Graefe-Mody_2010_Int.J.Clin.Pharmacol.Ther_48_652

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.