title: Lack of effect of aprepitant on the pharmacokinetics of docetaxel in cancer patients.
abstract: BACKGROUND
  Aprepitant is a selective neurokinin-1 receptor antagonist that is effective for the prevention of nausea and vomiting caused by highly emetogenic chemotherapy. In vitro, aprepitant is a moderate inhibitor of the CYP3A4 enzyme, which is involved in the clearance of several chemotherapeutic agents. In this study we examined the potential for aprepitant to affect the pharmacokinetics and toxicity of intravenously administered docetaxel, a chemotherapeutic agent that is primarily metabolized by CYP3A4.
  
  
  METHODS
  A total of 11 cancer patients (4 male, 7 female, aged 50-68 years) were enrolled in this multicenter, randomized, open-label, two-period, crossover study. Patients received a single infusion of docetaxel monotherapy, 60-100 mg/m(2), on two occasions at least 3 weeks apart. During one of the cycles (treatment A), patients received docetaxel alone. During the alternate cycle (treatment B), they also received aprepitant 125 mg orally 1 h prior to docetaxel infusion (day 1), and a single oral dose of aprepitant 80 mg on days 2 and 3. The pharmacokinetic profile of docetaxel was assessed over 30 h following docetaxel infusion. Blood counts were monitored on days 1, 4, 7, and 14.
  
  
  RESULTS
  Ten patients completed the study. Concomitant administration of aprepitant did not cause any statistically or clinically significant changes in docetaxel pharmacokinetics. Values for docetaxel alone (treatment A) versus docetaxel with aprepitant (treatment B) were as follows: geometric mean AUC(0-last) was 3.26 vs 3.17 microg h/ml (P>0.25; ratio B/A 0.97); geometric mean AUC(0-infinity) 3.51 vs 3.39 microg h/ml (P>0.25; ratio B/A 0.96); geometric mean C(max) was 3.53 vs 3.37 microg/ml (P>0.25; ratio B/A 0.95); and geometric mean plasma clearance was 23.3 vs 24.2 l/h/m(2) (P>0.25; ratio B/A 1.04). The corresponding harmonic mean half-life values were 10.1 and 8.5 h. The two treatment regimens had similar tolerability profiles; the median absolute neutrophil count nadirs were 681/mm(3) during treatment with docetaxel alone and 975/mm(3) during aprepitant coadministration.
  
  
  CONCLUSIONS
  Aprepitant had no clinically significant effect on either the pharmacokinetics or toxicity of standard doses of docetaxel in cancer patients. Aprepitant at clinically recommended doses may have a low potential to affect the pharmacokinetics of intravenous chemotherapeutic agents metabolized by CYP3A4.
authors.affiliation: Department of Oncology, Radiology, and Clinical Immunology, Uppsala University Hosipital, Uppsala, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Nygren
authors.forename: Kenneth
authors.initials: K
authors.lastname: Hande
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Petty
authors.forename: Margaret
authors.initials: M
authors.lastname: Fedgchin
authors.forename: Kristien
authors.initials: K
authors.lastname: van Dyck
authors.forename: Anup
authors.initials: A
authors.lastname: Majumdar
authors.forename: Debbie
authors.initials: D
authors.lastname: Panebianco
authors.forename: Marina
authors.initials: M
authors.lastname: de Smet
authors.forename: Tuli
authors.initials: T
authors.lastname: Ahmed
authors.forename: M Gail
authors.initials: MG
authors.lastname: Murphy
authors.forename: Keith M
authors.initials: KM
authors.lastname: Gottesdiener
authors.forename: Veronique
authors.initials: V
authors.lastname: Cocquyt
authors.forename: Simon
authors.initials: S
authors.lastname: van Belle
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000932:Antiemetics / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000077608:Aprepitant; D018592:Cross-Over Studies; D000077143:Docetaxel; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D009325:Nausea / Q000517:prevention & control; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D043823:Taxoids / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000932:Antiemetics; D000972:Antineoplastic Agents, Phytogenic; D009025:Morpholines; D043823:Taxoids; D000077143:Docetaxel; D000077608:Aprepitant