title: Assessment of the pharmacokinetic interaction between the novel DPP-4 inhibitor linagliptin and a sulfonylurea, glyburide, in healthy subjects.
abstract: 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.
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany. Ulrike.Graefe-Mody@boehringer-ingelheim.com
authors.forename: Ulrike
authors.initials: U
authors.lastname: Graefe-Mody
authors.forename: Peter
authors.initials: P
authors.lastname: Rose
authors.forename: Arne
authors.initials: A
authors.lastname: Ring
authors.forename: Kerstin
authors.initials: K
authors.lastname: Zander
authors.forename: Mario
authors.initials: M
authors.lastname: Iovino
authors.forename: Hans-Juergen
authors.initials: HJ
authors.lastname: Woerle
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors; D001682:Biological Availability; D018592:Cross-Over Studies; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005260:Female; D005905:Glyburide / Q000493:pharmacokinetics*; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D000069476:Linagliptin; D008297:Male; D008875:Middle Aged; D011687:Purines / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000493:pharmacokinetics*; D013453:Sulfonylurea Compounds / Q000493:pharmacokinetics*
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D011687:Purines; D011799:Quinazolines; D013453:Sulfonylurea Compounds; D000069476:Linagliptin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D005905:Glyburide