CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`201281Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`
`

`

`CLINICAL PHARMACOLOGY REVIEW
`
`
`
`
`
`NDA:
`Submission Date(s):
`Brand Name:
`
`Generic Name:
`
`Clinical Pharmacology Reviewer:
`Clinical Pharmacology Team Leader:
`OCP Division:
`OND division:
`Sponsor:
`Submission Type; Code:
`Formulation; Strength(s):
`
`Proposed Indication:
`
`and Metformin Hydrochloride
`
`in
`
`201281
`01/19/2011
`Trade®
`Linagliptin
`combination
`Manoj Khurana, Ph.D.
`Jayabharathi Vaidyanathan, Ph.D. (Acting)
`Clinical Pharmacology -2
`Metabolism and Endocrinology Products
`Boehringer Ingelheim Pharmaceuticals, Inc.
`NDA 505(b)(2); Standard
`Film-coated, Immediate-Release,
`combination tablets;
`2.5 mg Linagliptin / 500 mg Metformin HCl,
`2.5 mg Linagliptin / 850 mg Metformin HCl, and
`2.5 mg Linagliptin / 1000 mg Metformin HCl
`Adjunct to diet and exercise to improve glycemic control
`in adults with type 2 diabetes mellitus when treatment
`with linagliptin and metformin is appropriate
`
` fixed-dose
`
`
`
`LIST OF FIGURES AND TABLES ........................................................................................................... 3
`1 EXECUTIVE SUMMARY .................................................................................................................. 4
`1.1
`RECOMMENDATION ....................................................................................................................... 4
`1.2
`PHASE IV COMMITMENTS............................................................................................................. 4
`1.3
`SUMMARY OF IMPORTANT CLINICAL PHARMACOLOGY FINDINGS............................................. 4
`2 QUESTION BASED REVIEW ........................................................................................................... 8
`2.1 GENERAL ATTRIBUTES.................................................................................................................. 8
`2.1.1 What are the proposed dosage regimens for Trade®? .......................................................................................................8
`2.1.2 What is the composition of the intended commercial Trade® formulation?...................................................................9
`2.2 GENERAL CLINICAL PHARMACOLOGY....................................................................................... 11
`2.2.1 What are the known genral clinical pharmacology characteristics of linaglitin and metformin after oral
`administration, in the context of current application? ...............................................................................................................11
`2.2.2 What are the PK chacracteristics of linaglitin and metformin from Trade® formulation after oral administration
`and how do they compare to the Phase 3 individual tablet formulations?...............................................................................12
`2.2.3 What are the pharmacokinetic/pharmacodynamic characteristics of linagliptin after oral administration of the 2.5
`mg BID and 5 mg QD dose?...........................................................................................................................................................13
`2.2.4 What are the characteristics of the Trade® exposure-response relationship (dose-response, concentration-
`response) for HbA1c reduction (efficacy) in T2DM patients? ...................................................................................................16
`2.2.5 What are the characteristics of the exposure-response relationship (dose-response, concentration-response) for
`safety with regards to adverse reactions in T2DM patients when linagliptin and metformin are co-administered?..........17
`2.3
`INTRINSIC FACTORS .................................................................................................................... 18
`
`Reference ID: 3027133
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`2.3.1 What intrinsic factors (e.g., age, gender, race, weight, 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? ..........................................................................................................................................................18
`2.3.2 Does the renal function affect linagliptin and metformin pharmacokinetics from Trade®?.......................................18
`2.3.3 Does the hepatic function affect linagliptin and metformin pharmacokinetics from Trade®?...................................18
`2.3.3 What is the proposed use of Trade® in pediatric subjects?.............................................................................................19
`2.4
`EXTRINSIC FACTORS ................................................................................................................... 19
`2.4.1 What is the effect of food on the bioavailability of linagliptin and metformin from Trade®? ....................................19
`2.4.2 Drug-Drug Interactions (DDIs)...........................................................................................................................................20
`2.4.2.1 What is the CYP inhibition potential of linagliptin and metformin?......................................... 20
`2.4.2.3 What is the mutual effect of co-administration of linagliptin and metformin on the
`pharmacokinetics of both drugs? ................................................................................................................... 20
`2.4.2.2 What is the effect of Trade® co-administration on the pharmacokinetics of other drugs?..... 21
`2.5 GENERAL BIOPHARMACEUTICS .................................................................................................. 24
`2.5.1 Is bioequivalence established between the to-be-marketed formulation and the Phase 3 formulations and how does
`it relate to the overall product development? ..............................................................................................................................24
`2.6
`ANALYTICAL................................................................................................................................ 26
`2.6.1 Is the analytical method for quantitation of linagliptin and metformin in human plasma appropriately validated?
`26
`
`3 LABELING COMMENTS ................................................................................................................ 30
`4 APPENDIX ......................................................................................................................................... 33
`4.1
`PROPOSED LABEL ........................................................................................................................ 33
`4.2
`INDIVIDUAL STUDY REVIEWS...................................................................................................... 53
`4.2.1 BE Study (1218.1)..................................................................................................................................................................53
`4.2.2 BE Study (1218.2)..................................................................................................................................................................59
`4.2.3 BE Study (1218.3)..................................................................................................................................................................65
`4.2.4 BE Study (1288.4)..................................................................................................................................................................71
`4.2.5 PKPD (1218 57).....................................................................................................................................................................77
`4.2.6 PKPD Study (1218.45)..........................................................................................................................................................84
`4.3 OCP FILING MEMO..................................................................................................................... 90
`
`Reference ID: 3027133
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`List of Figures and Tables
`
`FIGURE 1 COMBINATION TREATMENT PROVIDES NUMERICALLY HIGHER HBA1C REDUCTION VERSUS THE
`LINAGLIPTIN AND METFORMIN GIVEN AS MONOTHERAPY IN THE 24-WEEK PHASE 3 CONFIRMATORY
`TRIAL (1218.46) ...................................................................................................................................... 5
`FIGURE 2 TRADE® FIXED-DOSE COMBINATION FORMULATION IS BIOEQUIVALENT TO CO-ADMINISTRATION
`OF INDIVIDUAL COMPONENTS FOR LINAGLIPTIN AND METFORMIN........................................................... 7
`FIGURE 3 CHEMICAL STRUCTURES OF LINAGLIPTIN AND METFORMIN. ...................................................... 8
`FIGURE 4 MEAN PLASMA CONCENTRATION TIME PROFILE OF LINAGLIPTIN AND METFORMIN AFTER SINGLE
`ORAL DOSE OF LINA 2.5 /MET 1000 MG FDC TABLET (RED DASHED LINE) VERSUS SINGLE CO-
`ADMINISTRATION OF LINA 2.5 MG AND MET 1000 MG IR FORMULATIONS (BLUE SOLID LINE) UNDER
`FASTED STATE ....................................................................................................................................... 12
`FIGURE 5 PKPD RELATIONSHIP OF LINAGLIPTIN FOR DPP4 INHIBITION................................................... 14
`FIGURE 6 LINAGLIPTIN EXPOSURE-RESPONSE FOR EFFICACY SUPPORT THE USE OF 2.5 MG BID UNDER
`FIXED-DOSE REGIMEN WITH METFORMIN............................................................................................... 15
`FIGURE 7 TIME COURSE OF CHANGE IN HBA1C FROM BASELINE IN THE 24-WEEK PHASE 3 CONFIRMATORY
`TRIAL (1218.46) .................................................................................................................................... 16
`FIGURE 8 COMBINATION OF LINAGLIPTIN AND METFORMIN RESULTS IN ADDITIVE REDUCTION IN HBA1C
`VERSUS MONOTHERAPY BASED ON MEAN(±SE) CHANGE FROM BASELINE IN HBA1C AT WEEK 24 (PHASE
`3 TRIAL 1218.46)................................................................................................................................... 17
`FIGURE 9 EFFECT OF FOOD ON LINAGLIPTIN AND METFORMIN EXPOSURE FROM TRADE® ........................ 19
`FIGURE 10
`SUMMARY OF BE EVALUATIONS CONDUCTED FOR THE FORMULATIONS UTILIZED DURING
`CLINICAL DEVELOPMENT INCLUDING THE INTENDED COMMERCIAL FORMULATION .............................. 24
`FIGURE 11
`SUMMARY OF BE EVALUATIONS CONDUCTED USING THE PREDICTED DOSE FOR THE INTENDED
`COMMERCIAL FORMULATION ................................................................................................................ 25
`
`
`TABLE 1 QUANTITATIVE COMPOSITION OF THE TRADE® TABLETS......................................................... 10
`TABLE 2 APPROXIMATE YIELDS FOR
` BATCH SIZE.............................................................. 10
`
`TABLE 3
`SUMMARY OF KEY LINAGLIPTIN PHARMACOKINETIC PARAMETERS AFTER SINGLE ORAL DOSE OF
`LINA 2.5 /MET 1000 MG FDC TABLET VERSUS SINGLE CO-ADMINISTRATION OF LINA 2.5 MG AND MET
`1000 MG IR FORMULATIONS.................................................................................................................. 13
`TABLE 4
`SUMMARY OF KEY METFORMIN PHARMACOKINETIC PARAMETERS AFTER SINGLE ORAL DOSE OF
`LINA 2.5 /MET 1000 MG FDC TABLET VERSUS SINGLE DOSE OF LINA 2.5 MG AND MET 1000 MG IR
`FORMULATIONS..................................................................................................................................... 13
`TABLE 5
`SUMMARY OF LINAGLIPTIN PK AND DPP4 INHIBITION OBSERVED WITH 2.5 MG BID AND 5 MG
`QD REGIMENS ....................................................................................................................................... 14
`TABLE 6 DDI ASSESSMENT FOR TRADE® FORMULATION DURING THE DEVELOPMENT............................ 22
`TABLE 7 SUMMARY OF ANALYTICAL METHOD USED FOR THE CPB STUDIES ........................................... 26
`TABLE 8 PERFORMANCE SUMMARY OF ANALYTICAL METHODS USED FOR THE CPB STUDIES TO
`QUANTITATED LINAGLIPTIN IN HUMAN PLASMA.................................................................................... 29
`TABLE 9 PERFORMANCE SUMMARY OF METFORMIN ANALYTICAL METHOD USED FOR THE CPB STUDIES
`............................. 29
`(ASSAY VALIDATION PERFORMED AT
`
`Reference ID: 3027133
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`

`
`Note to readers:
`• At the time of compilation of this review the trade name is not finalized. Therefore it is
`referred to as “Trade®” throughout the review
`• Throughout this review, treatments are designated as follows:
`•
`“L+M,” “lina+met,” and “linagliptin+metformin”: used interchangeably to represent
`any dosage of the free combination therapy with linagliptin and metformin
`“L/M,” “lina/met,” and “linagliptin/metformin”: only used for the single-tablet
`(fixed-dose) combination formulation
`
`•
`
` 1
`
`Executive Summary
`Boehringer Ingelheim Pharmaceuticals, Inc. (hereafter BI/the sponsor) is seeking an approval of
`Trade®;Linagliptin (L) + Metformin hydrochloride (M) (hereafter L/M) film-coated fixed-dose
`combination (FDC) tablets for the treatment of type 2 diabetes mellitus (T2DM). The proposed
`indication for L/M is “an adjunct to diet and exercise to improve glycemic control in adults with
`T2DM when treatment with linagliptin and metformin is appropriate”. The active pharmaceutical
`ingredients in L/M drug product are linagliptin, a dipeptidyl peptidase (DPP4) inhibitor, and
`metformin HCl, a widely prescribed oral antidiabetic.
`
`The proposed FDC will be available as three dosage strength immediate-release tablets:
`
`•
`
`•
`
`•
`
`2.5 mg Linagliptin / 500 mg Metformin HCl,
`
`2.5 mg Linagliptin / 850 mg Metformin HCl, and
`
`2.5 mg Linagliptin / 1000 mg Metformin HCl
`
`The proposed recommended daily dose of Trade® is one tablet taken twice daily (BID).
`
`Since both active ingredients are approved in the US for use in T2DM, this application is
`submitted by the sponsor as a 505(b)(2) NDA. The sponsor has referenced pertinent information
`from approved US prescribing information for Tradjenta® (linagliptin; NDA 201280) and
`Glucophage® (metformin hydrochloride; NDA 20-357).
`
`1.1 Recommendation
`
`The Office of Clinical Pharmacology/Division of Clinical Pharmacology 2 (OCP/DCP-2) has
`reviewed the NDA 201281 for Trade®. The clinical pharmacology information submitted under
`this NDA is acceptable and supports a recommendation of approval of Trade®.
`
`Phase IV Commitments
`1.2
`None.
`
`Summary of Important Clinical Pharmacology Findings
`1.3
`The efficacy and safety of the concomitant use of linagliptin and metformin has been reviewed in
`the NDA 201280 for Tradjenta(cid:163) (Linagliptin). The Trade® clinical development program is
`composed of 13 clinical studies: 6 Phase I studies (one of these, 1218.4, was conducted as part of
`the development of linagliptin as monotherapy), one Phase 2 study (also part of the monotherapy
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`development program), and 6 Phase 3 studies, 2 of which were long-term extensions. At the time
`of this NDA submission, 10 of these studies were completed; for the 3 ongoing studies (1218.20,
`1218.40, and 1218.52) results of the planned interim analyses were included. Study 1218.57,
`which was conducted to show bioequivalence between the European sourced Glucophage(cid:163) (used
`in Pivotal Phase 3 Study 1218.46) and US Glucophage® reference products, was also conducted
`as part of the development of the fixed-dose combination for linagliptin and metformin. Clinical
`Pharmacology review of the information submitted by the sponsor, in support of their application,
`revealed the following important findings:
`Dose -Response for HbA1c (Efficacy)/safety:
`• Dose-response relationship demonstrated additional reduction in HbA1c with co-
`administration of 2.5 mg linagliptin and metformin 500 mg BID or 1000 mg BID over
`linagliptin 5 mg QD, metformin 500 mg and metformin 1000 mg BID monotherapy in a
`24-week therapy (Trial 1218.46) (Figure. 1).
`• The linagliptin 2.5 mg/metformin 1000 mg provided numerically higher reduction in
`HbA1c over the linagliptin 2.5 mg/metformin 500 mg BID dose in a 24-week therapy
`(Trial 1218.46)
`5 mg dose was more likely to achieve >80% inhibition of DPP-4 at steady state compared
`to 2.5 mg dose.
`• Overall, the percentages of patients with adverse events (AEs) were comparable between
`treatment groups, ranging from 49.0% in the Lina 2.5 + Met 500 group to 56.6% in the
`Lina 2.5 + Met 1000 group.
`Figure 1 Combination treatment provides numerically higher HbA1c reduction versus
`the linagliptin and metformin given as monotherapy in the 24-week Phase 3
`confirmatory trial (1218.46)
`
`•
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`Reference ID: 3027133
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`

`General ADME:
`
`Linagliptin: The linagliptin pharmacokinetic profile from Trade® was similar to that observed
`with the administration of linagliptin alone.
`
`Metformin: The metformin pharmacokinetic profile from Trade® was similar to that observed
`with the administration of metformin alone.
`
`Intrinsic Factors (Body weight, Age, BMI, Gender, Race, Genetics etc.) Affecting Exposure:
`None of the covariates are known to affect either linagliptin or metformin pharmacokinetics and
`no dose adjustments are proposed based on these in the individual product labels. Therefore, no
`dose adjustments are warranted for Trade® based on any of these covariates.
`Specific Populations
`Elderly patients: In the elderly, Trade® should be carefully titrated to establish the minimum
`dose for adequate glycemic effect and should be based on the age-appropriate upper limit of
`creatinine clearance as aging can be associated with reduced renal function. Before initiation of
`therapy with Trade® and at least annually thereafter, renal function should be assessed.
`
`Renal Impairment: Effect of renal impairment on linagliptin and metformin PK from Trade®
`was not specifically evaluated. While no dose adjustment is recommended for linagliptin in
`patients with renal impairment, risk of metformin accumulation and lactic acidosis increases with
`the degree of impairment of renal function. Thus, in accordance with the current labeling
`recommendations for metformin, patients with renal impairment (e.g., serum creatinine >1.5
`mg/dL [males] or >1.4 mg/dL [females], or abnormal creatinine clearance) should not receive
`Trade®. In patients in whom development of renal dysfunction is anticipated, including elderly
`patients, renal function should be assessed more frequently and Trade® discontinued if evidence
`of renal impairment is present.
`
`Hepatic Impairment: Effect of hepatic impairment was not evaluated specifically for Trade®.
`While no dose adjustment of linagliptin is recommended in patients with hepatic impairment,
`impaired hepatic function has been associated with cases of lactic acidosis with metformin
`therapy as impaired hepatic function may significantly limit the ability to clear lactate. Therefore,
`Trade® use should generally be avoided in patients with clinical or laboratory evidence of hepatic
`disease.
`
`Extrinsic Factors:
`Food Effect: Food lowered the peak exposure of metformin from the Trade® formulation by
`18% and from a clinical pharmacology perspective Trade® could be taken with or without food.
`However, considering that metformin is administered with food to improve the gastrointestinal
`tolerability, the Trade® is indicated to be administered with food.
`
`PK Comparison of Intended Commercial vs. Phase 3 Formulations:
`Bioequivalence was demonstrated between intended commercial FDC formulation and co-
`administration of Phase 3 individual tablet formulations for Linagliptin 2.5/Metformin 500 mg
`and Linagliptin 2.5/Metformin 1000 mg FDC. Bioequivalence was demonstrated between
`intended commercial FDC formulation and co-administration of individual tablet formulations for
`Linagliptin 2.5/Metformin 850 mg, and also between the EU sourced Glucophage(cid:163) formulation
`
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`

`(used in the pivotal Phase 3 trial and all BE studies) and the US approved Glucophage(cid:163)
`formulation.
`is bioequivalent
`formulation
`fixed-dose combination
`Figure 2 Trade®
`administration of individual components for linagliptin and metformin.
`
`to co-
`
`Bioanalytical Methodology:
`For the clinical pharmacology assessments, linagliptin and metformin were quantitated in plasma
`using validated HPLC-MS/MS assay methods. The assay methods were validated for analyzing
`these 2 analytes in plasma samples in terms of range, accuracy, precision and sensitivity. The
`changes to the analytical sites or procedures were adequately supported by partial/cross validation
`of methods whenever necessary.
`
`
`
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`Reference ID: 3027133
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`

`2 Question Based Review
`
`2.1 General Attributes
`BI is seeking the approval of combination product Trade® (Linagliptin and Metformin HCl FDC)
`Immediate-Release Tablets, for the treatment of type 2 diabetes mellitus (T2DM). Linagliptin
`(Figure 3a) is an approved DPP-4 inhibitor and metformin (Figure 3b) is an approved biguanide,
`both are indicated for the treatment of type 2 diabetes mellitus. Trade® is indicated as an adjunct
`to diet and exercise to improve glycemic control in adults with T2DM when treatment with both
`linagliptin and metformin is appropriate.
`
`Since both active ingredients are approved in the US for T2DM, sponsor submitted a 505(b)(2)
`NDA, and referenced pertinent information from approved US prescribing information for
`Tradjenta® (linagliptin; NDA 201280 approved 05/02/2011) and Glucophage® (metformin
`hydrochloride; NDA 20-357).
`
`The chemical structures of linagliptin and metformin are illustrated in Figure 3 below:
`
`Figure 3 Chemical Structures of Linagliptin and Metformin.
`
`(a) Linagliptin
`
`(b) Metformin hydrochloride
`
`
`
`
`
`Linagliptin is an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme which
`rapidly degrades incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent
`insulinotropic polypeptide (GIP). Both incretin hormones are involved in the physiological
`regulation of glucose homeostasis. Linagliptin binds in a reversible manner selectively to DPP-4
`and exhibits a >10,000-fold selectivity versus DPP-8 or DPP-9 activity.
`
`Metformin is a biguanide that works by increasing insulin sensitivity and decreasing hepatic
`glucose production.
`
`Sponsor’s intent of combining linagliptin with metformin hydrochloride is based on convenience
`for patients. The combination would allow decreasing the number of tablets to be taken by the
`patient and improve patient compliance with medication.
`
`The sponsor has supported the Trade® application with clinical pharmacology studies, which
`compare intended commercial drug product formulations with the Phase 3 individual
`formulations, evaluate food effect, and DDI between linagliptin and metformin.
`2.1.1 What are the proposed dosage regimens for Trade®?
`
` tablet containing the
`The proposed Trade® tablet is a film-coated, immediate-release,
`two drugs and excipients. Trade® is available as three dosage strength tablets:
`
`Reference ID: 3027133
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`

`2.5 mg Linagliptin / 500 mg Metforrnin HCL.
`2.5 mg Linagliptin / 850 mg Metformin HCL. and
`2.5 mg Linagliptin/ 1000 mg Metformin HCL.
`
`o
`
`Treatment with the linagliptin/metfonnin (L/M) FDC is recommended for:
`0 Adults with T2DM when treatment with both linagliptin and metformin is appropriate
`including-
`0 patients who have been previously treated with the free combination of both
`components,
`0 patients treated with either metformin or linagliptin monotherapy,
`(I!) (4)
`
`“’0
`
`Initial combination therapy or maintenance of combination therapy should be individualized and
`left to the discretion of the health-care provider. In accordance with the recommended dosing
`schedule for metformin, metformin therapy should be gradually increased from lower starting
`doses
`(such as 500 mg BID)
`to minimize gastrointestinal
`symptoms. The maximum
`recommended daily dose of the UM combination is 5 mg linagliptin plus 2000 mg metformin
`(given as 2.5/1000 mg BID).
`
`(4’ patients may begin with the Trade® 2.5/500 mg dose. For patients whose
`HbAlc is poorly controlled (i.e.. 211.0%), treatment with a Trade® dose of 2.5/1000 mg BID
`could be recommended. with initial titration of the metformin component from 500 mg BID after
`2 weeks.
`
`Compared to metformin 1000 mg BID monotherapy, the L+M 2.5/500 mg BID dose presents
`comparable efficacy and a safety profile that is relatively free of the GI events normally
`associated with the 1000 mg BID dose of metformin. Therefore. the Trade® 2.5/500 mg BID
`dose represents an alternative for patients who cannot tolerate the GI side effects associated with
`the higher dose of metformin.
`
`The two tablet strengths of Trade® L/M 2.5/500 mg or W 2.5/1000 mg tablet are designed to
`enable the titration regimen for metformin component after treatment initiation. The availability
`of UM 2.5 /850 mg tablet would allow for dosing of subject who cannot tolerate 1000 mg BID
`metformin and help in titration of Trade®.
`
`2.1.2 What is the composition of the intended commercial Trade® formulation?
`
`The details on the tablet composition and manufacturing should be referred to the CMC review.
`In brief, the proposed commercial presentations of Trade® are film-coated innnediate-release
`m4) tablets. The three presentations of the intended commercial drug product (i.e. W
`2.5/500 mg 2.5/850 mg and 2.5/1000 mg) differin the amount of metformin
`
`om
`
`(m4)
`
`\W “I The
`
`compositions of UM tablets are listed in Table 1 below.
`
`Reference ID: 30271 33
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`

`linagllptin / metformin hydrochloride
`
`2.5 mg/
`500 m
`
`2.5 mg}
`850 m
`lms/
`tablet
`
`2.5 mg I
`1000 III
`[mg/
`tablet
`
`2.500
`
`l000.000
`
`Total weightmm mm um
`
`Colloidal silicon
`dioxide
`
`col
`lene -
`Pr- -
`H p romellose
`
`The approved dose of linagliptin is 5 mg once a day (NDA 201280). Metformin hydrochloride is
`approvedintheUSindose strengths of500mg,850mgand lOOOmgforaBID use. The
`development of the combination product was intended to match this metfonnin regimen, and
`thus, the therapeutic dose of linagliptin of 5 mg once a day was split into two doses of 2.5 mg
`each.
`The 5
`lies for the three bioequivalence studies (1288.1 - 1288.3) were manufactured-
`& (See Table 2).
`
`Table 2
`
`Approximate yields for_ batch size
`
`Dosage strength
`
`A roximate yield
`n umber of film coated tablets
`
`2.5 m_/1000 m_
`
`2.5 m_/500 m_
`
`2.5 m/850 m
`
`Reference ID: 3027133
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`

`2.2 General Clinical Pharmacology
`
`2.2.1 What are the known genral clinical pharmacology characteristics of linagliptin and
`metformin after oral administration, in the context of current application?
`The detailed clinical pharmacology information can be found in the prescribing information for
`the approved linagliptin and metformin products. The key aspects are mentioned below:
`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 partially be explained by concentration
`dependent binding to dipeptidyl peptidase-4 (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.
`• The accumulation half-life of linagliptin ranges from 8-12 hours.
`• The majority of drug is eliminated unchanged in feces (~85%) and a minor proportion
`appears in urine (~4.5%). Metabolism is a minor pathway of elimination for linagliptin.
`However, linagliptin appears to undergo enterohepatic re-circulation.
`• The predominant metabolite, CD1790 (formed by CYP3A4 isoform), is therapeutically
`inactive.
`• Co-administration with high-fat meal reduced linagliptin rate of absorption (i.e., Cmax)
`by ~15 to 25% but had no effect on AUC. These changes were not considered clinically
`relevant.
`• The extent of DPP-4 inhibition increased with increases in linagliptin doses from 1 to 10
`mg. Average steady-state DPP-4 inhibitions at 24 hours after the last dose were 62.5%,
`76.9%, 85%, and 89.4% for 1 mg, 2.5 mg, 5 mg, and 10 mg dose groups, respectively.
`Metformin (Glucophage®):
`• Metformin is an antihyperglycemic agent which improves glucose tolerance in patients
`with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin
`decreases hepatic glucose production, decreases intestinal absorption of glucose, and
`improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
`• The absolute bioavailability of a Glucophage® 500 mg tablet given under fasting
`conditions is approximately 50% to 60%. Studies using single oral doses of
`Glucophage® 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack
`of dose proportionality with increasing doses, which is due to decreased absorption rather
`than an alteration in elimination.
`Food decreases the extent of and slightly delays the absorption of metformin, as shown
`by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower
`area under the plasma concentration versus time curve (AUC), and a 35-minute
`prolongation of time to peak plasma concentration (Tmax) following administration of a
`single 850 mg tablet of metformin with food, compared to the same tablet strength
`administered fasting. The clinical relevance of these decreases is unknown.
`• The apparent volume of distribution (V/F) of metformin following single oral doses of
`Glucophage® 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma
`proteins. Metformin partitions into erythrocytes, most likely as a function of time. At
`usual clinical doses and dosing schedules of Glucophage®, steady state plasma
`concentrations of metformin are reached within 24 to 48 hours and are generally <1000
`ng/mL.
`
`•
`
`Reference ID: 3027133
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`•
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`Intravenous single-dose studies in normal subjects demonstrate that metformin is
`excreted unchanged in the urine and does not undergo hepatic metabolism (no
`metabolites have been identified in humans) or biliary excretion. Renal clearance is
`approximately 3.5 times greater than creatinine clearance, which indicates that tubular
`secretion is the major route of metformin elimination. Following oral administration,
`approximately 90% of the absorbed drug is eliminated via the renal route within the first
`24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the
`elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass
`may be a compartment of distribution.1
`2.2.2 What are the PK characteristics of linagliptin and metformin from Trade®
`formulation after oral administration and how do they compare to the Phase 3 individual
`tablet formulations?
`
`A representative mean plasma concentration time profiles of linagliptin and metformin from one
`of the BE studies (1288.1), comparing Trade® formulation (single oral dose of Lina 2.5/Met
`1000 mg FDC) versus single co-administration of Lina 2.5 mg and Met 1000 mg IR
`(Glucophage®) formulations, are presented in Figure 4 below.
`
`On average, the systemic exposures of both linagliptin and metformin from Lina 2.5/Met 1000
`mg FDC were comparable to that observed from co-administration of individual Lina 2.5 mg and
`Met 1000 mg IR formulations used in Phase 3 trial.
`
`Figure 4 Mean plasma concentration time profile of linagliptin and metformin after
`single oral dose of Lina 2.5 /Met 1000 mg FDC tablet (red dashed line) versus
`single co-administration of Lina 2.5 mg and Met 1000 mg IR formulations (blue
`solid line) under fasted state
`
`
`1 Glucophage® prescribing information, NDA 20357.
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`Reference ID: 3027133
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`The summary of pharmacokinetic parameters for linagliptin and metformin from the BE study
`(1288.1). comparing Trade® formulation (single oral dose of Lina 2.5/Met 1000 mg FDC) versus
`single co