title: Model-based approach for optimization of atazanavir dose recommendations for HIV-infected pediatric patients.
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.
authors.affiliation: Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb, Princeton, New Jersey 08543, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hong
authors.forename: Kenneth G
authors.initials: KG
authors.lastname: Kowalski
authors.forename: Jenny
authors.initials: J
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.forename: Mariaarantxa
authors.initials: M
authors.lastname: Horga
authors.forename: Richard
authors.initials: R
authors.lastname: Bertz
authors.forename: Marc
authors.initials: M
authors.lastname: Pfister
authors.forename: Amit
authors.initials: A
authors.lastname: Roy
mesh_terms: D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D000069446:Atazanavir Sulfate; D001835:Body Weight / Q000187:drug effects; D002648:Child; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008297:Male; D008954:Models, Biological; D009842:Oligopeptides / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010372:Pediatrics; D017410:Practice Guidelines as Topic; D011725:Pyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D000069446:Atazanavir Sulfate