Effects of aprepitant on cytochrome P450 3A4 activity using midazolam as a probe

Clin Pharmacol Ther. 2003 Aug;74(2):150-6. doi: 10.1016/S0009-9236(03)00123-1.


Background: Aprepitant is a neurokinin(1) receptor antagonist that enhances prevention of chemotherapy-induced nausea and vomiting when added to conventional therapy with a corticosteroid and a 5-hydroxytryptamine(3) (5-HT(3)) antagonist. Because aprepitant may be used with a variety of chemotherapeutic agents and ancillary support drugs, which may be substrates of cytochrome P450 (CYP) 3A4, assessment of the potential of this drug to inhibit CYP3A4 activity in vivo is important. The effect of aprepitant on in vivo CYP3A4 activity in humans with oral midazolam used as a sensitive probe of CYP3A4 activity was evaluated in this study.

Methods: In this open-label, randomized, single-period study, 16 healthy male subjects were enrolled. Subjects received one of two oral aprepitant regimens for 5 days (8 subjects per regimen): (1) 125 mg aprepitant on day 1 and then 80 mg/d on days 2 to 5 or (2) 40 mg aprepitant on day 1 and then 25 mg/d on days 2 to 5. All subjects also received a single oral dose of midazolam, 2 mg, at prestudy (3 to 7 days before aprepitant treatment) and on days 1 and 5 (1 hour after aprepitant administration).

Results: Coadministration of midazolam and 125/80 mg aprepitant increased the midazolam area under the plasma concentration-time curve by 2.3-fold on day 1 (P <.01) and by 3.3-fold on day 5 (P <.01), as compared with midazolam alone (prestudy). The 125/80-mg regimen of aprepitant also increased the midazolam maximum observed concentration by 1.5-fold on day 1 (P <.05) and by 1.9-fold on day 5 (P <.01). The midazolam half-life values increased from 1.7 hours (prestudy) to 3.3 hours on both day 1 and day 5. Coadministration of 40/25 mg aprepitant and midazolam did not result in significant changes in the midazolam area under the plasma concentration-time curve, maximum observed concentration, and half-life at either day 1 or day 5.

Conclusions: The 5-day 125/80-mg regimen of aprepitant produced moderate inhibition of CYP3A4 activity in humans, as measured with the use of midazolam as a probe drug.

Publication types

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

MeSH terms

  • Adult
  • Anti-Anxiety Agents / pharmacokinetics*
  • Antiemetics / pharmacology*
  • Aprepitant
  • Area Under Curve
  • Chromatography, High Pressure Liquid
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors*
  • Drug Interactions
  • Half-Life
  • Humans
  • Male
  • Midazolam / pharmacokinetics*
  • Morpholines / pharmacology*
  • Neurokinin-1 Receptor Antagonists


  • Anti-Anxiety Agents
  • Antiemetics
  • Cytochrome P-450 Enzyme Inhibitors
  • Morpholines
  • Neurokinin-1 Receptor Antagonists
  • Aprepitant
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Midazolam