Aims: To investigate the safety, tolerability, pharmacokinetic and pharmacodynamic properties of multiple oral doses of the dipeptidyl peptidase‐4 (DPP‐4) inhibitor linagliptin (BI 1356) in patients ...with type 2 diabetes mellitus.
Methods: Forty‐seven male type 2 diabetic patients received linagliptin 1, 2.5, 5 or 10 mg, or placebo, once daily for 12 days.
Results: Linagliptin exposure area under the plasma concentration–time curve and maximum plasma concentration (Cmax) increased less than proportionally with dose. Accumulation half‐life was short (8.6–23.9 h), resulting in rapid attainment of steady state (2–5 days) and little accumulation (range: 1.18–2.03). The long terminal half‐life (113–131 h) led to a sustained inhibition of DPP‐4 activity. Renal excretion was below 1% on day 1 in all dose groups. Inhibition of plasma DPP‐4 activity correlated well with linagliptin plasma concentrations, resulting in DPP‐4 inhibition >90% in the two highest dose groups; even 24 h postdose, DPP‐4 inhibition was >80%. Following an oral glucose tolerance test, 24 h after the last dose, statistically significant reductions of glucose excursions were observed with linagliptin (2.5, 5 and 10 mg doses) compared with placebo. Linagliptin was well tolerated. The frequency of adverse events (AEs) was not higher with linagliptin (54%) than with placebo (75%). No serious AEs and no episodes of hypoglycaemia were reported.
Conclusions: In type 2 diabetic patients, multiple rising doses of linagliptin were well tolerated and resulted in significant improvements of glucose parameters. Together with the favourable pharmacokinetics, these results confirm the unique profile of linagliptin in the DPP‐4 inhibitor class.
This randomized, double‐blind, parallel, placebo‐controlled, single rising‐dose study investigated the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of BI 1356 (once‐daily, ...given orally) in healthy men. BI 1356 was well tolerated and safe up to and including a dose of 600 mg. The incidence of drug‐related adverse events was equal in subjects receiving BI 1356 (30%) or placebo (31%). No clinically relevant deviations in laboratory or ECG parameters were reported. Exposure of BI 1356 increased less than proportionally from 2.5 mg to 5 mg, more than proportionally from 25 mg to 100 mg and approximately proportionally for doses from 100 mg to 600 mg. The geometric mean terminal half‐life was up to 184 hours. Renal excretion was low. All doses of BI 1356 inhibited plasma dipeptidyl peptidase 4 activity. Single doses of 2.5 mg and 5 mg inhibited dipeptidyl peptidase 4 activity by 72.7% and 86.1% from baseline, respectively. The time to achieve maximum inhibition shifted with increasing doses from 3 hours (2.5 mg) to <0.7 hours (≥200 mg). Within the dose range tested, a direct pharmacokinetic/pharmacodynamic relationship was observed. The pharmacokinetic and pharmacodynamic profile results demonstrate the potency and full 24‐hour duration of action of BI 1356. Based on an estimated therapeutic dose of 5 mg, the therapeutic window of BI 1356 is expected to be >100‐fold.
ABSTRACT
Objective: Linagliptin (BI 1356) is a novel, orally available inhibitor of dipeptidyl peptidase-4 (DPP-4). Linagliptin improves glycaemic control in type 2 diabetic patients by increasing ...the half-life of the incretin hormone glucagon-like peptide-1 (GLP-1). Linagliptin is expected to be used as monotherapy or in combination with other antihyperglycaemic agents. This study was conducted to investigate potential pharmacokinetic or pharmacodynamic interactions between linagliptin and metformin.
Methods: This randomised, monocentric, open-label, two-way crossover design study was conducted in 16 healthy male subjects. Linagliptin (10 mg/day) and metformin (850 mg three times daily) were each administered alone and concomitantly. The steady-state pharmacokinetics of linagliptin and metformin and the inhibition of DPP-4 activity were determined at the end of each dosing period.
Results: Co-administration of linagliptin had no apparent effect on metformin exposure (metformin AUCτ,ss; geometric mean ratio GMR co-administration:individual administration was 1.01; 90% confidence interval CI was 0.89-1.14). Effects on maximum concentration (Cmax,ss) were small (GMR: 0.89; 90% CI: 0.78-1.00). Co-administration of metformin did not significantly affect Cmax,ss of linagliptin (GMR: 1.03; 90% CI: 0.86-1.24), but increased AUCτ,ss by 20% (GMR: 1.20; 90% CI: 1.07-1.34). Metformin alone had no effect on DPP-4 activity, and the inhibition of DPP-4 caused by linagliptin was not affected by concomitant administration of metformin. Tolerability was good whether linagliptin and metformin were administered alone or concomitantly. No serious adverse events occurred and the frequency of adverse events was low; 7 events in 6 subjects. The most frequent events were related to the gastrointestinal tract, as expected with metformin. Importantly, no subjects experienced signs or symptoms relating to episodes of hypoglycaemia.
Conclusion: In this small, multiple dose study carried out in healthy subjects, co-administration of linagliptin with metformin did not have a clinically relevant effect on the pharmacokinetics or pharmacodynamics of either agent. This study suggests linagliptin and metformin can safely be administered concomitantly in type 2 diabetes patients without dose adjustment; larger, longer-term clinical trials in diabetic patients are underway.
Co-administration of the dipeptidyl peptidase-4 inhibitor linagliptin (BI 1356) with pioglitazone may improve glycemic control in patients with Type 2 diabetes due to their complementary mechanisms ...of action. This study aimed to investigate any potential pharmacokinetic interaction between linagliptin and pioglitazone, a CYP 2C8 substrate.
20 (10 male and 10 female) healthy subjects, between 22 and 65 years of age with a BMI range of > = 18.5 and < =29.9 kg/m2, took part in this single center open-label, randomized,two-way cross-over study. The subjects were administered linagliptin 10 mg/day and/orpioglitazone 45 mg/day until steady state was reached.
Co-administration of pioglitazone did not significantly affect linagliptin Cmax,ss (geometric mean ratio(GMR) 107.3; 90% confidence interval (CI);92.3 – 124.8) or AUC tau,ss (GMR 113.4; 90%CI 103.0 – 124.9). Co-administration of linagliptin did not significantly affect pioglitazoneAU tau,ss (GMR 94.4; 90% CI 87.1 –102.2), but reduced Cmax,ss by 14% (GMR85.6; 90% CI 78.1 – 93.8). As expected, linagliptin and pioglitazone were well tolerated,whether administered alone or concomitantly.There were no reported serious adverse events. The investigator defined 5 adverse events as drug-related with linagliptin,and 4 with pioglitazone.
Linagliptinand pioglitazone have no clinically relevant pharmacokinetic interaction and may be co-administered without dose adjustment.These data further confirm that linagliptin is not an inhibitor of CYP2C8 in vivo.As the pharmacokinetic profiles of linagliptin and pioglitazone are similar in Type 2 diabetes patients and healthy subjects, it is reasonable to assume that they may be administered together to Type 2 diabetes patients without dose adjustment.
The aim of this study was to investigate whether multiple doses of the oral and highly selective dipeptidyl peptidase-4 inhibitor linagliptin affect the steady-state pharmacokinetics of the ...P-glycoprotein substrate digoxin. This single-center, open-label, two-period cross-over study involved healthy subjects (
n
= 20), randomized to treatment sequence AB or BA, where A comprised 0.25 mg digoxin qd for 5 days, then 0.25 mg digoxin qd plus 5 mg linagliptin qd for 6 days, and B comprised 0.25 mg digoxin qd for 11 days. A treatment-free period (≥35 days for AB and 14 days for BA) separated each treatment in both sequences. There were no clinically significant changes in steady-state pharmacokinetic parameters of digoxin when it was co-administered with linagliptin. The ratio of the adjusted-by-treatment geometric mean ratios and associated 90% confidence intervals for the AUC
τ,ss
,
C
max,ss
and renal clearance (CL
R
,0
–
24,ss
) of digoxin were all within the bioequivalence range 80–125%, which is important as digoxin has a narrow therapeutic range. There was a low incidence of adverse events, which were randomly distributed between treatment groups. In conclusion, linagliptin did not alter the pharmacokinetics of digoxin in this study, indicating that linagliptin does not inhibit P-glycoprotein or other transporters relevant for digoxin pharmacokinetics. These results suggest that linagliptin and digoxin can be co-administered without dose adjustment. Administration of digoxin alone and with linagliptin was well tolerated.
BIBT986 is a dual inhibitor of factors Xa and IIa. The aim of this study was to compare with placebo the effect of three doses of BIBT986 on coagulation, platelet activation, and inflammation. This ...was a prospective, randomized, double‐blind, placebo‐controlled, parallel‐group dose escalation trial in 48 healthy male volunteers. Participants received one of three doses of BIBT986 or placebo intravenously together with a bolus infusion of 2 ng/kg lipopolysaccharide (LPS). BIBT986 dose‐dependently changed global coagulation parameters and in vivo markers of thrombin generation and action: BIBT986 doses, which prolonged activated partial thromboplastin time by 100%, completely suppressed the LPS‐induced increases in prothrombin fragment, thrombin‐antithrombin complexes, and D‐dimer, which were 6.1‐, 14.5, and 3.5‐fold in the placebo group, respectively. BIBT986 did not influence inflammation, fibrinolysis, or platelet activation. Therefore, BIBT986 is a potent anticoagulant in the human endotoxemia model.
Clinical Pharmacology & Therapeutics (2007) 81, 858–866. doi:10.1038/sj.clpt.6100153; published online 4 April 2007
Background: Current anticoagulant development focuses on agents with predictable pharmacokinetic and pharmacodynamic (PD) properties. BIBT 986 is a novel potent anticoagulant with a dual mechanism of ...action: it competitively inhibits factor (F) Xa and FIIa. Aims: To determine the safety, tolerability, pharmacokinetics (PK) and PD of BIBT 986 following intravenous infusion in healthy male volunteers. Methods: In three randomized, double‐blind, placebo‐controlled trials, subjects were administered by intravenous infusion escalating doses of BIBT 986 for up to 32 h. BIBT 986 concentrations were determined in plasma and urine samples by high pressure liquid chromatography tandem mass spectrometry. Pharmacodynamic response was assessed by measuring the changes in blood coagulation times. Activated partial thromboplastin time, International Normalized Ratio, thrombin time and ecarin clotting time were determined and compared with baseline results. Results: In all three studies, intravenous infusion of BIBT 986 was safe and well tolerated. BIBT 986 exhibited linear PK over the dose range tested. Clearance was about 8 L h−1 and Vss about 50 L. Apparent steady state concentrations were reached within 24 h, indicating a dominant half‐life of about 6 h. The terminal half‐life of BIBT 986 was approximately 12 h. Renal excretion contributes approximately 50% to total elimination. Overall interindividual variability in pharmacokinetic and PD parameters was < 40%. There was a linear correlation between plasma concentrations and PD responses, suggesting excellent predictability. Conclusion: BIBT 986 is the first small molecule of a novel class of anticoagulants that potently and directly inhibits both coagulation FXa and thrombin. It has predictable pharmacokinetic and PD characteristics.
To investigate the effect of the estimated highest therapeutic dose of linagliptin (5 mg) on the pharmacokinetics and pharmacodynamics of warfarin, a CYP2C9 substrate.
This open-label, 2-period, ...fixed-sequence trial enrolled 18 healthy male volunteers, 17 of whom were homozygous for CYP2C9*1/*1. Subjects received a single oral dose of warfarin (10 mg) followed by a washout period of at least 14 days. Subjects then received oral linagliptin 5 mg once daily for 12 days (i.e. steady state) with a single dose of warfarin (10 mg) on Day 6. R(+) warfarin, S(-) warfarin, prothrombin time (PT) and international normalized ratio (INR) were assayed pre-dose and up to 168 h post-dose.
The geometric mean ratios (GMRs) (90% confidence interval (CI)) of AUC0-∞ and Cmax for (linagliptin + warfarin)/warfarin were 98.5 (95.7 - 101.5) and 99.7 (94.7 - 104.9), respectively, for R-warfarin; 103.0 (99.1 - 107.0) and 100.9 (93.7 - 108.6), respectively, for S-warfarin. Concomitant administration of linagliptin and warfarin had o clinically relevant effect on the AUC0-168 for INR or PT. The GMRs (90% CI) of INR nd PT AUC0-168 for (linagliptin + warfarin)/ warfarin were 93.4 (86.2 - 101.1) and 103.2 (95.4 - 111.6), respectively. The corresponding Eax values for both INR and PT were slightly increased after co-administration of linagliptin and warfarin compared with warfarin alone, being 104.3 (85.2 - 127.6) and 15.1 (94.3 -140.6), respectively, reflecting the higher variability of these endpoints. Co-administration of linagliptin and warfarin was well tolerated.
Coadministration of linagliptin did not alter the pharmacokinetics or pharmacodynamics of R- or S-warfarin, indicating that no dosage adjustment for warfarin is necessary when co-administered with linagliptin.
Objectif La Linagliptine (LINA) puissant I-DPP4 est principalement éliminée par voie non rénale. Cas unique parmi les I-DPP4 actuellement disponibles. L’objectif de cette étude était d’évaluer ...l’influence de l’Insuffisance Rénale (IR) à différents stades, sur la pharmacocinétique (PK) de la LINA Matériels et méthodes Sujets avec différents degrés d’IR : légère (clairance créatinine (ClCr) 51-80 ml/min ; n = 6), modérée (ClCr 31-50 ml/min ; n = 6), sévère (ClCr30 ml/min ; n = 6), terminale (n = 6), et chez Volontaires Sains (VS) (ClCr > 80 ml/min ; n = 6). Egalement, patients DT2 avec IR sévère (n = 10), patients DT2 avec fonction rénale normale (n = 11). Posologie LINA 5 mg 1/j, en dose unique (groupes : IR sévère, terminale) ou pendant 7 jours (groupes : VS, IR légère, modérée) ou pendant 10 jours (groupes : DT2). L’analyse principale comparait l’exposition à la LINA : • à l’Etat d’Equilibre (EE) (IR légère ou modérée vs VS et patients DT2 avec IR sévère vs DT2 normorénaux) • ou a Résultats Exposition totale à LINA à l’EE (AUCt, EE) et concentrations maximales à EE (Cmax, EE) étaient comparables entre sujets avec IR légère et groupe témoin, et augmentation modérée si IR modérée et sévère, respectivement de 71 % et 42 %. Après 1 dose, tous les patients IR ont présenté une augmentation de 30 à 60 % de l’exposition totale (AUC0-24) vs groupes témoins. Pas d’augmentation de la demi-vie terminale selon stade IR. Demi-vies d’accumulation comprises entre 14-15 h dans groupes témoins vs 18 h pour IR sévère. Faible corrélation observée entre ClCr et exposition à EE. L’excrétion rénale du médicament inchangé à l’EE était < 7 % de la dose dans tous les groupes. L’IR n’a pas altérée la liaison aux protéines plasmatiques ni la corrélation entre PK et inhibition DPP-4. Conclusion L’altération de la fonction rénale n’a qu’un effet mineur sur l’élimination de la Linagliptine. Les variations d’exposition observées (∼40% dans IR sévère) ne justifient pas d’adaptation posologique de la Linagliptine chez le DT2 insuffisant rénal.
Objective: Linagliptin (BI 1356) is a novel, orally available inhibitor of dipeptidyl peptidase-4 (DPP-4). Linagliptin improves glycaemic control in type 2 diabetic patients by increasing the ...half-life of the incretin hormone glucagon-like peptide-1 (GLP-1). Linagliptin is expected to be used as monotherapy or in combination with other antihyperglycaemic agents. This study was conducted to investigate potential pharmacokinetic or pharmacodynamic interactions between linagliptin and metformin.
Methods: This randomised, monocentric, open-label, two-way crossover design study was conducted in 16 healthy male subjects. Linagliptin (10 mg/day) and metformin (850 mg three times daily) were each administered alone and concomitantly. The steady-state pharmacokinetics of linagliptin and metformin and the inhibition of DPP-4 activity were determined at the end of each dosing period.
Results: Co-administration of linagliptin had no apparent effect on metformin exposure (metformin AUC
τ
,ss
; geometric mean ratio GMR co-administration:individual administration was 1.01; 90% confidence interval CI was 0.89-1.14). Effects on maximum concentration (C
max,ss
) were small (GMR: 0.89; 90% CI: 0.78-1.00). Co-administration of metformin did not significantly affect C
max,ss
of linagliptin (GMR: 1.03; 90% CI: 0.86-1.24), but increased AUC
τ
,ss
by 20% (GMR: 1.20; 90% CI: 1.07-1.34). Metformin alone had no effect on DPP-4 activity, and the inhibition of DPP-4 caused by linagliptin was not affected by concomitant administration of metformin. Tolerability was good whether linagliptin and metformin were administered alone or concomitantly. No serious adverse events occurred and the frequency of adverse events was low; 7 events in 6 subjects. The most frequent events were related to the gastrointestinal tract, as expected with metformin. Importantly, no subjects experienced signs or symptoms relating to episodes of hypoglycaemia.
Conclusion: In this small, multiple dose study carried out in healthy subjects, co-administration of linagliptin with metformin did not have a clinically relevant effect on the pharmacokinetics or pharmacodynamics of either agent. This study suggests linagliptin and metformin can safely be administered concomitantly in type 2 diabetes patients without dose adjustment; larger, longer-term clinical trials in diabetic patients are underway.
