Effect of repeated doses of darunavir plus low-dose ritonavir on the pharmacokinetics of sildenafil in healthy male subjects: phase I randomized, open-label, two-way crossover study

Clin Drug Investig. 2008;28(8):479-85. doi: 10.2165/00044011-200828080-00002.

Abstract

Background and objectives: Darunavir (DRV, TMC114) is a novel protease inhibitor administered in combination with low-dose ritonavir (DRV/r) and is highly active against both wild-type and multidrug-resistant HIV-1 strains. Sildenafil is an oral therapy for erectile dysfunction. Concomitant administration of protease inhibitors and sildenafil increases sildenafil plasma concentrations. The potential for a pharmacokinetic drug interaction exists when sildenafil and DRV/r are co-administered, as these drugs are primarily metabolized by cytochrome P450 (CYP) 3A, and darunavir and ritonavir are CYP3A inhibitors. The primary objective of this open-label, crossover, phase I study was to assess the effect of multiple doses of DRV/r on the pharmacokinetics of sildenafil and its active metabolite N-desmethyl sildenafil. The secondary objective was to assess the short-term safety and tolerability of co-administration of sildenafil and DRV/r.

Methods: Sixteen HIV-negative healthy male subjects were randomized to one of two sequences. In two sessions each subject received treatments A and B. In treatment A, a single dose of sildenafil 100 mg was administered. In treatment B, the subjects received DRV/r 400/100 mg twice daily for 8 days and on day 7 a single dose of sildenafil 25 mg was co-administered. Full pharmacokinetic profiles of sildenafil, N-desmethyl sildenafil, darunavir and ritonavir were determined. Safety and tolerability were also assessed.

Results: Sildenafil exposure (area under the plasma concentration-time curve [AUC]) was comparable between the two treatments despite administration of a lower dose of sildenafil (25 mg) with DRV/r than when sildenafil (100 mg) was administered alone. When sildenafil 25 mg was co-administered with DRV/r, the sildenafil maximum plasma concentration (Cmax) was 38% lower compared with Cmax after administration of sildenafil alone at a dose of 100 mg. N-desmethyl sildenafil Cmax and AUC from the time of administration until the last time point with a measurable concentration after dosing (calculated by linear trapezoidal summation [AUClast]) values decreased by approximately 95% when sildenafil 25 mg was co-administered with DRV/r compared with sildenafil 100 mg alone. Combined treatment with DRV/r and sildenafil was generally safe and well tolerated.

Conclusion: Sildenafil exposure is increased in the presence of DRV/r. In this setting, a dose adjustment for sildenafil is warranted; no more than 25 mg of sildenafil is recommended over a 48-hour period when co-administered with DRV/r.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Anti-HIV Agents / administration & dosage
  • Anti-HIV Agents / pharmacology*
  • Area Under Curve
  • Cross-Over Studies
  • Darunavir
  • Drug Administration Schedule
  • Drug Interactions
  • HIV Protease Inhibitors / administration & dosage*
  • HIV Protease Inhibitors / pharmacology
  • Humans
  • Male
  • Middle Aged
  • Phosphodiesterase Inhibitors / administration & dosage
  • Phosphodiesterase Inhibitors / adverse effects
  • Phosphodiesterase Inhibitors / blood
  • Phosphodiesterase Inhibitors / pharmacokinetics*
  • Piperazines / administration & dosage
  • Piperazines / adverse effects
  • Piperazines / blood
  • Piperazines / pharmacokinetics*
  • Purines / administration & dosage
  • Purines / adverse effects
  • Purines / blood
  • Purines / pharmacokinetics
  • Ritonavir / administration & dosage
  • Ritonavir / pharmacology*
  • Sildenafil Citrate
  • Sulfonamides / administration & dosage
  • Sulfonamides / pharmacology*
  • Sulfones / administration & dosage
  • Sulfones / adverse effects
  • Sulfones / blood
  • Sulfones / pharmacokinetics*

Substances

  • Anti-HIV Agents
  • HIV Protease Inhibitors
  • Phosphodiesterase Inhibitors
  • Piperazines
  • Purines
  • Sulfonamides
  • Sulfones
  • Sildenafil Citrate
  • Ritonavir
  • Darunavir