No pharmacokinetic alteration of docetaxel following coadministration of aprepitant 3 h before docetaxel infusion.

Abstract

Aprepitant, a CYP3A4 substrate, effectively prevents chemotherapy-induced nausea and vomiting. Oral aprepitant 1 h before intravenous infusion of docetaxel does not change the pharmacokinetics of docetaxel. In practical combination chemotherapy, oral aprepitant is given 3 h before docetaxel infusion. We examined effects of this treatment schedule on the pharmacokinetics of docetaxel. Inhibition constant (K(i)) of aprepitant for CYP3A-mediated docetaxel hydroxylation was estimated with human liver microsomes. A prospective, open-label, triple-crossover study was performed in balanced groups of cancer patients who received three consecutive cycles of docetaxel, consisting of docetaxel alone (A), docetaxel plus aprepitant given 3 h before docetaxel (B1), and docetaxel plus aprepitant given 1 h before docetaxel (B2). Three treatment arms were studied: Arm I, B1 followed by A and B2, respectively; Arm II, B2 followed by A and B1, respectively; and Arm III, A followed by B2 and B1, respectively. Pharmacokinetics of docetaxel and aprepitant were evaluated on day 1. The K(i) value was estimated to be 9.82 µM. Eligible patients (20) were allocated to Arm I (8), Arm II (7), or Arm III (5). On combined analysis of data from all patients assigned to Arms I-III, there were no significant differences among cycles A, B1, and B2 in the area under the plasma concentration-time curve (AUC) of docetaxel or the docetaxel AUC divided by actual dose. Pharmacokinetics of aprepitant showed large interindividual variability. Administration of aprepitant 3 h before docetaxel infusion did not alter the pharmacokinetics of docetaxel.