title: No pharmacokinetic alteration of docetaxel following coadministration of aprepitant 3 h before docetaxel infusion.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Administration of aprepitant 3 h before docetaxel infusion did not alter the pharmacokinetics of docetaxel.
authors: Department of Medical Oncology, International Medical Center-Comprehensive Cancer Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan.
authors: Toshikado
authors: T
authors: Kaneta
authors: Ken-Ichi
authors: K
authors: Fujita
authors: Yuko
authors: Y
authors: Akiyama
authors: Kaori
authors: K
authors: Kawara
authors: Yu
authors: Y
authors: Sunakawa
authors: Asuka
authors: A
authors: Kawachi
authors: Ken
authors: K
authors: Shimada
authors: Yasutsuna
authors: Y
authors: Sasaki
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics*; D000077608:Aprepitant; D019540:Area Under Curve; D018592:Cross-Over Studies; D000077143:Docetaxel; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage / Q000493:pharmacokinetics; D011446:Prospective Studies; D043823:Taxoids / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D009025:Morpholines; D043823:Taxoids; D000077143:Docetaxel; D000077608:Aprepitant