PIII-17Effect of a single cyclosporine a (NEORAL™) dose on the single-dose pharmacokinetics (PK) of sitagliptin (MK-0431), a dipeptidyl peptidase-IV inhibitor (DPP-IV), in healthy male subjects

BACKGROUND Sitagliptin (MK-0431), an orally active, potent and selective DPP-IV inhibitor being developed for Type 2 diabetes mellitus, is a substrate for p-glycoprotein (Pgp). High dose cyclosporine A (CSA) was used as a probe Pgp inhibitor to evaluate the effect of potent Pgp inhibition on sitagliptin PK. METHODS 8 healthy young men received Treatments A (single oral 600 mg dose of CSA[NEORAL™] with a single 100 mg oral sitagliptin dose) and B (single oral 100 mg sitagliptin dose alone) in an open-label, randomized, 2-period, crossover study, separated by a 2-week washout. Pre-specified bounds of[0.50, 2.00] were used for AUC GMR whether any alterations in MK-0431 PK was clinically meaningful. RESULTS Sitagliptin with or without CSA was generally well tolerated. Sitagliptin AUC0-∞ GMR (1.29) with 90% CI[1.24, 1.34], and Cmax GMR (1.68) with 90% CI[1.35, 2.08] indicated modest effects by CSA and unlikely to be clinically relevant. There were no meaningful differences in CLr, apparent t1/2 or C24hr. CONCLUSIONS This study with high dose CSA confirmed that sitagliptin was a substrate for Pgp. Co-administration of CSA with sitagliptin only modestly increased Cmax of sitagliptin without a meaningful effect on overall exposure. Given only modest alterations in PK (i.e., on Cmax) with a highly potent Pgp inhibitor, the magnitude of changes in sitagliptin PK with other medications that are Pgp inhibitors, albeit less potent ones, is unlikely to be clinically meaningful. Clinical Pharmacology & Therapeutics (2005) 79, P63–P63; doi: 10.1016/j.clpt.2005.12.225