Silke Retlich
Boehringer Ingelheim
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Diabetes, Obesity and Metabolism | 2011
Ulrike Graefe-Mody; Christian Friedrich; Andreas Port; Arne Ring; Silke Retlich; T. Heise; A. Halabi; Hj Woerle
Aim: This study assessed the influence of various degrees of renal impairment on the exposure of linagliptin, a dipeptidyl peptidase‐4 (DPP‐4) inhibitor with a primarily non‐renal route of excretion, in subjects with type 2 diabetes mellitus (T2DM).
Clinical Pharmacokinectics | 2012
Ulrike Graefe-Mody; Silke Retlich; Christian Friedrich
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 anti-hyperglycaemic 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 (∼150nmol · 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 impair-ment, hepatic impairment, coadministration with food, race, body weight, sex or age. In vitro, linagliptin is a weak substrate and weak inhibitor of cytochrome P450 (CYP) 3 A4 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.
British Journal of Clinical Pharmacology | 2012
Ulrike Graefe-Mody; Peter Rose; Silke Retlich; Arne Ring; Lisa Waldhauser; Rodica Cinca; Hans-Juergen Woerle
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Linagliptin is an oral, highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor that was approved in the United States, Europe and elsewhere in 2011 for the treatment of type 2 diabetes mellitus. • The elimination of linagliptin is primarily non-renal. Therefore, a potential effect of hepatic impairment on the elimination of linagliptin may have important implications for dosing recommendations. WHAT THIS STUDY ADDS • This study shows that mild, moderate or severe hepatic impairment did not result in an increase in linagliptin exposure after single and multiple dosing as compared with normal hepatic function. • No linagliptin dose adjustment is required in patients with any degree of hepatic impairment. AIM To investigate whether hepatic impairment affects linagliptin pharmacokinetics, pharmacodynamics and tolerability. METHOD This open label, parallel group, single centre study enrolled patients with mild (n= 8), moderate (n= 9) or severe (n= 8) hepatic impairment and healthy subjects (n= 8). Groups were matched with regard to age, weight and gender. Primary endpoints were linagliptin exposure following 5 mg linagliptin once daily for 7 days in patients with mild and moderate hepatic impairment vs. healthy subjects or after a single 5 mg dose for patients with severe hepatic impairment vs. healthy subjects. RESULTS In mild hepatic impairment, steady-state linagliptin exposure was slightly lower than in healthy subjects [AUC(τ,ss) geometric mean ratio (GMR) 75.5%, 90% confidence interval (CI) 61.6%, 92.5%, and C(max,ss) GMR 64.4%, 90% CI 43.2%, 96.0%]. Exposure also tended to be lower in moderate hepatic impairment (AUC(τ,ss) GMR 85.5%, 90% CI 70.2%, 104.2% and C(max,ss) GMR 92.3%, 90% CI 62.8%, 135.6%). After a single dose, AUC(0,24 h) in patients with severe hepatic impairment was similar to that in healthy subjects (GMR 100.4%, 90% CI 75.0%, 134.3%) and C(max) was lower (GMR 77.0%, 90% CI 44.9%, 132.3%). Accumulation based on AUC or C(max) and renal excretion of unchanged linagliptin (≤ 7%) were comparable across groups. Median plasma DPP-4 inhibition was similar in healthy subjects (91%), and patients with mild (90%) and moderate (89%) hepatic impairment at steady-state trough concentrations, and in patients with severe hepatic impairment 24 h after a single dose (84%). Linagliptin was well tolerated. CONCLUSION Mild, moderate or severe hepatic impairment did not result in an increase in linagliptin exposure after single and multiple dosing compared with normal hepatic function. Dose adjustment with linagliptin is not required in patients with hepatic impairment.
BMJ Open | 2013
Jorge Luiz Gross; James Rogers; Daniel Polhamus; William R. Gillespie; Christian Friedrich; Yan Gong; Brigitta U. Monz; Sanjay Patel; Alexander Staab; Silke Retlich
Objectives To develop a longitudinal statistical model to indirectly estimate the comparative efficacies of two drugs, using model-based meta-analysis (MBMA). Comparison of two oral dipeptidyl peptidase (DPP)-4 inhibitors, sitagliptin and linagliptin, for type 2 diabetes mellitus (T2DM) treatment was used as an example. Design Systematic review with MBMA. Data sources MEDLINE, EMBASE, http://www.ClinicalTrials.gov, Cochrane review of DPP-4 inhibitors for T2DM, sitagliptin trials on Food and Drug Administration website to December 2011 and linagliptin data from the manufacturer. Eligibility criteria for selecting studies Double-blind, randomised controlled clinical trials, ≥12 weeks’ duration, that analysed sitagliptin or linagliptin efficacies as changes in glycated haemoglobin (HbA1c) levels, in adults with T2DM and HbA1c >7%, irrespective of background medication. Model development and application A Bayesian model was fitted (Markov Chain Monte Carlo method). The final model described HbA1c levels as function of time, dose, baseline HbA1c, washout status/duration and ethnicity. Other covariates showed no major impact on model parameters and were not included. For the indirect comparison, a population of 1000 patients was simulated from the model with a racial composition reflecting the average racial distribution of the linagliptin trials, and baseline HbA1c of 8%. Results The model was developed using longitudinal data from 11 234 patients (10 linagliptin, 15 sitagliptin trials), and assessed by internal evaluation techniques, demonstrating that the model adequately described the observations. Simulations showed both linagliptin 5 mg and sitagliptin 100 mg reduced HbA1c by 0.81% (placebo-adjusted) at week 24. Credible intervals for participants without washout were −0.88 to −0.75 (linagliptin) and −0.89 to −0.73 (sitagliptin), and for those with washout, −0.91 to −0.76 (linagliptin) and −0.91 to −0.75 (sitagliptin). Conclusions This study demonstrates the use of longitudinal MBMA in the field of diabetes treatment. Based on an example evaluating HbA1c reduction with linagliptin versus sitagliptin, the model used seems a valid approach for indirect drug comparisons.
British Journal of Clinical Pharmacology | 2013
Christian Friedrich; Stephan Glund; Dominick A Lionetti; C. James Kissling; Julian Righetti; Sanjay Patel; Ulrike Graefe-Mody; Silke Retlich; Hans-Juergen Woerle
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.
Journal of Pharmacy and Pharmaceutical Sciences | 2013
Yusuke Tadayasu; Akiko Sarashina; Yasuhiro Tsuda; Shinji Tatami; Christian Friedrich; Silke Retlich; Alexander Staab; Mikihisa Takano
OBJECTIVES Linagliptin is a novel, highly selective and long acting DPP-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM). Linagliptin exhibits non-linear pharmacokinetics (PK) due to saturable binding to plasma and tissue DPP-4. The aim of this study was to characterize the PK and PK/DPP-4 inhibition relationship of linagliptin in Japanese patients with T2DM using a population PK/DPP-4 model and to support the rationale for the therapeutic dose in Japanese patients by simulation. METHODS Linagliptin plasma concentration and DPP-4 inhibition measurements from a placebo-controlled, parallel group multiple (28 days) dose trial that included 36 T2DM patients (18 patients each in 2.5 mg and 10 mg dose group) were used for analysis. Modeling was performed using FOCE INTERACTION estimation method implemented in NONMEM V. The linagliptin plasma concentration- and DPP-4 inhibition- time profiles were simulated for Japanese patients receiving 5 mg linagliptin once daily by the model established. RESULTS Nonlinear PK of linagliptin in T2DM patients were well described by a 2-compartment model assuming concentration-dependent binding to DPP-4 in the central and peripheral compartment. Plasma DPP-4 inhibition was integrated in the model by relating the model-predicted DPP-4 occupancy with linagliptin linearly to DPP-4 inhibition. The simulation predicted that for the 5 mg dose group the trough DPP-4 inhibition at steady-state was 84.2%, which is higher than the target inhibition (≥80%) for an effective dose of DPP-4 inhibitor. In 2.5 mg dose group, steady-state DPP-4 inhibition of >80% was not maintained over 24 hours (observed and simulated). CONCLUSIONS The nonlinear PK of linagliptin and its plasma DPP-4 inhibition in patients were well characterized by a target-mediated drug disposition model relating DPP-4 occupancy with linagliptin to DPP-4 inhibition. Simulations of plasma DPP-4 inhibition suggest that 5 mg linagliptin once daily is an appropriate therapeutic dose for Japanese patients with T2DM.
Drug Research | 2013
Christian Friedrich; Arvid Jungnik; Silke Retlich; Arne Ring; T. Meinicke
Linagliptin is an oral antihyperglycemic drug that acts by inhibiting the dipeptidyl peptidase-4 enzyme. A 5-mg once-daily regimen is available, but an alternative regimen was needed for twice-daily fixed-dose combinations. Although linagliptin has non-linear pharmacokinetics, simulation suggested 2.5 mg twice-daily would provide bioequivalent exposure and comparable plasma dipeptidyl peptidase-4 inhibition to 5 mg once-daily.This crossover study compared steady-state pharmacokinetics and pharmacodynamics of linagliptin 5 mg once-daily and 2.5 mg twice-daily, both administered for 7 days.In total, 16 healthy volunteers entered the study, and 15 completed both treatment periods. Exposure over 24-h at steady state (AUC0-24,ss) was similar for linagliptin 5 mg once-daily and 2.5 mg twice-daily (132 vs. 124 nmol · h/L), and the 90% confidence interval of the adjusted geometric mean ratio of AUC0-24,ss was well within the acceptance range for bioequivalence (ratio 93.9%; 90% confidence interval 89.5, 98.5). Median dipeptidyl peptidase-4 inhibition over a 24-h interval at steady state was 85.9% with linagliptin 5 mg once-daily and 86.5% with 2.5 mg twice-daily, and median dipeptidyl peptidase-4 inhibition values were approximately 80.0% at trough. Most subjects had no adverse events and there were no serious adverse events.Linagliptin 5 mg once-daily and 2.5 mg twice-daily provided bioequivalent exposure and similar inhibition of dipeptidyl peptidase-4 over the whole dosing interval.
Diabetes, Obesity and Metabolism | 2016
J. Mondick; M. Riggs; T. Sasaki; Akiko Sarashina; Uli C. Broedl; Silke Retlich
To quantify the effect of the sodium‐glucose co‐transporter 2 inhibitor, empagliflozin, on renal glucose reabsorption in patients with type 2 diabetes, and to evaluate covariate effects, using a mechanistic population pharmacokinetic–pharmacodynamic (PK–PD) model.
principles and practice of constraint programming | 2012
Sasiporn Wright; Silke Retlich; Ulrike Graefe-Mody; Hartmut Derendorf
OBJECTIVES Linagliptin (BI 1356) is a dipeptidyl peptidase-4 (DPP-4) inhibitor for treatment of Type 2 diabetes which recently gained approval in the US, Europe, and Japan. Linagliptin showed nonlinear pharmacokinetics after intravenous and oral administration, which is due to a concentration-dependent protein binding of linagliptin to its target enzyme DPP-4. The aim of this analysis was to investigate this target-mediated binding of linagliptin and its implication on efficacy and safety. METHODS Pharmacokinetic modeling and simulations were performed using a two-compartment model with concentration-dependent binding in the central and in one peripheral compartment. The optimum therapeutic dose with minimal off-target side effects was simulated assuming that an antidiabetic effect of linagliptin was due to the linagliptin concentration bound to DPP-4 and that off-target side effects were related to free linagliptin. RESULTS The difference between steady state AUCs of specifically bound and free linagliptin was maximized at oral doses of 2 - 5 mg. Since plasma DPP-4 inhibition increased slightly from 2.5 to 10 mg, pharmacokinetic simulations and the pharmacodynamic measurements taken together suggest that 5 mg linagliptin could be considered an optimum dose. Simulations with missed doses and additional doses at steady state showed the effect on DPP-4 bound linagliptin and change in DPP-4 inhibition was minimal after missing one 5 mg oral dose of linagliptin while two doses of 5 mg linagliptin resulted in a less than proportional increase of steady state AUC of free linagliptin. CONCLUSIONS Results from modeling and simulation support a stable antidiabetic effect of linagliptin over 24 h at steady state and further indicate a low risk for off-target side effects.
Pediatric Diabetes | 2018
William V. Tamborlane; Lori Laffel; Jacques Weill; Maud Gordat; Dietmar Neubacher; Silke Retlich; Willem Hettema; Cornelia E Hoesl; Stefan Kaspers; Jan Marquard
To identify the dose of the dipeptidyl peptidase‐4 (DPP‐4) inhibitor linagliptin in pediatric patients with type 2 diabetes (T2D).