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Aims/Introduction The efficacy and safety of drugs can vary between different races or ethnic populations because of differences in the relationship of dose to exposure, pharmacodynamic response or clinical efficacy and safety. In the present post-hoc analysis, we assessed the influence of race on the pharmacokinetics, pharmacodynamics, efficacy and safety of monotherapy with the dipeptidyl peptidase-4 inhibitor, linagliptin, in patients with type 2 diabetes enrolled in two comparable, previously reported randomized phase III trials. Materials and Methods Study 1 (with a 12-week placebo-controlled phase) recruited Japanese patients only (linagliptin, n = 159; placebo, n = 80); study 2 (24-week trial) enrolled Asian (non-Japanese; linagliptin, n = 156; placebo, n = 76) and white patients (linagliptin, n = 180; placebo, n = 90). Results Linagliptin trough concentrations were equivalent across study and race groups, and were higher than half-maximal inhibitory concentration, resulting in dipeptidyl peptidase-4 inhibition >80% at trough. Linagliptin inhibited plasma dipeptidyl peptidase-4 activity to a similar degree in study 1 and study 2. Linagliptin reduced fasting plasma glucose concentrations by a similar magnitude across groups, leading to clinically relevant reductions in glycated hemoglobin in all groups. Glycated hemoglobin levels decreased to a slightly greater extent in study 1 (Japanese) and in Asian (non-Japanese) patients from study 2. Linagliptin had a favorable safety profile in each race group. Conclusions Trough exposure, pharmacodynamic response, and efficacy and safety of linagliptin monotherapy were comparable among Japanese, Asian (non-Japanese) and white patients, confirming that the recommended 5-mg once-daily dose of linagliptin is appropriate for use among different race groups. [ABSTRACT FROM AUTHOR]

Background and Objectives: Linagliptin is a dipeptidyl peptidase (DPP)-4 inhibitor, used to treat type 2 diabetes mellitus (T2DM). Population pharmacokinetic and pharmacodynamic analyses were performed to characterize the impact of clinically relevant intrinsic/extrinsic factors (covariates) on linagliptin exposure and DPP-4 inhibition in patients with T2DM. Methods: Linagliptin plasma concentrations and DPP-4 activities were obtained from four studies (two phase 1, two phase 2b). Non-linear mixed-effects modelling techniques were implemented using NONMEM software. The covariates that were studied comprised demographic information and laboratory values, including liver enzyme levels and creatinine clearance, as well as study-related factors such as metformin co-treatment. Covariate effects on parameters describing the pharmacokinetics and pharmacokinetic/pharmacodynamic relationship were investigated using stepwise forward inclusion/backward elimination. Results: The pharmacokinetic analysis included 6,907 measurements of plasma linagliptin concentrations from 462 patients; the pharmacokinetic/pharmacodynamic analysis included 9,674 measurements of plasma DPP-4 activity and linagliptin plasma concentrations from 607 patients. The non-linear pharmacokinetics were described by a target-mediated drug disposition model accounting for the concentration-dependent binding of linagliptin to its target, DPP-4. The difference in exposure between the 5th and 95th percentiles of the covariate distributions and median was <20 % for each single covariate. Likewise, the impact of the covariates on both the half-maximum effect (EC) and the concentration leading to 80 % DPP-4 inhibition was <20 %. Conclusion: These analyses show that the investigated factors do not alter the pharmacokinetics and DPP-4 inhibitory activity of linagliptin to a clinically relevant extent and that dose adjustment is not necessary on the basis of factors including age, sex and weight. [ABSTRACT FROM AUTHOR]

Aim This was an open label, multicentre phase I trial to study the pharmacokinetics and pharmacodynamics of the dipeptidyl peptidase-4 ( DPP-4) inhibitor linagliptin in African American patients with type 2 diabetes mellitus ( T2DM). Methods Forty-one African American patients with T2DM were included in this study. Patients were admitted to a study clinic and administered 5 mg linagliptin once daily for 7 days, followed by 7 days of outpatient evaluation. Results Primary endpoints were area under the plasma concentration-time curve ( AUC), maximum plasma concentration ( Cmax) and plasma DPP-4 trough inhibition at steady-state. Linagliptin geometric mean AUC was 194 nmol l−1 h (geometric coefficient of variation, 26%), with a Cmax of 16.4 nmol l−1 (41%). Urinary excretion was low (0.5% and 4.4% of the dose excreted over 24 h, days 1 and 7). The geometric mean DPP-4 inhibition at steady-state was 84.2% at trough and 91.9% at maximum. The exposure range and overall pharmacokinetic/pharmacodynamic profile of linagliptin in this study of African Americans with T2DM was comparable with that in other populations. Laboratory data, vital signs and physical examinations did not show any relevant findings. No safety concerns were identified. Conclusions The results of this study in African American patients with T2DM support the use of the standard 5 mg dose recommended in all populations. [ABSTRACT FROM AUTHOR]

Linagliptin is an orally active small-molecule inhibitor of dipeptidyl peptidase (DPP)-4, which was first licensed in the US, Europe, Japan and other territories in 2011 to improve glycaemic control in adults with type 2 diabetes mellitus. Linagliptin is the first and thus far the only DPP-4 inhibitor, and oral antihyperglycaemic drug in general, to be approved as a single-strength once-daily dose (5 mg). Compared with other available DPP-4 inhibitors, linagliptin has a unique pharmacokinetic/pharmacodynamic profile that is characterized by target-mediated nonlinear pharmacokinetics, concentration-dependent protein binding, minimal renal clearance and no requirements for dose adjustment for any intrinsic or extrinsic factor. After single or multiple oral doses of 1-10 mg, linagliptin displays less than dose-proportional increases in maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC). Linagliptin is rapidly absorbed after oral administration, with Cmax occurring after approximately 90 minutes, and reaches steady-state concentrations within 4 days. With the therapeutic dose, steady-state Cmax (11-12nmol/L) and AUC (~150 nmol⋅h/L) are approximately 1.3-fold greater than after a single dose, indicating little drug accumulation with repeat dosing. Linagliptin exhibits concentration-dependent protein binding in human plasma in vitro (99% at 1 nmol/L to 75-89% at >30 nmol/L) and has a large apparent volume of distribution, demonstrating extensive distribution into tissues. The nonlinear pharmacokinetics of linagliptin are best described by a two-compartmental model that incorporates target-mediated drug disposition resulting from high-affinity, saturable binding to DPP-4. The oral bioavailability of linagliptin estimated with this model is approximately 30%. Linagliptin has a long terminal half-life (>100 hours); however, its accumulation half-life is much shorter (approximately 10 hours), accounting for the rapid attainment of steady state. The majority of linagliptin is eliminated as parent compound, demonstrating that metabolism plays a minor role in the overall pharmacokinetics in humans. The main, pharmacologically inactive S-3-hydroxypiperidinyl metabolite accounted for approximately 17% of the total drug-related compounds in plasma. Linagliptin is eliminated primarily in faeces, with only around 5% of the oral therapeutic dose excreted in the urine at steady state. Linagliptin potently inhibits DPP-4 (inhibition constant 1 nmol/L), and trough drug concentrations achieved with therapeutic dosing inhibit >80% of plasma DPP-4 activity, the threshold associated with maximal antihyperglycaemic effects in animal models. There are no clinically relevant alterations in linagliptin pharmacokinetics resulting from renal impairment, hepatic impairment, coadministration with food, race, body weight, sex or age. In vitro, linagliptin is a weak substrate and weak inhibitor ofcytochrome P450 (CYP) 3A4 and permeability glycoprotein (P-gp) but not of other CYP isozymes or ATP-binding cassette transporters. Clinical studies have revealed no relevant drug interactions when coadministered with other drugs commonly prescribed to patients with type 2 diabetes, including the narrow therapeutic index drugs warfarin and digoxin. Linagliptin plasma exposure is reduced by potent inducers of CYP3A4 or P-gp. Linagliptin has demonstrated a large safety window (>100-fold the recommended daily dose) and clinically relevant antihyperglycaemic effects in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of the novel dipeptidyl-peptidase 4 (DPP-4) inhibitor linagliptin is nonlinear. Based on in vitro experiments, concentration-dependent binding to DPP-4 is the most likely cause for the nonlinearity. Population pharmacokinetic/pharmacodynamic modeling was performed using linagliptin plasma concentrations and plasma DPP-4 activities from 2 phase 2a studies. In these studies, type 2 diabetic patients received either 1, 2.5, 5, or 10 mg of linagliptin once daily over 12 days (study 1) or 2.5, 5, or 10 mg of linagliptin once daily over 28 days (study 2). The modeling results supported the hypothesis that linagliptin exhibits target-mediated drug disposition. The linagliptin plasma concentrations were best described by a 2-compartment model including concentration-dependent protein binding in the central and peripheral compartment. The plasma DPP-4 activity was included in the model in a semi-mechanistic way by relating it to the model-calculated plasma DPP-4 occupancy with linagliptin. The target binding has a major impact on linagliptin pharmacokinetics. Although unbound linagliptin is cleared efficiently (CL/F 220 L/h), the concentration dependent binding is responsible for the long terminal half-life (~120 hours) of linagliptin and its nonlinear pharmacokinetics. The model allowed a comprehensive understanding of the impact of target-mediated drug disposition and provides a useful tool to support clinical development. [ABSTRACT FROM AUTHOR]

BI 1356 is a novel, potent, and selective DPP-IV inhibitor currently in development for type 2 diabetes. The safety, pharmacokinetics, and pharmacodynamic properties of BI 1356 were investigated in a randomised, double-blind, placebo-controlled study in patients with type 2 diabetes. Forty-seven male type 2 diabetic patients, aged 21-65 and with a BMI of 18-35 kg/m², were treated once daily with 1, 2.5, 5, or 10 mg BI 1356, or placebo for 12 days. Treatment with BI 1356 was well tolerated. The incidence of adverse events in patients treated with BI 1356 (54%) was not higher when compared to placebo (75%). There were no serious adverse events and no episodes of hypoglycaemia. BI 1356 plasma concentrations and exposure increased less than proportionally with dose. The maximum plasma concentrations of BI 1356 at steady-state ranged from 4.5 nmol/L (1 mg dose group) to 13.6 nmol/L (10 mg), with a median t[sub max] of 1.5 h. Reductions in plasma DPP-IV activity were well correlated with plasma concentrations of BI 1356. Two hours after administration of 2.5 mg BI 1356, DPP-IV activity was reduced by >80% and remained at that level at steady-state. Levels of GLP-1 were increased by more than 2-fold. Following an oGTT on day 13, 24 h after the last dose of BI 1356, area under the plasma glucose excursions were reduced by 53 (1 mg BI 1356), 106 (2.5 mg), 82 (5 mg), 111 (10 mg), and 25 (placebo) mg.h/dL, respectively. Despite the small group sizes, these reductions reached statistical significance for 2.5, 5, and 10 mg BI 1356 compared to baseline and compared to placebo (p<0.05 for both). In summary, 24 h after the last dose, DPP-IV inhibition was >70% after administration of BI 1356 doses of > 1 mg, and significant improvements in glucose parameters were observed in patients with type 2 diabetes. Given this potency and duration of action, BI 1356 has the potential to be a best in class DPP-IV inhibitor. [ABSTRACT FROM AUTHOR]