Effects of Ketoconazole and Rifampicin on the Pharmacokinetics of Gemigliptin, a Dipeptidyl Peptidase-IV Inhibitor: A Crossover Drug-Drug Interaction Study in Healthy Male Korean Volunteers

Background: Gemigliptin (LC15-0444) is a newly developed selective and competitive inhibitor of dipeptidyl peptidase (DPP)-4 and has potential for the treatment of type 2 diabetes mellitus. Gemigliptin is metabolized by the cytochrome P450 (CYP) 3A4 isozyme to yield the active major metabolite LC15-0636. Objective: The effects of multiple oral doses of ketoconazole (a potent CYP3A4 inhibitor) and multiple oral doses of rifampicin (a potent CYP3A4 inducer) on the pharmacokinetic properties of a single oral dose of gemigliptin were evaluated in fasting healthy male Korean volunteers. Methods: In this open-label, 2-part, 3-treatment, 1-sequence, 2-period crossover drug-drug interaction study, 1 group of subjects received a single 50-mg oral dose of gemigliptin on 2 separate occasions-once as monotherapy and again after pretreatment with 400 mg of oral ketoconazole once daily for 7 days. The other group of subjects received a single 50-mg oral dose of gemigliptin on 2 separate occasions-once without pretreatment and again after pretreatment with 600 mg of oral rifampicin once daily for 10 days. Blood samples were obtained at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 48, and 72 hours after gemigliptin dosing. Plasma concentrations were determined using LC-MS/MS. Pharmacokinetic parameters were estimated via noncompartmental methods. Tolerability was assessed using measurements of vital signs, clinical chemistry tests, and interviews. Results: Twenty-four subjects were enrolled (12 per group). Concurrent administration of ketoconazole was associated with increased total gemigliptin plasma exposure (AUC(0-infinity); 2.36-fold [90% CI, 2.19-2.54]) and decreased metabolism of gemigliptin until negligible concentrations of LC15-0636 were detected. Pretreatment with rifampicin was associated with decreased AUC(0-infinity) of gemigliptin (by 80% [90% CI, 78%-82%]) and a 2.9-fold increase (mean [SD], 0.18 [0.08] to 0.52 [0.10]) in the metabolic ratio of gemigliptin to LC15-0636. The treatments were well-tolerated, with no severe adverse events reported. Six of the 24 subjects (25%) experienced AEs during the first period of gemigliptin monotherapy administration. Six of 12 subjects (50%) each experienced AEs during concurrent administration with ketoconazole and rifampicin. Conclusions: In this select group of healthy male Korean volunteers, concurrent administration of gemigliptin with ketoconazole or rifampicin was associated with significantly increased or decreased systemic exposure to gemigliptin, respectively. These findings suggest that gemigliptin may require a dose adjustment when concurrently administered with drugs that alter CYP3A4 activity. Concurrent administration of gemigliptin with ketoconazole or rifampicin was well tolerated. ClinicalTrials.gov identifier: NCT01426906. (Clin Ther. 2012;34:1182-1194) (C) 2012 Elsevier HS Journals, Inc. All rights reserved.