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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.

Author(s): Krishna R, Bergman A, Larson P, Cote J, Lasseter K, Dilzer S, Wang A, Zeng W, Chen L, Wagner J, Herman G

Affiliation(s): Department of Clinical Pharmacology, Merck Research Laboratories, Merck & Co, Inc, 126 East Lincoln Avenue, Rahway, NJ 07065; e-mail: rajesh_krishna@merck.com.

Publication date & source: 2007-02, J Clin Pharmacol., 47(2):165-74.

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-infinity) 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((1/2)), 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.

Page last updated: 2007-02-12

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