Lack of effect of aprepitant on hydrodolasetron pharmacokinetics in CYP2D6 extensive and poor metabolizers

J Clin Pharmacol. 2006 Jul;46(7):792-801. doi: 10.1177/0091270006288954.

Abstract

To prevent chemotherapy-induced nausea and vomiting, aprepitant is given with a corticosteroid and a 5-hydroxytryptamine type 3 antagonist, such as dolasetron. Dolasetron is converted to the active metabolite hydrodolasetron, which is cleared largely via CYP2D6. The authors determined whether aprepitant, a moderate CYP3A4 inhibitor, alters hydrodolasetron pharmacokinetics in CYP2D6 poor and extensive metabolizers. Six CYP2D6 poor and 6 extensive metabolizers were randomized in an open-label, crossover fashion to treatment A (dolasetron 100 mg on day 1) and treatment B (dolasetron 100 mg plus aprepitant 125 mg on day 1, aprepitant 80 mg on days 2-3). For hydrodolasetron area under the concentration-versus-time curve (AUC0-infinity) and peak plasma concentration (Cmax), geometric mean ratios (B/A) and 90% confidence intervals (CIs) fell below the predefined limit (2.0) for clinical significance (AUC0-infinity, 1.09 [90% CI, 1.01-1.18], Cmax, 1.08 [90% CI, 0.94-1.24]). Aprepitant did not affect the pharmacokinetics of hydrodolasetron, regardless of CYP2D6 metabolizer type, and was generally well tolerated when coadministered with dolasetron in volunteers.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Antiemetics / administration & dosage
  • Antiemetics / adverse effects
  • Antiemetics / pharmacology*
  • Aprepitant
  • Cross-Over Studies
  • Cytochrome P-450 CYP2D6 / genetics
  • Cytochrome P-450 CYP2D6 / metabolism*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / metabolism
  • Electrocardiography
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / adverse effects
  • Enzyme Inhibitors / pharmacology
  • Female
  • Genotype
  • Humans
  • Indoles / administration & dosage
  • Indoles / adverse effects
  • Indoles / pharmacokinetics*
  • Male
  • Middle Aged
  • Morpholines / administration & dosage
  • Morpholines / adverse effects
  • Morpholines / pharmacology*
  • Quinolizines / administration & dosage
  • Quinolizines / adverse effects
  • Quinolizines / pharmacokinetics*
  • Reference Values
  • Serotonin Antagonists / administration & dosage
  • Serotonin Antagonists / adverse effects
  • Serotonin Antagonists / pharmacokinetics*

Substances

  • Antiemetics
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Indoles
  • Morpholines
  • Quinolizines
  • Serotonin Antagonists
  • Aprepitant
  • dolasetron
  • Cytochrome P-450 Enzyme System
  • Cytochrome P-450 CYP2D6
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • hydrodolasetron