Effect of Low-Dose Ritonavir (100 Mg Twice Daily) on the Activity of Cytochrome P450 2D6 in Healthy Volunteers

Clin Pharmacol Ther. 2005 Dec;78(6):664-74. doi: 10.1016/j.clpt.2005.09.001.

Abstract

Objective: In the treatment of human immunodeficiency virus infection, the protease inhibitor ritonavir is used in a low dose (100 mg twice daily) to inhibit cytochrome P450 (CYP) 3A4 and thereby increase plasma concentrations of coadministered protease inhibitors. When applied in a therapeutic dose (600 mg twice daily), ritonavir also inhibits CYP2D6. The effect of low-dose ritonavir on CYP2D6 is unknown and was investigated in this study.

Methods: This was a 1-arm, 2-period, fixed-order study in 13 healthy male volunteers who were extensive metabolizers of CYP2D6. The first period examined baseline CYP2D6 activity by evaluating the pharmacokinetics of a single dose of desipramine and by metabolic phenotyping with dextromethorphan. During the second period, participants took ritonavir, 100 mg twice daily, for 2 weeks, followed by repeat assessment of desipramine pharmacokinetics and the dextromethorphan metabolic phenotype in the presence of ritonavir.

Results: Low-dose ritonavir (100 mg twice daily) significantly increased the exposure to single-dose desipramine, as reflected in a geometric mean ratio (with ritonavir/without ritonavir) of 1.26 (95% confidence interval, 1.13-1.40) for the desipramine area under the concentration versus time curve from time 0 to infinity (P < .001). Coadministration of low-dose ritonavir did not significantly affect the dextromethorphan/dextrorphan urinary metabolic ratio and did not convert any extensive metabolizer to a poor metabolizer.

Conclusions: Low-dose ritonavir (100 mg twice daily) exerts a modest inhibitory effect on the activity of CYP2D6 in extensive metabolizers, as assessed with desipramine as the index substrate. This effect was not apparent with the dextromethorphan/dextrorphan metabolic ratio as an indicator for CYP2D6 activity. It is expected that the effect of low-dose ritonavir on CYP2D6 will not require standard dose reductions for CYP2D6 substrates.

Publication types

  • Clinical Trial
  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Area Under Curve
  • Cytochrome P-450 CYP2D6 / genetics
  • Cytochrome P-450 CYP2D6 / metabolism*
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Desipramine / administration & dosage
  • Desipramine / pharmacokinetics
  • Dextromethorphan / urine
  • Dextrorphan / urine
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • HIV Protease Inhibitors / administration & dosage
  • HIV Protease Inhibitors / pharmacokinetics
  • Heterozygote
  • Homozygote
  • Humans
  • Male
  • Middle Aged
  • Ritonavir / administration & dosage
  • Ritonavir / pharmacokinetics*
  • Time Factors

Substances

  • Cytochrome P-450 CYP2D6 Inhibitors
  • HIV Protease Inhibitors
  • Dextrorphan
  • Dextromethorphan
  • Cytochrome P-450 CYP2D6
  • Ritonavir
  • Desipramine