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.
OBJECTIVE
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.


CONCLUSIONS
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.
Sekar
V
V
Tibotec Inc., Yardley, Pennsylvania 19067, USA. vsekar@tibus.jnj.com
Lefebvre
E
E
De Marez
T
T
De Pauw
M
M
De Paepe
E
E
Vangeneugden
T
T
Hoetelmans
R M W
RM
D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019540:Area Under Curve; D018592:Cross-Over Studies; D000069454:Darunavir; D004334:Drug Administration Schedule; D004347:Drug Interactions; D017320:HIV Protease Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011687:Purines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D019438:Ritonavir / Q000008:administration & dosage / Q000494:pharmacology*; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D013450:Sulfones / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013449:Sulfonamides; D013450:Sulfones; D000068677:Sildenafil Citrate; D019438:Ritonavir; D000069454:Darunavir