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

Jennifer J. Kiser, Courtney V. Fletcher, Patricia M. Flynn, Coleen K. Cunningham, Craig M. Wilson, Bill G. Kapogiannis, Hanna Major-Wilson, Rolando M. Viani, Nancy X. Liu, Larry R. Muenz, D. Robert Harris, Peter L. Havens, Ana Puga, Esmine Leonard, Zulma Eysallenne, Marvin Belzer, Cathy Salata, Diane Tucker, Jaime Martinez, Kelly BojanRachel Jackson, Donna Futterman, Elizabeth Enriquez-Bruce, Maria Campos, Linda Levin-Carmine, Mary Geiger, Angela Lee, Nehali Patel, Aditya Gaur, Mary Dillard, Ligia Peralta, Leonel Flores, Esther Collinetti, Lawrence Friedman, Donna Maturo, Bret Rudy, Mary Tanney, Adrienne DiBenedetto, Patricia Emmanuel, Silvia Callejas, Priscilla Julian

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Abstract

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 ≥ 18 to < 25 years old receiving (≥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 (AUC0-24), maximum concentration of drug in serum (Cmax), concentration at 24 h postdose (C24), and total apparent oral clearance (CL/F) values were 35,971 ng · 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, Cmax, C24, 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 ≤ 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 Cmax 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.

Original languageEnglish (US)
Pages (from-to)631-637
Number of pages7
JournalAntimicrobial agents and chemotherapy
Volume52
Issue number2
DOIs
StatePublished - Feb 2008

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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    Kiser, J. J., Fletcher, C. V., Flynn, P. M., Cunningham, C. K., Wilson, C. M., Kapogiannis, B. G., Major-Wilson, H., Viani, R. M., Liu, N. X., Muenz, L. R., Harris, D. R., Havens, P. L., Puga, A., Leonard, E., Eysallenne, Z., Belzer, M., Salata, C., Tucker, D., Martinez, J., ... Julian, P. (2008). Pharmacokinetics of antiretroviral regimens containing tenofovir disoproxil fumarate and atazanavir-ritonavir in adolescents and young adults with human immunodeficiency virus infection. Antimicrobial agents and chemotherapy, 52(2), 631-637. https://doi.org/10.1128/AAC.00761-07