U Graefe-Mody1, S Huettner, H Stähle, A Ring, K A Dugi. 1. Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach/Riss, Ingelheim, Germany. Ulrike.Graefe-Mody@boehringer-ingelheim.com
Abstract
OBJECTIVE: This study was conducted to investigate any potential effect of the dipeptidyl peptidase-4 inhibitor linagliptin (which is being developed to improve glycemic control in patients with Type 2 diabetes) on the pharmacokinetics of simvastatin (a lipid-lowering, HMG-CoA reductase inhibitor). METHODS: This open-label, multiple-dose study was conducted in 20 healthy male Caucasian subjects. Simvastatin (40 mg/day) was administered alone for 6 days, followed by co-administration with linagliptin (10 mg/ day) for 6 days, followed by simvastatin single administration for a further 8 days. Plasma concentrations of simvastatin and its active metabolite simvastatin beta-hydroxy acid were determined on Day 6 (before co-administration of linagliptin) and Days 12, 16 and 20 (after co-administration of linagliptin). RESULTS: The geometric mean ratio (GMR) (90% confidence interval (CI)) following co-administration of linagliptin with simvastatin (Day 12) compared with administration of simvastatin alone (Day 6) for simvastatin AUC was 134.2% (119.4, 150.7) and for simvastatin acid AUC was 133.3% (118.1, 150.3). The GMR (90% CI) for simvastatin Cmax,ss was 110.0% (89.3, 135.6) and for simvastatin acid Cmax,ss was 120.7% (101.5, 143.6). 20 adverse events were reported by 11 subjects. Both simvastatin and linagliptin were well tolerated. CONCLUSIONS: Linagliptin-mediated effects on simvastatin exposure are not considered to be clinically relevant in terms of patient tolerability or safety. Therefore, a dose adjustment of linagliptin is not necessary when these two agents are administered together and linagliptin co-administration is not expected to exert a clinically relevant effect on the pharmacokinetics of other CYP3A4 substrates.
OBJECTIVE: This study was conducted to investigate any potential effect of the dipeptidyl peptidase-4 inhibitor linagliptin (which is being developed to improve glycemic control in patients with Type 2 diabetes) on the pharmacokinetics of simvastatin (a lipid-lowering, HMG-CoA reductase inhibitor). METHODS: This open-label, multiple-dose study was conducted in 20 healthy male Caucasian subjects. Simvastatin (40 mg/day) was administered alone for 6 days, followed by co-administration with linagliptin (10 mg/ day) for 6 days, followed by simvastatin single administration for a further 8 days. Plasma concentrations of simvastatin and its active metabolite simvastatin beta-hydroxy acid were determined on Day 6 (before co-administration of linagliptin) and Days 12, 16 and 20 (after co-administration of linagliptin). RESULTS: The geometric mean ratio (GMR) (90% confidence interval (CI)) following co-administration of linagliptin with simvastatin (Day 12) compared with administration of simvastatin alone (Day 6) for simvastatin AUC was 134.2% (119.4, 150.7) and for simvastatin acid AUC was 133.3% (118.1, 150.3). The GMR (90% CI) for simvastatin Cmax,ss was 110.0% (89.3, 135.6) and for simvastatin acid Cmax,ss was 120.7% (101.5, 143.6). 20 adverse events were reported by 11 subjects. Both simvastatin and linagliptin were well tolerated. CONCLUSIONS:Linagliptin-mediated effects on simvastatin exposure are not considered to be clinically relevant in terms of patient tolerability or safety. Therefore, a dose adjustment of linagliptin is not necessary when these two agents are administered together and linagliptin co-administration is not expected to exert a clinically relevant effect on the pharmacokinetics of other CYP3A4 substrates.
Authors: C Friedrich; A Ring; T Brand; R Sennewald; E U Graefe-Mody; H-J Woerle Journal: Eur J Drug Metab Pharmacokinet Date: 2011-02-22 Impact factor: 2.441
Authors: Christian Friedrich; Andreas Port; Arne Ring; Ulrike Graefe-Mody; Thomas Giessmann; Mario Iovino; Hans-Juergen Woerle Journal: Clin Drug Investig Date: 2011 Impact factor: 2.859