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Effect of a Single Cyclosporine Dose on the Single-Dose Pharmacokinetics of Sitagliptin (MK-0431), a Dipeptidyl Peptidase-4 Inhibitor, in Healthy Male Subjects

From Merck & Co, Inc, Whitehouse Station, New Jersey (Dr Krishna, Dr Bergman, Mr Larson, Ms Cote, Dr Wang, Mr Zeng, Mr Chen, Dr Wagner, Dr Herman) and SFBCI, Miami, Florida (Dr Lasseter, Ms Dilzer).

Sitagliptin (MK-0431) is an orally active, potent, and selective dipeptidyl peptidase-4 inhibitor used for the treatment of patients with type 2 diabetes mellitus. Sitagliptin has been shown to be a substrate for P-glycoprotein in preclinical studies. Cyclosporine was used as a probe P-glycoprotein inhibitor at a high dose to evaluate the potential effect of potent P-glycoprotein inhibition on single-dose sitagliptin pharmacokinetics in healthy male subjects. Eight healthy young men received a single oral 600-mg dose of cyclosporine with a single 100-mg oral sitagliptin dose and a single oral 100-mg sitagliptin dose alone in an open-label, randomized, 2-period, crossover study. Single doses of sitagliptin with or without single doses of cyclosporine were generally well tolerated. The sitagliptin AUC_0- geometric mean ratio was 1.29 with a 90% confidence interval of (1.24, 1.34). The sitagliptin C_max geometric mean ratio was 1.68 with a 90% confidence interval of (1.35, 2.08). Cyclosporine coadministration did not appear to affect apparent sitagliptin renal clearance, t, or C_{24 h}, suggesting that effects of these high doses of cyclosporine are more likely due to enhanced absorption of sitagliptin, potentially through inhibition of intestinal P-glycoprotein. These results rationalize the use of a single high-dose cyclosporine as a probe inhibitor of P-glycoprotein for compound candidates whose elimination is less dependent on CYP3A4-mediated metabolism.

Key Words: Sitagliptin • DPP-4 inhibitor • P-glycoprotein • drug interaction • cyclosporine A

Address for reprints: Address for correspondence: Rajesh Krishna, PhD, FCP, Department of Clinical Pharmacology, Merck Research Laboratories, Merck & Co, Inc, 126 East Lincoln Avenue, Rahway, NJ 07065; e-mail: rajesh_krishna{at}merck.com.

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