title: Pharmacokinetics of darunavir (TMC114) and atazanavir during coadministration in HIV-negative, healthy volunteers.
abstract: 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.
authors.affiliation: Tibotec Inc, Yardley, PA, USA.
authors.forename: Vanitha J
authors.initials: VJ
authors.lastname: Sekar
authors.forename: Eric
authors.initials: E
authors.lastname: Lefebvre
authors.forename: Tine
authors.initials: T
authors.lastname: De Marez
authors.forename: Sabrina
authors.initials: S
authors.lastname: Spinosa-Guzman
authors.forename: Martine
authors.initials: M
authors.lastname: De Pauw
authors.forename: Els
authors.initials: E
authors.lastname: De Paepe
authors.forename: Tony
authors.initials: T
authors.lastname: Vangeneugden
authors.forename: Richard M W
authors.initials: RM
authors.lastname: Hoetelmans
mesh_terms: 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
chemical_list: D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D013449:Sulfonamides; D000069446:Atazanavir Sulfate; D000069454:Darunavir