Population pharmacokinetics of nevirapine, zidovudine, and didanosine in human immunodeficiency virus-infected patients

Xiao Jian Zhou, Lewis B. Sheiner, Richard T. D'Aquila, Michael D. Hughes, Martin S. Hirsch, Margaret A. Fischl, Victoria A. Johnson, Maureen Myers, Jean Pierre Sommadossi

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78 Scopus citations

Abstract

The population pharmacokinetics of nevirapine (NVP), zidovudine (ZDV), and didanosine (ddI) were evaluated in a total of 175 patients infected with human immunodeficiency virus randomized to receive either a double combination of ZDV plus ddI or a triple combination of NVP plus ZDV plus ddI as a substudy of the AIDS Clinical Trials Group Protocol 241. Levels (approximating 3.5 determinations/patient) of the three drugs in plasma were measured during 44 of a total 48 weeks of study treatment, and a set of potential covariates was available for nonlinear mixed-effect modeling analysis. A one-compartment model with zero-order input and first-order elimination was fitted to the NVP data. Individual oral clearance (CL) and volume of distribution (V) averaged 0.0533 liters/h/kg of body weight and 1.17 liters/kg, respectively. Gender was the only covariate which significantly correlated with the CL of NVP. ZDV and ddI data were described by a two-compartment model with zero-order input and first-order elimination. Individual mean oral CL, V(SS) (volume of distribution at steady state), and V of ZDV were 1.84 liters/h/kg and 6.68 and 2.67 liters/kg, respectively, with body weight and age as correlates of CL and body weight as a correlate of V(SS). The average individual oral CL, V(SS), and V of ddI were 1.64 liters/h/kg and 3.56 and 2.74 liters/kg, respectively, with body weight as a significant correlate of both CL and V(SS). The relative bioavailability (F) of ZDV and ddI in the triple combination compared to that in the double combination was also evaluated. No significant effects of the combination regimens on the F of ddI were detected (F(TRIPLE) = 1.05 and F(DOUBLE) = 1 by definition), but the F of ZDV was markedly reduced by the triple combination, being only 67.7% of that of the double combination. Large (>50%) intraindividual variability was associated with both ZDV and ddI pharmacokinetics. Individual cumulative area under the plasma drug level- time curve of the three drugs was calculated for the entire study period as a measure of drug exposure based on the individual data and the final-model estimates of structural and statistical parameters.

Original languageEnglish (US)
Pages (from-to)121-128
Number of pages8
JournalAntimicrobial agents and chemotherapy
Volume43
Issue number1
DOIs
StatePublished - 1999

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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    Zhou, X. J., Sheiner, L. B., D'Aquila, R. T., Hughes, M. D., Hirsch, M. S., Fischl, M. A., Johnson, V. A., Myers, M., & Sommadossi, J. P. (1999). Population pharmacokinetics of nevirapine, zidovudine, and didanosine in human immunodeficiency virus-infected patients. Antimicrobial agents and chemotherapy, 43(1), 121-128. https://doi.org/10.1128/aac.43.1.121