Two clinical studies (PRINCE-1 and -2) in HIV-1-infected children assessed the safety, efficacy, and pharmacokinetics of dual nucleos(t)ide reverse transcriptase inhibitor (NRTI) background therapy plus once-daily atazanavir powder formulation boosted with ritonavir (ATV+RTV). Here, we present a combined analysis of ATV pharmacokinetics and pharmacodynamics across these studies.
Intensive 24-hour pharmacokinetic profiles at steady state compared ATV exposures (area under the concentration–time curve in one dosing interval [AUCτ]) in 5 ATV+RTV baseline weight-band dosing categories with historic data in adults receiving ATV+RTV 300/100-mg capsules. Repeated ATV Ctrough measurements over 48 weeks explored relationships between ATV composite Ctrough quartiles (CCQs) with virologic efficacy and key safety parameters.
Of 146 children included in this combined analysis, 49.3% were male, 56.8% were Black/African American, and 62.3% were antiretroviral-experienced. Proportions with HIV-1 RNA <50 copies/mL at Week 48 were 13/32, 24/32, 19/32, and 13/28 in the lowest through highest ATV CCQs, respectively. Mean changes from baseline in total bilirubin at Week 48 were +0.3, +0.5, +0.6, and +1.0 mg/dL in the lowest through highest ATV CCQs, respectively. Corresponding proportions with adverse events of hyperbilirubinemia by Week 48 were 1/36, 4/36, 5/36 and 13/35, respectively. Changes from baseline in total amylase or electrocardiogram parameters and adverse events of diarrhea did not vary by ATV CCQs.
Weight-band dosing of ATV+RTV plus optimized dual NRTIs in young HIV-1-infected children achieved similar ATV exposure to that in adults; no unexpected safety findings occurred, and, with the exception of lower virologic suppression in the lowest ATV CCQ, there was no apparent trend in virologic suppression across ATV CCQs.
*Bristol-Myers Squibb, Princeton, New Jersey; †Bristol-Myers Squibb, Hopewell, New Jersey; and ‡Bristol-Myers Squibb, Wallingford, Connecticut
Conflicts of Interest and Source of Funding: These studies were supported by Bristol-Myers Squibb, the manufacturer of atazanavir. LZ, RW, XX, and TAC are all employees of and own stock in Bristol-Myers Squibb. HS was an employee of Bristol-Myers Squibb at the time the study was conducted and is now an employee of ViiV Healthcare. CP was an employee of Bristol-Myers Squibb at the time this study was conducted and is now an employee of Gilead Sciences, Inc. TE was an employee of Bristol-Myers Squibb at the time the study was conducted and is now an employee of Arbutus Biopharma Corporation.
ACKNOWLEDGMENTS: The authors would like to thank all study investigators and participants. Medical writing assistance was provided by Julian Martins of inScience Communications, Springer Healthcare, which was funded by Bristol-Myers Squibb.
Address for Correspondence: Todd Correll, PharmD, Bristol-Myers Squibb, Route 206, Province Line Road, Princeton, New Jersey 08543, USA. Tel: (609) 252-7214; Fax: Not available; E-mail: email@example.com