and 25 mg/5mg immediate release tablets
`is recommended for approval from the Biopharmaceutics perspective.
`
` Kareen Riviere, Ph.D. Tapash Ghosh, Ph.D.
` Biopharmaceutics Reviewer Biopharmaceutics Team Leader
` Office of New Drug Quality Assessment Office of New Drug Quality Assessment
`
` cc: Dr. Paul Seo
`
`Reference ID: 3643612
`
`1
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`KAREEN RIVIERE
`10/15/2014
`
`TAPASH K GHOSH
`10/15/2014
`
`Reference ID: 3643612
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`206073
`January 30, 2014
`Glyxambi
`Empagliflozin / Linagliptin FDC
`Clinical Pharmacology -2
`Metabolism and Endocrinology Products
`Boehringer Ingelheim Pharmaceuticals, Inc.
`NDA 505(b)(1); Standard
`
`Tablets:
`• 10 mg empagliflozin/5 mg linagliptin
`• 25 mg empagliflozin/5 mg linagliptin
`• Adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes
`mellitus when both empagliflozin and
`linagliptin is appropriate.
`• The recommended starting dose of Glyxambi is
`10 mg empagliflozin/5 mg linagliptin once
`daily.
`• Dose can be increased to 25 mg
`empagliflozin/5 mg linagliptin once daily in
`patients who require additional glycemic
`control.
`• Glyxambi can be taken with or without food.
`• Do not initiate Glyxambi if eGFR is below 45
`mL/min/1.73 m2
`Suryanarayana Sista, PhD
`
`Manoj Khurana, PhD
`
`
`NDA:
`Submission Date(s):
`Brand Name
`Generic Name
`OCP Division
`OND division
`Sponsor
`Submission Type;
`Code
`Formulation;
`Strength(s)
`
`Proposed Indication
`
`Dosage &
`Administration
`
`Clinical Pharmacology
`Reviewer
`Clinical Pharmacology
`Team Leader (Acting)
`
`
`
`
`
`Reference ID: 3640237
`
`
`
`Page 1 of 45
`
`

`

`
`1
`
`2
`
`3
`4
`
`2.5.3
`
`2.6
`2.6.1
`
`2.7
`2.7.1
`
`TABLE OF CONTENTS
`
`Executive Summary ................................................................................................................ 5
`1.1
`Recommendation ............................................................................................................. 5
`1.2
`Phase IV Commitments.................................................................................................... 5
`1.3
`Summary of Important Clinical Pharmacology Findings ................................................ 5
`Question-Based Review (QBR) .............................................................................................. 6
`2.1
`What are the in vivo Clinical Pharmacology and Biopharmaceutics studies with PK
`information submitted in the NDA .............................................................................. 6
`2.1.1 What are the highlights of the Glyxambi drug product as they relate to clinical
`pharmacology review? ............................................................................................ 9
`2.1.2 What is the composition of to-be-marketed formulation of Glyxambi? ................. 9
`2.1.3 What are the proposed mechanism of action and therapeutic indications? ........... 10
`2.1.4 What are the proposed dosages and routes of administration? ............................. 12
`2.2
`General Clinical Pharmacology ..................................................................................... 12
`2.2.1 What is known about the PK characteristics of Empagliflozin and Linagliptin following
`the administration of approved drugs, Jardiance and Tradjenta tablets? .............. 12
`2.2.2 Were the active moieties in the plasma appropriately identified and measured to assess
`the pharmacokinetics? ........................................................................................... 13
`Intrinsic Factors .............................................................................................................. 14
`2.3
`2.3.1 What intrinsic factors (e.g., weight, gender, race, age, height, disease, genetic
`polymorphism, pregnancy, and organ dysfunction) influence exposure (PK usually)
`and/or response, and what is the impact of any differences in exposure on efficacy or
`safety responses?................................................................................................... 14
`Extrinsic Factors ............................................................................................................ 14
`2.4
`2.4.1 What extrinsic factors (drugs, herbal products, diet, smoking, and alcohol use) influence
`exposure and/or response and what is the impact of any differences in exposure on
`pharmacodynamics? .............................................................................................. 14
`General Biopharmaceutics ............................................................................................. 14
`2.5
`2.5.1 Was bioequivalence established between Empagliflozin and Linagliptin FDC
`formulations and individual components? ............................................................ 14
`2.5.2 What is the effect of food on the bioavailability of Empagliflozin and Linagliptin from
`the FDC ................................................................................................................. 15
`How did the systemic exposure of empagliflozin and linagliptin from FDA compare to
`the individual treatment in the Phase III program? ............................................... 21
`Exposure Response ........................................................................................................ 23
`Is there an exposure-response (e.g. dose-response, concentration-response) relationship
`for effectiveness and safety for empagliflozin/linagliptin FDC in T2DM patients?23
`Analytical ....................................................................................................................... 27
`Is the analytical method for Empagliflozin and Linagliptin appropriately validated?
` .............................................................................................................................. 27
`Labeling Comments (Preliminary) ....................................................................................... 29
`APPENDIX ........................................................................................................................... 38
`OCP Filing Memo .............................................................................................................................. 38
`General Information About the Submission ........................................................................... 39
`
`
`
`
`Reference ID: 3640237
`
`
`
`Page 2 of 45
`
`

`

`
`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
`
`
`
`
`List of Tables
`
`Overview of studies with pharmacokinetic assessments relevant to the clinical
`pharmacology and biopharmaceutics of Glyxambi ......................................................... 7
`Qualitative and quantitative composition of empagliflozin / linagliptin film-coated
`tablets ............................................................................................................................... 9
`Summary Statistics for Empagliflozin Pharmacokinetic Parameters following
`administration of FDC formulation consisting of 25 mg empagliflozin and 5 mg
`linagliptin under fasting and fed conditions to healthy subjects .................................... 16
`Bioequivalence and Food Effect Comparisons for Empagliflozin following
`administration of FDC formulation consisting of 25 mg empagliflozin and 5 mg
`linagliptin under fasting and fed conditions in healthy subjects .................................... 16
`Summary Statistics for Linagliptin Pharmacokinetic Parameters following
`administration of FDC formulation consisting of 25 mg empagliflozin and 5 mg
`linagliptin under fasting and fed conditions to healthy subjects .................................... 19
`Bioequivalence and Food Effect Comparisons for Linagliptin following administration
`of FDC formulation consisting of 25 mg empagliflozin and 5 mg linagliptin under
`fasting and fed conditions in healthy subjects ............................................................... 19
`Empagliflozin plasma trough concentrations (geometric mean, CV) in patients who
`were on metformin background therapy and treatment naïve patients from Study 1275.1
` ....................................................................................................................................... 22
`Linagliptin plasma trough concentrations (geometric mean, CV) in patients who were
`on metformin background therapy and treatment naïve patients from Study 1275.1 .... 22
`HbA1c (%) change from baseline MMRM results at week 24 − FAS(OC) (add-on
`therapy to metformin background) ................................................................................ 24
`HbA1c (%) change from baseline MMRM results at week 52 − FAS(OC) (add-on
`therapy to metformin background) ................................................................................ 24
`HbA1c (%) change from baseline MMRM results at week 24 – FAS (OC) (treatment
`naïve) ............................................................................................................................. 26
`HbA1c (%) change from baseline MMRM results at week 52 – FAS (OC) (treatment
`naïve) ............................................................................................................................. 26
`Summary of key descriptive parameters for Empagliflozin and Linagliptin bioanalytical
`assays used in clinical studies ........................................................................................ 28
`
`
`
`Reference ID: 3640237
`
`
`
`Page 3 of 45
`
`

`

`
`
`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:
`
`
`
`
`List of Figures
`Food-effect Comparison for Empagliflozin and linagliptin following 25 mg
`Empagliflozin/5 mg Linagliptin FDC Formulation under Fasting and Fed Conditions .. 6
`Empagliflozin mechanism of action .............................................................................. 11
`Linagliptin mechanism of action ................................................................................... 11
`Mean plasma concentration time profile of empagliflozin following FDC formulation
`consisting of 25 mg empagliflozin and 5 mg linagliptin under fasting and fed conditions
` ....................................................................................................................................... 15
`Boxplot of Cmax vs. Treatment for Empagliflozin .......................................................... 17
`Boxplot of AUC0-t vs. Treatment for Empagliflozin ...................................................... 17
`Boxplot of AUC0-∞ vs. Treatment for Empagliflozin .................................................... 18
`Mean plasma concentration time profile of linagliptin following FDC formulation
`consisting of 25 mg empagliflozin and 5 mg linagliptin under fasting and fed conditions
` ....................................................................................................................................... 18
`Boxplot of Cmax vs. Treatment for Linagliptin ............................................................... 20
`Boxplot of AUC0-t vs. Treatment for Linagliptin ........................................................... 20
`Boxplot of AUC0-∞ vs. Treatment for Linagliptin.......................................................... 21
`Adjusted mean change in HbA1c (%) over time from baseline based on mixed-model
`repeated measures (MMRM) of the full analysis dataset (FAS) observed case (OC)
`(add-on therapy to metformin background) ................................................................... 23
`Adjusted mean change in HbA1c (%) over time from baseline based on mixed-model
`repeated measures (MMRM) of the full analysis dataset (FAS) observed case (OC)
`(treatment naïve) ............................................................................................................ 25
`
`
`
`Reference ID: 3640237
`
`
`
`Page 4 of 45
`
`

`

`1 Executive Summary
`
`Boehringer Ingelheim Pharmaceuticals, Incorporated Inc. (BI) is seeking US marketing approval for
`Glyxambi tablets under the provisions of Section 505(b)(1) of the Federal Food, Drug, and Cosmetic
`Act. Glyxambi is a fixed-dose combination (FDC) product of empagliflozin, a sodium-glucose co-
`transporter 2 (SGLT2)
`inhibitor, and
`linagliptin, a dipeptidyl peptidase-4 (DPP-4)
`inhibitor.
`Empagliflozin (Jardiance, NDA 204629, BI) and linagliptin (Tradjenta, NDA 201280, BI) were
`approved by the Agency on 08/01/2014 and 05/02/2011, respectively. The proposed indication of
`Glyxambi tablets is “adjunct to diet and exercise to improve glycemic control in adults with type 2
`diabetes mellitus when treatment with both empagliflozin and linagliptin is appropriate”.
`
`If approved, Glyxambi will be the first SGLT2/DPP-4 FDC to enter the market.
`
`1.1 Recommendation
`
`The Office of Clinical Pharmacology (OCP) has reviewed the clinical pharmacology data submitted under
`NDA 206073 and finds it acceptable to support the approval.
`
`
`1.2 Phase IV Commitments
`
`None.
`
`
`1.3 Summary of Important Clinical Pharmacology Findings
`
`Empagliflozin / linagliptin film-coated tablets, (Glyxambi) are manufactured in strengths of 10 mg / 5 mg,
`and 25 mg / 5 mg, and contain 10 mg or 25 mg of empagliflozin and 5 mg of linagliptin.
`
`The sponsor has proposed the recommended starting dose of Glyxambi of 10 mg empagliflozin/5 mg
`linagliptin once daily. In patients who require additional glycemic control, the dose can be increased to
`25 mg empagliflozin / 5 mg linagliptin once daily. The sponsor also proposed that Glyxambi can be
`taken with or without food.
`
`This NDA is supported by data from one bioequivalence (BE) and food-effect trial (Study 1275.3), one
`multiple-dose relative bioavailability study (Study 1245.3), and one safety and efficacy trial (1275.1).
`
`Evaluation of BE portion of study 1275.3 was conducted by the ONDQA reviewer. The review has
`concluded that the proposed tablet containing 25 mg empagliflozin and 5 mg linagliptin is bioequivalent
`to the individual tablets administered together (see review by Dr. Kareen Riviere in DARRTS dated
`09/16/2014).
`
`The multiple-dose relative bioavailability study (Study 1245.3) has already been reviewed under NDA
`204629 (see Clinical Pharmacology review by Dr. Manoj Khurana in DARRTS dated 11/08/2013). In
`brief, relative bioavailability of empagliflozin and of linagliptin after concomitant multiple oral
`administration of 50 mg empagliflozin tablets and 5 mg linagliptin were evaluated in comparison to 50
`mg empagliflozin and 5 mg linagliptin given alone. The steady-state bioavailability of 5 mg linagliptin
`q.d. (based on AUCτ,ss and Cmax,ss) was not affected by concomitant administration of 50 mg empagliflozin
`q.d. The 90% confidence intervals of the adjusted geometric mean ratios for linagliptin were completely
`located within the limits of 80 to 125%. For empagliflozin, the AUCτ,ss was similar when the drug was
`given alone and in combination with linagliptin, but Cmax,ss was reduced by approximately 12% when the
`drug was co-administered with linagliptin.
`
`The clinical pharmacology review of the food effect portion of study 1275.3 showed that:
`
`
`Reference ID: 3640237
`
`
`
`Page 5 of 45
`
`

`

`Food decreased the Cm of empagliflozin and linagliptin by 39% and 32%. respectively;
`however. empagliflozin and linagliptin AUCs were similar for fasting and fed treatments. This
`effect of food on relative BA is consistent with previous findings with Empagliflozin (Jardiance.
`NDA 20-4629). and Linagliptin (Tradjenta. NDA 201280).
`In NDA 204629.
`the sponsor
`reported that reduction in Cmax of empagliflozin did not influence the amounts of glucose excreted
`in the urine when empagliflozin was administered in the fed state. In NDA 20—1280. the sponsor
`reported that despite a reduction of Cmax under fed conditions. DPP—4 inhibition is comparable for
`fasted and fed linagliptin dosage regimens.
`Therefore.
`the observed food effect for the
`empagliflozin and linagliptin components of the FDC tablet
`is unlikely to be of clinical
`mlportance.
`
`A Forest plot showing the effect of food on empagliflozin and linagliptin Cmax and AUC is shown in
`Figgge 1.
`
`Food Effect Comparisons for Empagliflozin and Linagliptin Following 25 mg Empagliflozin/ 5 mg
`Linagliptin FDC Formulation under Fasting and Fed Conditions
`Cmax(90%CI)
`AUC(90%CI)
`
`Analyte/Type
`
`Assessment
`
`I
`'
`
`E
`
`.
`i
`
`:
`‘
`
`I
`:
`
`E
`
`H—i
`
`1.0
`
`l'
`1.2
`
`E.
`
`l—O—l
`
`:
`l
`0.8
`
`I
`0.6
`
`
`
`
`
`E
`
`Ei—o—i
`
`2
`i
`
`:
`
`E
`
`I
`i
`
`i—o—i
`l
`0.9
`
`1.0
`
`l
`0.8
`
`l'
`1.1
`
`I
`1.2
`
`Cmax Lower
`
`AUC Similar
`
`Cmax Lower
`
`AUC Similar
`
`Empagllflozln:
`
`Cmax
`
`AUC
`
`Llnagliptin
`
`Cmax
`
`AUC
`
`Fold Change in AUC
`Fold Change in Cmax
`The horizontal axis show the fold change in Cmax and AUC under fed condition relative to fasting condition
`The red dashed reference lines on x-axis show the lower (0.80) and upper (1.25) BE limits
`
`Figure 1: Foodeffect Comparison for Empaglit'lozin and linagliptin following 25 mg
`Empagliflozin/S mg Linagliptin FDC Formulation under Fasting and Fed Conditions
`
`The efficacy results from the efiicacy/safety trial (1275.1) suggest that. there is a trend for dose dependent
`reduction in HbAlc from baseline for the FDC treatment from add—on therapy to metfonnin portion of the
`trial. There is. however. lack of clear trend for dose dependent reduction in HbA1c from baseline for the
`FDC treatment in patients without background therapy (treatment naive). Therefore. the additional benefit
`for HbAlc reduction from 25 mg empagliflozin/S mg linagliptin once daily appears to be available only in
`select treatment settings (add-on to metformin). as demonstrated by the data.
`
`2 Question-Based Review (QBR)
`
`2.1 What are the in viva Clinical Pharmacology and Biophar'maceutics studies with PK
`information submitted in the NDA
`
`The clinical pharmacology and Biopharmaceutics program performed to evaluate the bioequivalence and
`relative bioavailability of the Glyxambi
`fixed-dose combination (FDC) compared to the mono
`components included a single Phase 1 trial conducted in healthy volunteers (Table 1). In addition. trough
`concentrations of empagliflozin and linagliptin were measured in a Phase 3 trial. which evaluated the
`safety and efficacy of once daily oral administration of empagliflozin 25 mg/linagliptin 5 mg and
`
`Reference ID: 3640237
`
`Page 6 of45
`
`

`

`empagliflozin 10 mg/linagliptin 5 mg FDC tablets compared with the individual components
`(empagliflozin 25 mg, empagliflozin 10 mg, and linagljptin 5 mg) for 52 weeks in treatment naive and
`metformin treated patients with type 2 diabetes mellitus with insufficient glycemic control.
`
`Table 1: Overview of studies with pharmacokinetie assessments relevant to the clinical
`pharmacology and biopharmaceutics of Glyxambi
`
`hadtoundergoa
`
`age 18-55 years,
`with a BMI of
`18.5 to 29.9
`
`TreatmentsA,B,C
`andDzsingle-dose
`
`The subjects were to
`undergo 3 treatment
`periods and were to
`receive a single dose
`oftrial medication in
`each munem
`puiod The 3 drug
`administrations were
`sepmated by washout
`phases of at least 35
`days.
`
`'
`
`Enrolled
`(overall): 2504
`patients
`
`Entered
`(overall): 1363
`patients
`
`Two—week single—
`blinded placebo run-
`in period followed by
`a 52-week double—
`blinded treatment
`period and a 4—week
`follow—up period
`
`(i)
`
`to detamine
`the relative
`bioavailability
`ofa 25 mg
`empaglifloa'n I
`5 mg linagliplin
`fixed dose
`combination
`(FDC) tablet
`(fmmulatim
`Al: ‘FDC Al ’)
`compared with
`the individual
`
`to receive 3 ofthe
`4 treatments
`investigated
`
`Randomized,
`
`mum-national,
`parallel-group
`comparison study.
`
`To investigate the
`efficacy, safety, and
`tolerability ofthe
`fixed-dose
`combination (FDC)
`empagliflozin 25
`mg/linagliptin 5 mg
`and ofthe
`FDC empagliflo-n
`10 mg/linagliptin 5
`
`Treatment A:
`Empagliflodn 25
`mg I linagliptin 5
`mg FDC tablet
`[inundation Al
`(FDC Al).
`Treatmmt B:
`Individual tablets
`of 25 mg
`ernpagliflo-
`and5 mg
`
`administered
`togetha'
`Treatment C: 25
`mg I linagliptin 5
`mg FDC Al
`tablet given afier
`a high-flit high
`caloric meal
`
`subjects were to be
`randomly assigred
`to l ofthe 6
`_
`_
`possrble sequences
`
`Treatments A, B,
`and C, wha'eas 24
`subject were to be
`randomly assigned
`to l ofthe 6
`possrble sequences
`containing
`Treatments A, B,
`and Dr Each
`mm was
`administu'ed as a
`fingle dose
`followed by a
`washout phase ofat
`least 35 days.
`
`Patimts who met the
`eligibility uituia at
`the end of 2—week
`placebo run-in
`period were
`randomly assigned
`to l ofthe 5 study
`treatment groups
`(FDC anpagliflozin
`25 mg/linagliptin 5
`
`Reference ID: 3640237
`
`Page 7 of45
`
`

`

`mgcomparedwifll
`
`components
`(unpasliflozinfimg
`orlOmg,and
`1iuntitlilnilfimg)
`givmoncedaily
`(q‘d)f01'52msin
`
`Sl0.5% (253 .0
`mmol/mol and
`$91.3
`mmol/mol);
`treatment naive
`
`or pie-heated
`with metfmmim
`unchanged fox [2
`weeks prior to
`nndmnizaticm;
`and body mass
`'
`(BMD S45
`
`mg)ina l:l:l:l:l
`ratioa
`
`Randomization was
`perfumed at Visit 3,
`and was stratified
`scpmtelyfor
`treatmem naive and
`fiotmetfounin—
`treated patients by
`HbAk at screwing
`(<8.5% or 459.4
`maul/ml, 28.5% at
`269.4 mmol/mol),
`renal fimction at
`screening (eGFR
`290 mUmin/LB
`ml, 60 to 89
`mUmin/1A73 m2),
`and geographical
`legim (Natl:
`Amuica, South
`
`kg/m2
`
`blocks of 10 were
`med for
`tandomization, and
`the blocks wue
`assigned to sham.
`
`Reference ID: 3640237
`
`Page 8 of45
`
`

`

`2.1.1 What are the highlights of the Glyrambi drug product as they relate to clinical pharmacologt'
`review?
`
`Empagliflozin/Linagliptin FDC tablets are are uiangular. flat faced. bevel-edged film-coated tablets. One
`side will be debossed with the Boehringer Ingelheim company symbol: the other side is debossed with
`"10/5" or "25/5" for the 10 mg empagliflozin / 5 mg linagliptin. or 25 mg empagliflozin/ 5 mg linagliptin
`strengths. respectively.
`
`2.1.2
`
`ll hat is the composition of to-be-marketed formulation of Glyxambi?
`
`The composition of the formulations for 10 mg empagliflozin / 5 mg linagliptin, and 25 mg
`
`empagliflozin/ 5 mg linagliptin strengths are shown in Table 2.
`
`Table 2 Qualitative and quantitative composition of empagliflozin / linagliptin film-coated tablets
`
`_
`
`.
`
`Tablet eore
`
`.~
`
`.
`
`Reference to
`
`magnam_m__
`_gliptin
`Drug substance
`Compam standard
`
`film-coated tablet
`
`Pregelatinized starch
`
`Crospovidone
`
`Magnesium stearate
`
`Total mass of
`
`Reference ID: 3640237
`
`Page 9 of45
`
`

`

`Table 2 (cont.) Qualitative and quantitative composition of empaglitlozin / linagliptin film-coated
`tablets
`
`.
`
`‘
`
`Tablet core
`
`.
`
`_
`
`Reference to
`
`Linagliptin
`
`5 ,00
`
`Drug substance
`
`Company standard
`
`film-coated tablet
`
`Magnesium stearate
`
`
`film-coat
`
`Company stande
`
`Total mass of
`
`(Source: Glyxambi NDA eCID module 3.2.P. 1; Description and Composition 10/5mg (A144065), Table 1, page 2; Dmcription
`and Composition 25/5mg (1144067), Table I, , page 2)
`
`2.1.3 What are the proposed mechanism of action and therapeutic indications?
`
`Empagliflozin:
`Sodium glucose co-transporter (SGLTZ) is the predominant transporter responsible for reabsorption of
`approximately 90% of glucose from the glomeiular filtrate back into the circulation. Empagliflozin
`inhibits SGLT2 thereby reducing renal reabsorption of glucose. This promotes increased urinary glucose
`excretion resulting in reduction of blood glucose levels. The am01mt of excess glucose removed by the
`kidney is dependent upon the blood glucose concentration and GFR.
`
`A schematic of the mechanism of action of empagliflozin is shown in Figue 2.
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`Figure 2: Empagliflozin mechanism of action
`(Source: Ferrannini, E. & Solini, A. (2012) SGLT2 inhibition in diabetes mellitus: rationale and clinicalprospects Nature
`Reviews Endocrinology 8, 495-502)
`
`Linagliptin:
`Linagliptin is an inhibitor of DPP—4. an enzyme that degrades the incretin hormones glucagon—like
`peptide-l (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) (Figure 3). Thus. linagliptin
`increases the concentrations of active incretin hormones. stimulating the release of insulin in a glucose-
`dependent manner and decreasing the levels of glucagon in the circulation. Both incretin hormones are
`involved in the physiological regulation of glucose homeostasis. Incretin hormones are secreted at a low
`basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase
`insulin biosynthesis and secretion from pancreatic beta-cells in the presence of normal and elevated blood
`glucose levels. Furthermore. GLP-l also reduces glucagon secretion from pancreatic alpha-cells. resulting
`in a reduction in hepatic glucose output.
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`Copyright Material Withheld
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`Figure 3: Linagliptin mechanism of action
`(Source: May, M (2009), Nature Biotechnology 27, 682 - 685)
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`2.1.4 What are the proposed dosages and routes of administration?
`
`The proposed starting dose of Glyxambi is 10 mg empagliflozin/5 mg linagliptin once daily, administered
`orally. In patients who require additional glycemic control, the dose can be increased to 25 mg
`empagliflozin/5 mg linagliptin once daily.
`
`
`
`2.2 General Clinical Pharmacology
`
`2.2.1 What is known about the PK characteristics of Empagliflozin and Linagliptin following the
`administration of approved drugs, Jardiance and Tradjenta tablets?
`
`Empagliflozin:
`After single dose administration of 10 mg or 25 mg empagliflozin tablet formulations under fasted
`conditions, empagliflozin was absorbed rapidly with a median Tmax of 1 hour for both doses. Thereafter,
`plasma levels declined in a biphasic fashion with a rapid distribution phase and a slower elimination
`phase. Empagliflozin exposure increased in proportion to the dose. Mean (%CV) AUC0-x was 2360
`nmol·h/L (26.7%) for the 10 mg dose and 5550 nmol·h/L (26.0%) for the 25 mg dose. Mean (%CV) Cmax
`was 377 nmol/L (26.2%) and 867 nmol/L (26.8%) for the 10 mg and 25 mg dose, respectively.
`
`The apparent steady-state volume of distribution ranged from 180-230 L. Following administration of an
`oral [14C]-empagliflozin solution (50 mg; ~100μCi) to healthy subjects, the total radioactivity exposure in
`blood was lower compared to plasma, consistent with moderate red blood cell (RBC) partitioning (28.6%
`to 36.8%) observed in vivo. Protein binding of total radioactivity ranged from 80.3% to 86.2%.
`
`No major metabolites of empagliflozin were detected in human plasma and the most abundant metabolites
`were three glucuronide conjugates (2-O, 3-O, and 6-O glucuronide). Systemic exposure of each
`metabolite was less than 10% of total drug related material. O-dealkylation gave rise to metabolite
`M380/1 (EX 609), an active metabolite of empagliflozin, which was not detected in plasma after single
`oral doses of 0.5 to 50 mg empagliflozin; only partial profiles were obtained at doses of 100 to 800 mg
`empagliflozin. At the highest dose level, the EX 609 metabolite exposure (AUC and Cmax) was
`approximately 0.12% of the parent drug. The total fraction of EX 609 excreted in urine ranged from 0.02
`to 0.05% of the administered empagliflozin dose. In vitro studies suggested that the primary route of
`metabolism of empagliflozin
`in humans
`is glucuronidation by
`the uridine 5'-diphospho-
`glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9.
`
`The typical apparent terminal elimination half-life of empagliflozin was 12.4 h and typical apparent oral
`clearance was 10.6 L/h. Mass balance study showed that overall drug related radioactivity recovered in
`urine and feces over the 168 h study period was 95.6%. A mean of 54.4% of the dose was excreted in
`urine and 41.2% was excreted in feces. Approximately 50% of the drug related radioactivity excreted in
`urine was unchanged parent (28.6%). PKPD studies in subjects with normal renal function in general
`showed that fraction of empagliflozin dose excreted unchanged ranged from 13- 18%. With once-daily
`dosing, steady-state plasma concentrations of empagliflozin were reached by the fifth dose. Consistent
`with half-life, up to 22% accumulation of empagliflozin was observed.
`
`Population pharmacokinetic/pharmacodynamic analyses suggest that dose-adjustments of Empagliflozin
`is not warranted based on covariates such as eGFR, body weight, age, BMI, race, and gender.
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`In patients with mild (eGFR: 60 to less than 90 mL/min/1.73 m2), moderate (eGFR: 30 to less than 60
`mL/min/1.73 m2), and severe (eGFR: less than 30 mL/min/1.73 m2) renal impairment and subjects with
`kidney failure/end stage renal disease (ESRD) patients, AUC of empagliflozin increased by
`approximately 18%, 20%, 66%, and 48%, respectively, compared to subjects with normal renal function.
`Peak plasma levels of empagliflozin were similar in subjects with moderate renal impairment and kidney
`failure/ESRD compared to patients with normal renal function. Peak plasma levels of empagliflozin were
`roughly 20% higher in subjects with mild and severe renal impairment as compared to subjects with
`normal renal function. Population pharmacokinetic analysis showed that the apparent oral clearance of
`empagliflozin decreased, with a decrease in eGFR leading to an increase in drug exposure. However, the
`fraction of empagliflozin that was excreted unchanged in urine, and urinary glucose excretion, declined
`with decrease in eGFR. No dose adjustment is needed in patients with an eGFR greater than or equal to
`45 mL/min/1.73 m2. Empagliflozin should not be initiated in patients with an eGFR less than 45
`mL/min/1.73 m2.
`
`In subjects with mild, moderate, and severe hepatic impairment according to the Child-Pugh
`classification, AUC of empagliflozin increased by approximately 23%, 47%, and 75%, and Cmax increased
`by approximately 4%, 23%, and 48%, respectively, compared to subjects with normal hepatic function.
`
`Linagliptin:
`Linagliptin follows non-linear PK for doses ranging from 1 mg to 600 mg. Increases in exposures were
`less than dose proportional for the dose range of 1 mg to 10 mg, more than dose proportional for the dose
`range of 25 mg to 100 mg, and almost dose proportional for the dose range of 100 mg to 600 mg. The
`non-linearity in dose range of 1 to 10 mg and long half-life of linagliptin (i.e., >100 hours) may be
`explained by concentration dependent binding to DPP-4. At concentrations of 1 nM, almost 99% of drug
`remains bound to DPP-4, which reduced to 70-80% at concentrations of about 100 nM. Following oral
`administration, Tmax is reached between 0.5 to 3 h. The