Pharmacokinetics of palonosetron in combination with aprepitant in healthy volunteers.

Background: Palonosetron is a second-generation 5-HT(3) receptor antagonist with a prolonged duration of action and higher receptor binding affinity than first-generation agents (ondansetron, granisetron, and dolasetron). Aprepitant is a selective antagonist of substance P/neurokinin 1 that augments the benefit of 5-HT(3) receptor antagonists in the prevention of chemotherapy-induced nausea and vomiting.

Methods: This randomized, open-label, two-way, crossover trial was designed to evaluate the effect of oral aprepitant on the pharmacokinetics and safety of a single intravenous (IV) dose of palonosetron in 12 healthy subjects. Treatment A consisted of a single IV bolus dose of palonosetron 0.25mg on day 1. Treatment B added oral aprepitant 125 mg on day 1 (30 minutes prior to palonosetron) and 80 mg on days 2 and 3. Blood for pharmacokinetic evaluations was collected through 168 hours after palonosetron administration on days 1 and 15; safety was monitored through day 22.

Results: Mean plasma concentration-time plots for palonosetron were virtually identical for palonosetron administered alone or with concomitant aprepitant. The ratio of geometric least-square mean values (with:without aprepitant) for C(max) was 98.6% (90% confidence interval [CI]: 61.8-157%), and for AUC(0-infinity) the ratio was 101% (90% CI: 85.6-119%). With and without aprepitant coadministration, respectively, mean plasma elimination half-life was 40 hours and 43 hours (difference: -3.0 hours; p = 0.348), mean total body clearance was 130 mL/min and 136 mL/min (difference: -5.6 mL/min; p = 0.735), and mean volume of distribution at steady-state was 410.9 L and 442.3 L (difference: -31.4 L; p = 0.463). Palonosetron alone and the palonosetron/aprepitant regimen were well tolerated.

Conclusion: These results indicate no significant differences in pharmacokinetic parameters for palonosetron between the two treatments, and suggest that palonosetron can be safely coadministered with aprepitant with no alterations in the expected safety profile and no dosage adjustment necessary.