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


CONCLUSIONS
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.
Sekar
Vanitha J
VJ
Tibotec Inc, Yardley, PA, USA.
Lefebvre
Eric
E
De Marez
Tine
T
Spinosa-Guzman
Sabrina
S
De Pauw
Martine
M
De Paepe
Els
E
Vangeneugden
Tony
T
Hoetelmans
Richard M W
RM
D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D000069446:Atazanavir Sulfate; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D000069454:Darunavir; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009842:Oligopeptides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011725:Pyridines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D014839:Vomiting / Q000139:chemically induced
D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D013449:Sulfonamides; D000069446:Atazanavir Sulfate; D000069454:Darunavir