`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`201280Orig1s000
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
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`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`
`NDA: 201280
`Brand Name
`Generic Name
`Clinical Pharmacology &
`Pharmacometric (PM) Reviewer
`Secondary PM Reviewer
`PM Team Leader
`Clinical Pharmacology Team
`Leader
`OCP Division
`OND Division
`Sponsor/Authorized Applicant
`Submission Type; Code
`Formulation; Strength(s)
`Indication
`
`
`
`Submission Date: 07/02/2010
`TBD
`Linagliptin
`Lokesh Jain, Ph.D.
`
`Justin Earp, Ph.D.
`Christine Garnett, Pharm.D.
`Sally Choe, Ph.D.
`
`Clinical Pharmacology II
`Metabolism and Endocrinology Products
`Boehringer Ingelheim Pharmaceuticals, Inc.
`Original NDA 505(b)(1); Standard
`IR Tablet ; 5 mg
`To improve glycemic control in patients with type
`2 diabetes mellitus
`
`EXECUTIVE SUMMARY................................................................................................................. 7
`1.1
`RECOMMENDATIONS.................................................................................................................... 7
`1.2
`PHASE IV COMMITMENTS ............................................................................................................ 7
`1.3
`SUMMARY OF CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS FINDINGS.......................... 7
`QUESTION-BASED REVIEW ....................................................................................................... 11
`2.1
`GENERAL ATTRIBUTES OF THE DRUG ........................................................................................ 11
`2.1.1 What are the highlights of the chemistry and physical-chemical properties of the drug
`substance and the formulation of the drug product? ............................................................ 11
`2.1.2 What are the proposed mechanism of action and therapeutic indications? ......................... 12
`2.1.3 What are the proposed dosages and routes of administration?............................................ 12
`2.2
`GENERAL CLINICAL PHARMACOLOGY ....................................................................................... 12
`2.2.1 What are the design features of the clinical pharmacology and the clinical studies used to
`support dosing or claims? .................................................................................................... 12
`2.2.2 What are the evidences of efficacy provided by the sponsor in support of the proposed 5 mg
`dose?..................................................................................................................................... 13
`2.2.3 What is the basis for selecting the response endpoints and how are they measured in clinical
`pharmacology studies? ......................................................................................................... 18
`2.2.4
`Are the active moieties in plasma appropriately identified and measured to assess
`pharmacokinetic parameters and exposure response relationships? ................................... 18
`2.2.5 What are the characteristics of the dose-response and exposure-response relationships for
`efficacy?................................................................................................................................ 18
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`2.2.6 What are the characteristics of the dose-response and exposure-response relationships for
`safety?................................................................................................................................... 20
`2.2.7 What are the PK characteristics of the drug? ...................................................................... 21
`2.2.7.1
`What are the single and multiple dose PK parameters? ............................................................. 22
`2.2.7.2
`How does the PK of the drug and its major metabolites in healthy adults compare to that in
`patients? ..................................................................................................................................... 29
`2.2.7.3
`What are the characteristics of drug absorption?........................................................................ 32
`What are the characteristics of drug distribution?...................................................................... 32
`2.2.7.4
`2.2.7.5
`Does the mass balance study suggest renal or hepatic as the major route of elimination? ......... 33
`2.2.7.6
`What are the characteristics of drug metabolism?...................................................................... 35
`2.2.7.7
`What are the characteristics of drug elimination? ...................................................................... 36
`2.2.7.8
`Based on PK parameters, what is the degree of linearity in the dose-concentration relationship?
`36
`
`2.3
`INTRINSIC FACTORS ................................................................................................................... 39
`2.3.1 What intrinsic factors influence exposure and/or response, and what is the impact of any
`differences in exposure on efficacy or safety responses? ..................................................... 39
`2.3.1.1
`Age, BMI, Weight, and Gender ................................................................................................. 39
`2.3.1.2
`Pediatric Patients........................................................................................................................ 45
`2.3.1.3
`Race ........................................................................................................................................... 46
`2.3.1.4
`Renal Impairment....................................................................................................................... 50
`2.3.1.5
`Hepatic Impairment.................................................................................................................... 53
`2.3.1.6
`Genetics ..................................................................................................................................... 54
`2.3.2 What pregnancy and lactation use information is there in the label? .................................. 55
`EXTRINSIC FACTORS .................................................................................................................. 55
`2.4
`2.4.1 What are the drug-drug interactions? .................................................................................. 55
`2.4.1.1
`Is there an in vitro basis to suspect in vivo drug-drug interactions?........................................... 55
`2.4.1.2
`Is the drug a substrate of CYP enzymes? ................................................................................... 55
`2.4.1.3
`Is the drug an inhibitor and/or an inducer of CYP enzymes?..................................................... 55
`2.4.1.4
`Is the drug a substrate and/or an inhibitor/ inducer of P-gp transport processes?....................... 56
`2.4.1.5
`Are there other metabolic/transporter pathways that may be important? ................................... 56
`2.4.1.6
`Are there any in vivo drug-drug interaction studies that indicate the exposure alone and/or
`exposure-response relationships are different when drugs are co-administered? ....................... 57
`2.4.1.7
`Is there in vivo chiral conversion of the drug? How is it addressed?.......................................... 60
`2.5
`GENERAL BIOPHARMACEUTICS.................................................................................................. 60
`2.5.1
`Based on BCS principles, in what class is this drug and formulation? What solubility,
`permeability, and dissolution data support this classification?............................................ 60
`2.5.2 What is the relative bioavailability of the proposed to-be-marketed formulation to the
`clinical trial formulations?................................................................................................... 61
`2.5.3 What is the effect of food on the bioavailability of the drug from the dosage form? ............ 61
`ANALYTICAL SECTION ............................................................................................................... 62
`2.6
`2.6.1 What bioanalytical methods were used to assess concentrations of linagliptin and/or
`metabolite? ........................................................................................................................... 62
`2.6.2 Which metabolites have been selected for analysis and why?.............................................. 62
`For all moieties measured, is free, bound, or total measured? ............................................ 62
`2.6.3
`2.6.4 What is the range of the standard curve? How does it relate to the requirements for clinical
`studies? What curve fitting techniques are used?................................................................. 62
`2.6.5 What are the lower and upper limits of quantification (LLOQ/ULOQ)? ............................. 63
`2.6.6 What are the accuracy, precision, and selectivity of this assay method? ............................. 63
`2.6.7 What is the sample stability under the conditions used in the study (long-term, freeze-thaw,
`autosampler etc.)? ................................................................................................................ 63
`2.6.8 What QC concentrations were used for sample analysis?.................................................... 63
`2.7
`DETAILED LABELING RECOMMENDATIONS................................................................................ 63
`
`
`PHARMACOMETRICS REVIEW
`1
`SUMMARY OF FINDINGS ............................................................................................................ 70
`1.1
`KEY REVIEW QUESTIONS........................................................................................................... 70
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`1.1.1 Does the population pharmacokinetic analysis support the sponsor’s proposed labeling
`claims regarding the effects of body weight, age, gender, and ethnicity? ............................ 70
`1.1.2 Does the dose-response or exposure-response analysis support the selection of 5 mg dose?..
`.............................................................................................................................................. 70
`
`1.2
`RECOMMENDATIONS.................................................................................................................. 70
`LABEL STATEMENTS .................................................................................................................. 70
`1.3
`RESULTS OF SPONSOR’S ANALYSIS ....................................................................................... 70
`2.1
`DATA SETS USED FOR MODEL DEVELOPMENT .......................................................................... 70
`2.2
`MODEL DEVELOPMENT.............................................................................................................. 72
`2.2.1
`Population PK model............................................................................................................ 72
`2.2.2 Covariate model ................................................................................................................... 74
`REVIEWER’S ANALYSIS.............................................................................................................. 78
`3.1
`INTRODUCTION........................................................................................................................... 78
`3.2
`OBJECTIVES ............................................................................................................................... 78
`3.3
`METHODS................................................................................................................................... 78
`3.3.1 Data Sets............................................................................................................................... 78
`3.3.2
`Software................................................................................................................................ 78
`3.3.3 Models .................................................................................................................................. 78
`3.4
`RESULTS .................................................................................................................................... 79
`LISTING OF ANALYSES CODES AND OUTPUT FILES......................................................... 81
`
`
`List of Tables
`
`Table 1: Linagliptin physical-chemical properties...................................................................... 11
`Table 2: Geometric mean (%gCV) DPP-IV activity on days 1 and 12 after oral administration of
`1, 2.5, 5 and 10 mg linagliptin once daily for 12 days in study 1218.2 ........................ 14
`Table 3: Change in efficacy endpoints or pharmacodynamic markers at week 12 for clinical
`trials supporting the selection of 5 mg dose.................................................................. 19
`Table 4: Key pharmacokinetic parameters of linagliptin after single oral administration of 2.5 to
`600 mg dose .................................................................................................................. 24
`Table 5: Key pharmacokinetic parameters of linagliptin after single intravenous infusion or oral
`administration of 0.5 mg and 10 mg doses.................................................................... 24
`Table 6: Key pharmacokinetic parameters after multiple oral administration of 1 mg to 10 mg
`linagliptin in a 12-day long study 1218.2...................................................................... 28
`Table 7: Key pharmacokinetic parameters after multiple oral administration of 2.5 mg to 10 mg
`linagliptin in a four-week long study 1218.3 ................................................................ 29
`Table 8: Metabolite pattern in urine and feces after a single oral dose of 10 mg (21.2 μmol) [14C]
`linagliptin (BI 1356 BS) (arithmetic mean of 6 individuals) ........................................ 34
`Table 9: Metabolite pattern in urine and faeces after a single intravenous infusion dose of 5 mg
`(10.6 μmol) [14C] linagliptin (BI 1356 BS) (arithmetic means of 6 individuals).......... 34
`Table 10: Investigation of the impact of single covariate† on AUCτ,ss after administration of 5 mg
`linagliptin ...................................................................................................................... 40
`Table 11: Investigation of impact of combined covariates* on AUCτ,ss after administration of 5
`mg linagliptin ................................................................................................................ 40
`Table 12: Number of patients per study and dose group for investigated categories.................... 41
`Table 13: Comparison of single-dose and steady-state PK between Caucasian and African-
`American type 2 diabetic patients from trials 1218.3 and 1218.55, respectively ......... 48
`Table 14: Single-dose and steady-state PK for Chinese subjects (Trial 1218.58)......................... 48
`Table 15: Single-dose and steady-state PK for Japanese subjects (Trial 1218.12) ....................... 49
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`Table 16: Analysis of relative bioavailability of linagliptin after single and/or multiple oral
`administration of 5 mg linagliptin to renally impaired subjects or subjects with normal
`renal function ................................................................................................................ 51
`Table 17: Geometric mean (%gCV) steady state noncompartmental PK parameters of linagliptin
`after oral administration of multiple 5 mg doses........................................................... 52
`Table 18: Analysis of relative bioavailability of linagliptin after single and/or multiple oral
`administration of 5 mg linagliptin to subjects with hepatic impairment or normal
`healthy subjects ............................................................................................................. 54
`Table 19: Key pharmacokinetic parameters of linagliptin after single and/or multiple oral
`administration of 5 mg linagliptin to hepatically impaired subjects or subjects with
`normal hepatic function................................................................................................. 54
`Table 20: Linagliptin as substrate or inhibitor for transporters ..................................................... 57
`Table 21: Effect of linagliptin on co-administered drugs.............................................................. 57
`Table 22: Effect of co-administered drugs on linagliptin.............................................................. 58
`Table 23: Comparison of linagliptin PK parameter ratios (point estimator and 90% CI) from food
`interaction trials in healthy subjects (trials 1218.8, 1218.34) ....................................... 62
`Table 24: PK sampling time points in study 1218.2...................................................................... 71
`Table 25: PK sampling time points in study 1218.3...................................................................... 71
`Table 26: PK sampling time points in studies 1218.5 and 1218.6 ................................................ 72
`Table 27: Parameter estimates of the base PK model ................................................................... 73
`Table 28: Covariate influence on AUCτ,ss after administration of 5 mg linagliptin ...................... 75
`Table 29: Parameter estimates from the final population PK model............................................. 77
`Table 30: Analysis Data Sets......................................................................................................... 78
`Table 31: Investigation of impact of combined covariates on AUCτ,ss after administration of 5 mg
`linagliptin ...................................................................................................................... 81
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`List of Figures
`
`Figure 1: Forest plot demonstrating the effect of high-fat mean on linaglipitn PK .................... 8
`Figure 2: Forest plot demonstrating the effect of renal and hepatic impairment on linagliptin
`PK ................................................................................................................................ 9
`Figure 3: Forest plot demonstrating the effect of co-administered drugs on linagliptin PK ..... 10
`Figure 4: Forest plot demonstrating the effect of linagliptin on PK of co-administered drugs. 10
`Figure 5: Linagliptin chemical structure ................................................................................... 11
`Figure 6: Linagliptin mechanism of action ............................................................................... 12
`Figure 7: DPP-4 inhibition from baseline induced by linagliptin in the multiple rising dose
`Phase 1 study 1218.2 ................................................................................................. 14
`Figure 8: Adjusted mean (SE) for HbA1c change from baseline and change versus placebo
`after linagliptin (BI 1356) oral administration in the add-on to metformin Phase 2
`study 1218.6. **p<0.01, ***p<0.001 ........................................................................ 15
`Figure 9: Adjusted means (SE) for HbA1c change from baseline and HbA1c change versus
`placebo after oral administration of linagliptin or placebo in monotherapy for 12
`weeks in Phase 2 study 1218.5. **p<0.01 ................................................................. 15
`Figure 10: Adjusted means (SE) for HbA1c change from baseline and HbA1c change versus
`placebo after oral administration of linagliptin or placebo in monotherapy for 12
`weeks in Phase 3 study 1218.23 ................................................................................ 16
`Figure 11: Arithmetic mean (standard error SE) difference of GLP-1 plasma concentrations
`measured before and 30 min after an MTT on days -1 and 29 (24h after last study
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`drug intake) after multiple administration of linagliptin or placebo for 28 days in the
`Phase I study 1218.3 .................................................................................................. 17
`Figure 12: Arithmetic mean (SE) change from baseline of glucose AUEC0-2h after an oGTT at
`steady state (day 13, 24h after the last study drug intake) after oral administration of
`1 mg, 2.5 mg, 5 mg or 10 mg linagliptin or placebo for 12 days in the multiple rising
`dose Phase 1 study 1218.2 ......................................................................................... 17
`Figure 13: Exposure-Response Relationship Based on Simulated Exposures for Phase 2 trials
`1218.5 & 1218.6 ........................................................................................................ 20
`Figure 14: % incidence of selected adverse events across time and across dose based on analysis
`of pooled safety data from Phase 2 and Phase 3 clinical trials .................................. 21
`Figure 15: ADME of linagliptin.................................................................................................. 22
`Figure 16: Arithmetic mean drug plasma concentration-time profiles of linagliptin (BI 1356)
`after single oral administration of 2.5 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 400
`mg and 600 mg linagliptin (upper panel: linear scale, time axis reduced to the first 24
`h after drug administration; lower panel semi-logarithmic scale) ............................. 23
`Figure 17: Arithmetic mean plasma concentration-time profiles of linagliptin after intravenous
`infusion of 0.5-10 mg and oral administration of 10 mg linagliptin.......................... 25
`Figure 18: Arithmetic mean plasma concentration-time profiles of linagliptin and CD 1790 after
`intravenous infusion of 10 mg linagliptin.................................................................. 26
`Figure 19: Arithmetic mean drug plasma concentration-time profiles of linagliptin after oral
`administration of 1 mg, 2.5 mg, 5 mg or 10 mg linagliptin (BI 1356 BS) once daily
`for 12 days to patients with T2DM (semi-logarithmic scale) .................................... 28
`Figure 20: Arithmetic mean drug plasma concentration-time profiles of linagliptin (BI 1356 BS)
`after oral administration of 2.5, 5 and 10 mg linagliptin once daily for 28 days to
`patients with type 2 diabetes (semi-log scale) ........................................................... 29
`Figure 21: Box plots showing no difference in single-dose AUC0-24 and Cmax values between
`healthy volunteers and patients after administration of 5 mg linagliptin................... 30
`Figure 22: Box plots showing no difference in steady-state AUCτ,ss and Cmax,ss values between
`healthy volunteers and patients after administration of 5 mg linagliptin................... 31
`Figure 23: Concentration dependency of the plasma protein binding of [3H] linagliptin in human
`plasma including the plot of non-linear regression (formula given in the plot)......... 33
`Figure 24: Human metabolism pathways of [14C] linagliptin (BI 1356 BS) (rectangle) after
`intravenous and oral administration; Metabolites in excreta and plasma (circle)...... 35
`Figure 25: Dose normalized single-dose AUC and Cmax geometric mean values in therapeutic
`dose range of 1 mg to 10 mg measured in Caucasian healthy volunteers and patients
`................................................................................................................................... 37
`Figure 26: Dose normalized steady-state (multiple-dose) AUC and Cmax geometric mean values
`in therapeutic dose range of 1 mg to 10 mg measured in Caucasian healthy volunteers
`and patients ................................................................................................................ 37
`Figure 27: Dose normalized AUC values of linagliptin (BI 1356 BS) after single oral
`administration of doses ranging from 0.5 mg to 600 mg in single rising dose trial
`1218.1 ........................................................................................................................ 38
`Figure 28: Dose normalized AUC values of CD 1790 at steady-state after oral administration of
`doses ranging from 1 mg to 5 mg in dose proportionality trial 1218.33.................... 38
`Figure 29: Linagliptin (BI1356) plasma concentration versus time profile at steady state. Dark
`color circles - patients with a BMI greater than 35 kg/m2, light color circles - patients
`with a BMI equal or less than 35 kg/m2. Top: PK profiles of the 1218.5 study by dose
`group, Bottom: PK profiles of the 1218.6 study by dose group ................................ 41
`Figure 30: Linagliptin (BI1356) plasma concentration versus time profile at steady state. Dark
`color circles –patients older than 65 years, light color circles –patients equal and
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`younger than 65 years. Top: PK profiles of the 1218.5 study by dose group, Bottom:
`PK profiles of the 1218.6 study by dose group.......................................................... 42
`Figure 31: Linagliptin (BI1356) plasma concentration versus time profile at steady state. Dark
`color circles –females, light color circles –male subjects. Top: PK profiles of the
`1218.5 study by dose group, Bottom: PK profiles of the 1218.6 study by dose group
`................................................................................................................................... 43
`Figure 32: Steady-state linagliptin trough concentrations vs. covariates for 5 mg oral dose group.
`Horizontal box plot for gender shows the smallest observation, lower quartile,
`median, upper quartile, and largest observation. In scatter plots the solid straight line
`shows the median, the dotted straight lines are the median + and – 25 %. Gender: 0-
`male and 1-female...................................................................................................... 44
`Figure 33: Linagliptin Cmax at steady-state vs. covariates for 5 mg oral dose group. Horizontal
`box plot for gender shows the smallest observation, lower quartile, median, upper
`quartile, and largest observation. In scatter plots the solid straight line shows the
`median, the dotted straight lines are the median + and – 25 %. Gender: 0-male and 1-
`female. ....................................................................................................................... 45
`Figure 34: Impact of race on clearance in population PK analysis ............................................. 46
`Figure 35: Box-and whisker plot showing linagliptin trough concentrations and Cmax at steady-
`state vs. ethnicity for 5 mg oral dose group. Ethnic origin: 0-white, 1-black, 2-Asian,
`and 3-Hispanic ........................................................................................................... 47
`Figure 36: Steady-state AUC values of linagliptin (BI 1356) after oral administration of multiple
`5 mg doses to subjects with normal renal function, patients with mild or moderate
`renal impairment, patients with T2DM and severe renal impairment, and patients
`with T2DM and normal renal function ...................................................................... 50
`Figure 37: Scatter plot of CrCl (eCcr) and steady state AUCτ,ss of linagliptin after oral
`administration of multiple 5 mg doses to subjects with normal renal function, patients
`with mild or moderate renal impairment, patients with T2DM and severe renal
`impairment, and patients with T2DM and normal renal function.............................. 51
`Figure 38: Box plot for comparison of trough concentrations in type 2 diabetic patients from PK
`renal impairment study 1218.26 and safety and efficacy trial in patients with renal
`impairment 1218.43. The shaded area shows the median and inter-quartile range for
`trough concentrations from 10 mg dose in Phase 3 trial in Japanese patients (#
`1218.20) ..................................................................................................................... 53
`Figure 39: Structure of the base PK model ................................................................................. 72
`Figure 40: Basic goodness-of-fit plots for the base PK model.................................................... 73
`Figure 41: Basic goodness-of-fit plots for the final population PK model ................................. 76
`Figure 42: Sensitivity analysis on the final population PK model. Impact of modifications in
`model on (A) dose normalized AUC and (B) AUC................................................... 80
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`1 Executive Summary
`Boehringer Ingelheim Pharmaceuticals, Inc. has submitted NDA 201280 to seek a
`marketing approval for linagliptin. If approved, it will be the third in DPP-4 inhibitor
`class to be marketed in the USA. Two of the previous drugs, sitagliptin (Januvia, NDA
`21-995) and saxagliptin (Onglyza, NDA 22-350), were approved by the FDA in 2006 and
`2009, respectively.
`
`Linagliptin is intended to improve glycemic control in patients with type 2 diabetes
`mellitus (T2DM). The proposed indication is the use of linagliptin as an adjunct to diet
`and exercise to improve glycemic control in adult patients with T2DM. To support this
`indication, the sponsor has studied linagliptin as monotherapy and in combination therapy
`with metformin, sulfonylureas, and pioglitazone. The clinical program presented in this
`submission includes 24 Phase 1, 4 Phase 2, and 9 Phase 3 clinical trials.
`1.1 Recommendations
`The Office of Clinical Pharmacology/Division of Clinical Pharmacology-2
`(OCP/DCP-2) has reviewed NDA 201280 for linagliptin and finds it acceptable.
`
`1.2 Phase IV Commitments
`None
`
`1.3 Summary of Clinical Pharmacology and Biopharmaceutics
`Findings
`Dose-Response
`• Dose-response relationship demonstrated no additional reduction in HbA1c
`with increase in dose from 5 mg to 10 mg following co-administration with
`metformin in a 12-week therapy (Trial 1218.6).
`• Reduction in HbA1c for 2.5 and 5 mg dose was also comparable after 12-
`week monotherapy with linagliptin (Trial 1218.5)
`• 5 mg dose was more likely to achieve >80% inhibition of DPP-4 at steady-
`state compared to 2.5 mg dose.
`
`
`Exposure-Response
`• A relationship was established between linagliptin exposure and HbA1c
`response by using the predicted steady-state exposures for 1 to 10 mg
`linagliptin doses. Changes in HbA1c from baseline (∆HbA1c) increased with
`increasing exposure and reached plateau at exposures greater than
`approximately 100 nM⋅h.
`• Exposures for 5 mg dose covered the exposure resulting in maximum
`reduction in HbA1c.
`
`
`
`Pharmacodynamics
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`• The extent of dipeptidyl peptidase-4 (DPP-4) inhibition increased with
`increases in 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 (Trial 1218.2).
`• The concentrations of incretin hormone glucagon-like peptide 1 (GLP-1)
`increased by about 3-fold for linagliptin doses ranging from 2.5 to 10 mg
`compared to placebo (Trial 1218.3).
`
`
`Pharmacokinetics
`• Linagliptin followed 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