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Aims/hypothesis: Individuals carrying variants of the transcription factor 7-like 2 gene (TCF7L2) are at increased risk for type 2 diabetes. These metabolic genetic risk factors have been linked to diminished pancreatic islet-cell responsiveness to incretins, thus pharmacological interventions aimed at amplifying endogenous incretin biology may be affected. However, clinical evidence from randomised controlled trials so far is lacking. We investigated the influence of TCF7L2 risk alleles on the response to treatment with the dipeptidylpeptidase-4 (DPP-4) inhibitor linagliptin from four 24 week, phase III, placebo-controlled trials., Methods: Pharmacogenomic samples and clinical data were available from 961 patients with type 2 diabetes. Whole-blood DNA samples were genotyped for TCF7L2 single-nucleotide polymorphisms in conjunction with assessments of 24 week changes in HbA1c., Results: Linagliptin lowered HbA1c meaningfully in all three genotypes of rs7903146 (non-risk variant carriers CC [n = 356]: -0.82% [-9.0 mmol/mol], p < 0.0001; heterozygous CT [n = 264]: -0.77% [-8.4 mmol/mol], p < 0.0001; homozygous risk variant carriers TT [n = 73]: -0.57% [-6.2 mmol/mol], p < 0.0006). No significant treatment differences were seen between CC and CT patients, although HbA1c response was reduced in TT compared with CC patients (~0.26% [~2.8 mmol/mol], p = 0.0182)., Conclusions/interpretation: Linagliptin significantly improved hyperglycaemia in patients with type 2 diabetes both with and without the TCF7L2 gene diabetes risk alleles. However, differences in treatment response were observed, indicating that diabetes susceptibility genes may be an important contributor to the inter-individual variability of treatment response.

Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor with a primarily nonrenal route of excretion. Consequently, renal impairment should not substantially affect drug exposure. This analysis was undertaken to compare steady-state trough concentrations of linagliptin among patients with type-2 diabetes receiving linagliptin 5 mg in phase 3 studies. Data were pooled from 3 randomized studies from the global phase 3 program of linagliptin (5 mg daily in each) in patients with type-2 diabetes. These studies were selected for their inclusion of pharmacokinetic data. Linagliptin plasma concentrations were available for 969 patients who were determined by estimated glomerular filtration rate to have normal renal function (n = 438), mild renal impairment (RI) (n = 429), moderate RI (n = 44), or severe RI (n = 58). In patients with normal renal function, the geometric mean linagliptin trough concentration (coefficient of variation) was 5.93 nmol/L (56.3%); in patients with mild, moderate, or severe RI, geometric mean concentrations were 6.07 nmol/L (62.9%), 7.34 nmol/L (58.6%), and 8.13 nmol/L (49.8%), respectively. In patients with type-2 diabetes, RI had a minor effect on linagliptin exposure. Therefore, neither dose-adjustment nor drug-related monitoring of estimated glomerular filtration rate is necessary for patients with RI.

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., (© 2013 The Authors. British Journal of Clinical Pharmacology © 2013 The British Pharmacological Society.)

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 (C(max)) and area under the plasma concentration-time curve (AUC). Linagliptin is rapidly absorbed after oral administration, with C(max) occurring after approximately 90 minutes, and reaches steady-state concentrations within 4 days. With the therapeutic dose, steady-state C(max) (11-12 nmol/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 of cytochrome 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.

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., (© 2012 Boehringer Ingelheim. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.)

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.

Objective: The objective of this study was to determine the relative bioavailability of the dipeptidyl-peptidase-4 (DPP-4) inhibitor linagliptin when administered with and without food, in accordance with regulatory requirements to support dosing recommendations for patients., Methods: This was a randomized, open-label, crossover study involving 32 healthy white male and female subjects. All subjects received a single dose of 5 mg linagliptin after an overnight fast of at least 10 hours, or immediately after ingestion of a high-fat, high-calorie breakfast. These treatments were separated by a period of 5 weeks. Plasma samples for pharmacokinetic analysis were collected before dosing and at prespecified time points after dosing. The concentration of linagliptin in these samples was analyzed by high-performance liquid chromatography coupled to tandem mass spectrometry. Relative bioavailability was assessed by the total area under the curve between 0 and 72 hours (AUC(0-72)) and maximum measured plasma concentration (C(max)) of linagliptin. Tolerability was also assessed., Results: In 32 subjects (mean age, 34.8 years; weight, 74.3 kg; male, 53%; white race, 100%), intake of a high-fat meal resulted in comparable bioavailability with regard to AUC(0-72) (geometric mean ratio [GMR] between the fed and fasted group means was 103.5%; 90% CI, 98.1%-109.2%). Individuals' responses to food ranged from a maximum increase in exposure of 38% to a decrease of 32% relative to the fasted state. The concurrent intake of food increased the time to reach maximum plasma concentration (T(max)) by approximately 2 hours and reduced C(max) by about 15% (GMR 84.7%; 90% CI, 75.9%-94.6%). Since adequate drug exposure for inhibition of DPP-4 was still given for the entire 24-hour dosing interval, this result was considered to be of no clinical relevance. Linagliptin was well tolerated during the study., Conclusions: Intake of a high-fat meal reduced the rate of linagliptin absorption but had no influence on the extent of absorption; this finding suggests that food has no relevant influence on the efficacy of linagliptin., (Copyright © 2011 Elsevier HS Journals, Inc. All rights reserved.)

Background: Linagliptin is an oral dipeptidyl peptidase (DPP)-4 inhibitor that has been recently approved for the treatment of type 2 diabetes mellitus. Microgynon® 30 is a combined oral contraceptive pill containing both ethinylestradiol 30 μg and levonorgestrel 150 μg (EE 30 μg/LNG 150 μg)., Objective: The objective of this study was to determine the effect of multiple doses of linagliptin (5 mg once daily) on the steady-state pharmacokinetics of EE and LNG following once-daily doses of EE 30 μg/LNG 150 μg., Methods: This was an open-label, two-period, fixed-sequence, multiple-dose study, consisting of a run-in period, a 14-day reference treatment period and a 7-day test treatment period. The study recruited 18 healthy pre-menopausal female subjects aged 18-40 years with a body mass index of 18.5-27.0 kg/m2. Only women with regular menstrual cycles were included in this study. The treatment sequence was divided into three steps: an individually tailored run-in period with EE 30 μg/LNG 150 μg to synchronize the menstrual cycles of the subjects followed by a washout period of 7 days; the reference treatment period, during which EE 30 μg/LNG 150 μg alone was taken on days 1-14; and the test treatment period, during which EE 30 μg/LNG 150 μg plus linagliptin were taken on days 15-21. The pharmacokinetic parameters measured were maximum steady-state plasma concentration during a dosage interval (C(max,ss)), time to reach maximum plasma concentration following administration at steady state (t(max,ss)) and area under the plasma concentration-time curve during a dosage interval (τ) at steady state (AUC(τ,ss))., Results: The AUC(τ,ss) and C(max,ss) of EE and LNG were comparable when EE 30 μg/LNG 150 μg was given alone or combined with linagliptin. The adjusted geometric mean ratios for AUC(τ,ss) and C(max,ss) of EE following EE 30 μg/LNG 150 μg plus linagliptin versus EE 30 μg/LNG 150 μg alone were 101.4 (90% CI 97.2, 105.8) and 107.8 (90% CI 99.7, 116.6), respectively. The adjusted geometric mean ratios for AUC(τ,ss) and C(max,ss) of LNG following EE 30 μg/LNG 150 μg plus linagliptin versus EE 30 μg/LNG 150 μg alone were 108.8 (90% CI 104.5, 113.3) and 113.5 (90% CI 106.1, 121.3), respectively. The combination was well tolerated., Conclusion: Linagliptin had no clinically relevant effect on the steady-state pharmacokinetics of EE and LNG in healthy female subjects, and the combination of EE 30 μg/LNG 150 μg and linagliptin was well tolerated in this study. Therefore, linagliptin has the potential to be used in the treatment of female patients with type 2 diabetes in combination with oral contraceptives containing these components, such as EE 30 μg/LNG 150 μg., Trial Registration: The EudraCT number for this study is 2008-000953-37.

The aim of this study was to investigate the effect of the dipeptidyl peptidase-4 inhibitor linagliptin on the pharmacokinetics of glyburide (a CYP2C9 and CYP3A4 substrate) and vice versa. This randomized, open-label, three-period, two-way crossover study examined the effects of co-administration of multiple oral doses of linagliptin (5 mg/day × 6 days) and single doses of glyburide (1.75 mg/day × 1 day) on the relative bioavailability of either compound in healthy subjects (n = 20, age 18-55 years). Coadministration of glyburide did not alter the steady-state pharmacokinetics of linagliptin. Geometric mean ratios (GMRs) [90% CI] for (linagliptin + glyburide)/linagliptin AUC(τ,ss) and C(max,ss) were 101.7% [97.7-105.8%] and 100.8% [89.0-114.3%], respectively. For glyburide, there was a slight reduction in exposure of ∼14% when coadministered with linagliptin (GMRs [90% CI] for (glyburide + linagliptin)/glyburide AUC(0-∞) and C(max) were 85.7% [79.8-92.1%] and 86.2% [79.6-93.3%], respectively). However, this was not seen as clinically relevant due to the absence of a reliable dose-response relationship and the known large pharmacokinetic interindividual variability of glyburide. These results further support the assumption that linagliptin is not a clinically relevant inhibitor of CYP2C9 or CYP3A4 in vivo. Coadministration of linagliptin and glyburide had no clinically relevant effect on the pharmacokinetics of linagliptin or glyburide. Both agents were well tolerated and can be administered together without the need for dosage adjustments.

Background and Objectives: Linagliptin (BI 1356) is a highly specific inhibitor of dipeptidyl peptidase (DPP)-4, which is currently in phase III clinical development for the treatment of type 2 diabetes mellitus. Linagliptin exhibits nonlinear pharmacokinetics after oral administration, which are mainly related to concentration-dependent binding of linagliptin to its target, DPP-4. The objectives of the study were to investigate the pharmacokinetics and pharmacodynamics after intravenous administration of linagliptin and to determine its absolute bioavailability (F)., Subjects and Methods: This was a single rising-dose, randomized, four-group, placebo-controlled, single-blind (within dose groups) study. Thirty-six healthy men aged 18-50 years were enrolled and randomized into four sequential treatment groups. Group 1 received linagliptin 0.5 mg intravenously, group 2 received 2.5 mg intravenously and group 4 received 10 mg intravenously. In group 3, subjects underwent a two-way randomized crossover, receiving 5 mg intravenously and a 10 mg oral tablet. Linagliptin concentrations in plasma and urine, as well as plasma DPP-4 activity, were determined by validated assays. Noncompartmental analysis and population pharmacokinetic modelling were performed., Results: Linagliptin showed nonlinear pharmacokinetics after intravenous infusion of 0.5-10 mg, with a less than dose-proportional increase in exposure. Noncompartmental parameters were calculated on the basis of total (i.e. bound and unbound) plasma concentrations. The total clearance value was low and increased with dose from 2.51 to 14.3 L/h. The apparent steady-state volume of distribution (V(ss)) increased with dose from 380 to 1540 L. Renal excretion of the unchanged parent compound increased with increasing plasma concentrations from 2.72% in the 0.5 mg dose group to 23.0% in the 10 mg dose group. The terminal elimination half-life was comparable across dose groups (126-139 hours). Because of the nonlinear pharmacokinetics, the standard approach of comparing the area under the plasma concentration-time curve (AUC) after oral administration with the AUC after intravenous administration led to dose-dependent estimates of the absolute bioavailability. Therefore, a population pharmacokinetic model was developed, accounting for the concentration-dependent protein binding of linagliptin to its target enzyme, DPP-4. The model-derived estimates of the V(ss) and clearance of linagliptin not bound to DPP-4 were 402.2 L and 26.9 L/h, respectively. The absolute bioavailability was estimated to be about 30% for the linagliptin 10 mg tablet., Conclusion: The nonlinear pharmacokinetic characteristics and the pharmacokinetic/pharmacodynamic relationship of linagliptin were independent of the mode of administration (intravenous or oral). Because of the nonlinear pharmacokinetics, the standard approach of comparing the AUC after oral administration with the AUC after intravenous administration was inappropriate to determine the absolute bioavailability of linagliptin. By a modelling approach, the absolute bioavailability of the 10 mg linagliptin tablet was estimated to be about 30%.

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 (approximatelly 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.