Effect of atazanavir and atazanavir/ritonavir on the pharmacokinetics of the next-generation HIV integrase inhibitor, S/GSK1349572

Br J Clin Pharmacol. 2011 Jul;72(1):103-8. doi: 10.1111/j.1365-2125.2011.03947.x.


Aims: S/GSK1349572 is an unboosted, once daily, next generation integrase inhibitor with potent activity, low pharmacokinetic (PK) variability and a novel resistance profile. As the primary route of metabolism is via glucuronidation, the effects of atazanavir (ATV, a UGT1A1 inhibitor) and atazanavir/ritonavir (ATV/RTV) on S/GSK1349572 PK were evaluated.

Methods: A randomized, open label, two period, crossover study was conducted in healthy adult subjects. Twenty-four subjects received S/GSK1349572 30 mg every 24 h for 5 days. Subjects then were administered S/GSK1349572 30 mg every 24 h in combination with either ATV/RTV 300/100 mg every 24 h (n= 12) or ATV 400 mg every 24 h (n= 12) for 14 days. Serial PK samples and safety assessments were obtained throughout the study.

Results: The combination of S/GSK1349572 with ATV/RTV or ATV was generally well tolerated. All adverse events were mild or moderate, and no subject withdrew because of an adverse event. The AE of highest frequency was ocular icterus, observed only during combination of S/GSK1349572 and ATV or ATV/RTV. Co-administration with ATV/RTV resulted in increased plasma S/GSK1349572 area under the concentration-time curve during a dosing interval (AUC(0,τ)), observed maximal concentration (C(max) ), and concentration at the end of dosing interval at steady state (C(τ) ) by 62%, 34% and 121%, respectively. Co-administration with ATV resulted in increased plasma S/GSK1349572 AUC(0,τ), C(max) , and C(τ) by 91%, 50% and 180%, respectively.

Conclusions: Co-administration of ATV/RTV and ATV was generally well tolerated and produced a modest, non-clinically significant increase in S/GSK1349572 exposure. No dose adjustment for S/GSK1349572 is necessary when co-administered with ATV and ATV/RTV.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Area Under Curve
  • Atazanavir Sulfate
  • Cross-Over Studies
  • Drug Administration Schedule
  • Drug Combinations
  • Drug Interactions
  • Female
  • Glucuronosyltransferase / antagonists & inhibitors
  • HIV Integrase Inhibitors / pharmacokinetics*
  • HIV Protease Inhibitors / pharmacology*
  • Heterocyclic Compounds, 3-Ring / pharmacokinetics*
  • Humans
  • Linear Models
  • Male
  • Middle Aged
  • Oligopeptides / pharmacology*
  • Oxazines
  • Piperazines
  • Pyridines / pharmacology*
  • Pyridones
  • Ritonavir / pharmacology*
  • Young Adult


  • Drug Combinations
  • HIV Integrase Inhibitors
  • HIV Protease Inhibitors
  • Heterocyclic Compounds, 3-Ring
  • Oligopeptides
  • Oxazines
  • Piperazines
  • Pyridines
  • Pyridones
  • Atazanavir Sulfate
  • dolutegravir
  • Glucuronosyltransferase
  • Ritonavir