Effect of a selective CYP2C9 inhibitor on the pharmacokinetics of nateglinide in healthy subjects.

Purpose: The objective of the study was to determine the effect of a potent and selective CYP2C9 inhibitor, sulfinpyrazone (Anturane), on the pharmacokinetics of nateglinide (Starlix), a novel antidiabetic drug which is primarily (approximately 70%) metabolized via CYP2C9.

Methods: This was a randomized, open-label, two-period, crossover study in 18 healthy volunteers. Nateglinide was administered as a single 120-mg oral dose alone (reference) on day 1 or in combination with sulfinpyrazone (test) on day 7, following twice-daily 200-mg oral doses (i.e., 400 mg/day) of sulfinpyrazone for 7 days. Pharmacokinetic parameters of nateglinide were determined following the administration of nateglinide alone, and when administered in combination with sulfinpyrazone. Plasma nateglinide concentrations were determined using a validated high-performance liquid chromatography method.

Results: The administration of nateglinide in combination with sulfinpyrazone resulted in approximately 28% higher mean AUC of nateglinide (90% CI for test-reference ratio: 1.20-1.39) with no differences in mean peak plasma concentration (Cmax; 90% CI test-reference ratio: 0.86-1.12) compared with nateglinide-alone treatment. The time to reach Cmax (tmax) and the elimination half-life of nateglinide were similar between the two treatments. Both treatments were safe and well tolerated.

Conclusions: Sulfinpyrazone increased the mean exposure of nateglinide by 28% when both drugs were administered in combination. Nateglinide, given as a single dose or co-administered with multiple doses of sulfinpyrazone, was safe and well tolerated in healthy subjects.