Pharmacokinetics of antiretroviral regimens containing tenofovir disoproxil fumarate and atazanavir-ritonavir in adolescents and young adults with human immunodeficiency virus infection.

TitlePharmacokinetics of antiretroviral regimens containing tenofovir disoproxil fumarate and atazanavir-ritonavir in adolescents and young adults with human immunodeficiency virus infection.
Publication TypePublication
Year of Publication2008
AuthorsKiser JJ, Fletcher CV, Flynn PM, Cunningham CK, Wilson CM, Kapogiannis BG, Major-Wilson H, Viani RM, Liu NX, Muenz LR, D Harris R, Havens PL
Corporate AuthorsAdolescent Trials Network for HIV/AIDS Interventions
JournalAntimicrob Agents Chemother
Volume52
Issue2
Pagination631-7
Date Published2008 Feb
ISSN0066-4804
KeywordsAdenine, Adolescent, Adult, Anti-HIV Agents, Area Under Curve, Atazanavir Sulfate, Drug Interactions, Drug Therapy, Combination, Female, HIV Infections, HIV-1, Humans, Leukocytes, Mononuclear, Male, Oligopeptides, Organophosphonates, Pyridines, Reverse Transcriptase Inhibitors, Ritonavir, Tenofovir
Abstract

<p>The primary objective of this study was to measure atazanavir-ritonavir and tenofovir pharmacokinetics when the drugs were used in combination in young adults with human immunodeficiency virus (HIV). HIV-infected subjects > or =18 to <25 years old receiving (> or =28 days) 300/100 mg atazanavir-ritonavir plus 300 mg tenofovir disoproxil fumarate (TDF) plus one or more other nucleoside analogs underwent intensive 24-h pharmacokinetic studies following a light meal. Peripheral blood mononuclear cells were obtained at 1, 4, and 24 h postdose for quantification of intracellular tenofovir diphosphate (TFV-DP) concentrations. Twenty-two subjects were eligible for analyses. The geometric mean (95% confidence interval [CI]) atazanavir area under the concentration-time curve from 0 to 24 h (AUC(0-24)), maximum concentration of drug in serum (C(max)), concentration at 24 h postdose (C(24)), and total apparent oral clearance (CL/F) values were 35,971 ng x hr/ml (30,853 to 41,898), 3,504 ng/ml (2,978 to 4,105), 578 ng/ml (474 to 704), and 8.3 liter/hr (7.2 to 9.7), respectively. The geometric mean (95% CI) tenofovir AUC(0-24), C(max), C(24), and CL/F values were 2,762 ng.hr/ml (2,392 to 3,041), 254 ng/ml (221 to 292), 60 ng/ml (52 to 68), and 49.2 liter/hr (43.8 to 55.3), respectively. Body weight was significantly predictive of CL/F for all three drugs. For every 10-kg increase in weight, there was a 10%, 14.8%, and 6.8% increase in the atazanavir, ritonavir, and tenofovir CL/F, respectively (P < or = 0.01). Renal function was predictive of tenofovir CL/F. For every 10 ml/min increase in creatinine clearance, there was a 4.6% increase in tenofovir CL/F (P < 0.0001). The geometric mean (95% CI) TFV-DP concentrations at 1, 4, and 24 h postdose were 96.4 (71.5 to 130), 93.3 (68 to 130), and 92.7 (70 to 123) fmol/million cells. There was an association between renal function, tenofovir AUC, and tenofovir C(max) and intracellular TFV-DP concentrations, although none of these associations reached statistical significance. In these HIV-infected young adults treated with atazanavir-ritonavir plus TDF, the atazanavir AUC was similar to those of older adults treated with the combination. Based on data for healthy volunteers, a higher tenofovir AUC may have been expected, but was not seen in these subjects. This might be due to faster tenofovir CL/F because of higher creatinine clearance in this age group. Additional studies of the exposure-response relationships of this regimen in children, adolescents, and adults would advance our knowledge of its pharmacodynamic properties.</p>

DOI10.1128/AAC.00761-07
Alternate JournalAntimicrob. Agents Chemother.
PubMed ID18025112
PubMed Central IDPMC2224775
Grant ListU01 HD040533 / HD / NICHD NIH HHS / United States
U01 HD040474 / HD / NICHD NIH HHS / United States
M01 RR00240 / RR / NCRR NIH HHS / United States
M01 RR165001 / RR / NCRR NIH HHS / United States
M01 RR000071 / RR / NCRR NIH HHS / United States
M01 RR00043 / RR / NCRR NIH HHS / United States
M01 RR000043 / RR / NCRR NIH HHS / United States
U01-HD040533 / HD / NICHD NIH HHS / United States
M01 RR00071 / RR / NCRR NIH HHS / United States
M01 RR000240 / RR / NCRR NIH HHS / United States