Model-based approach for optimization of atazanavir dose recommendations for HIV-infected pediatric patients

Antimicrob Agents Chemother. 2011 Dec;55(12):5746-52. doi: 10.1128/AAC.00554-11. Epub 2011 Sep 19.

Abstract

Atazanavir (Reyataz; ATV) is a well-tolerated protease inhibitor (PI) that is indicated as a once-daily treatment for HIV infections. These features of ATV, combined with its virologic potency, make it particularly desirable for the treatment of HIV-infected pediatric patients. The objective of this study was to use a model-based approach to recommend body weight-based ATV capsule doses for pediatric patients. ATV concentration-time data from three adult studies and one pediatric study were described by a C(0)-delinked one-compartment model to guard against introducing bias in pharmacokinetic (PK) parameter estimates due to the potential nonadherence in outpatient studies. The apparent clearance (CL/F) and apparent volume of distribution (V/F) were determined to increase with body weight, and CL/F was 40.9% lower in patients receiving ATV comedication with ritonavir (RTV). The relative bioavailability (F(rel)) of ATV was 132% higher with RTV comedication and was 35.5% lower for the ATV powder formulation than the capsule formulation. Model-based simulations were used to recommend weight-based ATV capsule doses of 150 to 300 mg boosted with 100 mg RTV for pediatric patients weighing ≥15 kg, such that the exposures in these patients are similar to those obtained in HIV-infected adults treated with the recommended ATV/RTV dose of 300/100 mg.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Anti-HIV Agents / administration & dosage
  • Anti-HIV Agents / pharmacokinetics
  • Anti-HIV Agents / therapeutic use
  • Atazanavir Sulfate
  • Body Weight / drug effects
  • Child
  • Clinical Trials as Topic
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • HIV Infections / drug therapy*
  • HIV Infections / virology
  • HIV Protease Inhibitors / administration & dosage*
  • HIV Protease Inhibitors / pharmacokinetics*
  • HIV Protease Inhibitors / therapeutic use
  • HIV-1 / drug effects
  • Humans
  • Male
  • Models, Biological*
  • Oligopeptides / administration & dosage*
  • Oligopeptides / pharmacokinetics*
  • Oligopeptides / therapeutic use
  • Pediatrics
  • Practice Guidelines as Topic
  • Pyridines / administration & dosage*
  • Pyridines / pharmacokinetics*
  • Pyridines / therapeutic use
  • Treatment Outcome

Substances

  • Anti-HIV Agents
  • HIV Protease Inhibitors
  • Oligopeptides
  • Pyridines
  • Atazanavir Sulfate