Pharmacokinetics of darunavir (TMC114) and atazanavir during coadministration in HIV-negative, healthy volunteers

Abstract

Background and objective: To investigate the potential for pharmacokinetic interactions between the protease inhibitors darunavir (DRV, TMC114) coadministered with low-dose ritonavir (darunavir/r), and atazanavir in HIV-negative, healthy volunteers.

Methods: This was an open-label, randomised, three-period, crossover study. Darunavir/r (400/100mg twice daily), atazanavir/r (300/100mg once daily) or darunavir/r (400/100mg twice daily) plus atazanavir (300mg once daily) were administered in three separate sessions, with a washout period of at least 7 days between regimens. The follow-up lasted 30 days. Twenty-three healthy volunteers participated. Pharmacokinetic assessments were performed at steady-state on day 7. Plasma drug concentrations were determined by liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters were compared between treatments. The safety and tolerability of the study medications were monitored throughout.

Results: Darunavir pharmacokinetics were unaffected by atazanavir. No change in overall exposure to atazanavir was observed during coadministration with darunavir/r. However, there was a 52% increase in minimum atazanavir plasma concentration (least squares mean ratio [90% CI 0.99, 2.34]). Mean systemic exposure to ritonavir was increased by 65% and 106%, respectively, with the combination treatment compared with darunavir/r alone or atazanavir/r alone. There were no apparent differences in mean changes in lipids between the darunavir/r, atazanavir/r or darunavir/r plus atazanavir regimens. Hyperbilirubinaemia and ocular icterus were reported with atazanavir-containing regimens.

Conclusion: Atazanavir at a dose of 300mg once daily can be coadministered with a darunavir/r twice-daily regimen without any dose adjustment if there is a clinical need to combine darunavir/r and atazanavir in HIV-1-infected patients.