Joint population pharmacokinetic analysis of zidovudine, lamivudine, and their active intracellular metabolites in HIV patients

Abstract

The population pharmacokinetic parameters of zidovudine (AZT), lamivudine (3TC), and their active intracellular metabolites in 75 naïve HIV-infected patients receiving an oral combination of AZT and 3TC twice daily as part of their multitherapy treatment in the COPHAR2-ANRS 111 trial are described. Four blood samples per patient were taken after 2 weeks of treatment to measure drug concentrations at steady state. Plasma AZT and 3TC concentrations were measured in 73 patients, and among those, 62 patients had measurable intracellular AZT-TP and 3TC-TP concentrations. For each drug, a joint population pharmacokinetic model was developed and we investigated the influence of different covariates. We then studied correlations between the mean plasma and intracellular concentrations of each drug. A one-compartment model with first-order absorption and elimination best described the plasma AZT concentration, with an additional compartment for intracellular AZT-TP. A similar model but with zero-order absorption was found to adequately described concentrations of 3TC and its metabolite 3TC-TP. The half-lives of AZT and 3TC were 0.81 h (94.8%) and 2.97 h (39.2%), respectively, whereas the intracellular half-lives of AZT-TP and 3TC-TP were 10.73 h (69%) and 21.16 h (44%), respectively. We found particularly a gender effect on the apparent bioavailability of AZT, as well as on the mean plasma and intracellular concentrations of AZT, which were significantly higher in females than in males. Relationships between mean plasma drug and intracellular metabolite concentrations were also highlighted both for AZT and for 3TC. Simulation with the model of plasma and intracellular concentrations for once- versus twice-daily regimens suggested that a daily dosing regimen with double doses could be appropriate.

Fig. 1.

Schematic representation of joint pharmacokinetic compartment models for the simultaneous prediction of plasma AZT and 3TC concentrations and intracellular concentrations of their active metabolites. AZT (or 3TC) in compartment 1 underwent irreversible biotransformation into AZT-TP (or 3TC-TP) in compartment 2. D, dose; F, bioavailability of the parent drug; k_a, first-order absorption rate constant of AZT; Tk0, zero-order absorption duration for 3TC; k_m, first-order metabolism rate constant; k_e, first-order elimination rate constant of the parent drug; V, volume of distribution of the parent drug; V_m, volume of distribution of the metabolite; k_em, first-order elimination rate constant of the metabolite.

Fig. 2.

VPCs of the basic joint population pharmacokinetic model for AZT (left) and AZT-TP (right) at steady state for 300 mg of AZT b.i.d. (A) and observed plasma concentrations of AZT (left) and intracellular concentrations of AZT-TP (right) (A) versus time. VPCs of the basic joint population pharmacokinetic model for 3TC (left) and 3TC-TP (right) at steady state for 150 mg of 3TC b.i.d. (B) and observed plasma concentrations of 3TC (left) and intracellular concentrations of 3TC-TP (right) (B) versus time. The dashed lines are the median predictions, and the shaded areas are the 90% prediction intervals. Intracellular concentrations of AZT-TP and 3TC-TP expressed from the assay in fmol/liter were transformed into mg/liter by using the following molar masses: AZT-TP, 507 g/mol; 3TC-TP, 469 g/mol.

Fig. 3.

Relationships between mean plasma AZT and 3TC concentrations (A), between mean intracellular AZT-TP and 3TC-TP concentrations (B), between mean plasma AZT concentrations and mean intracellular AZT-TP concentrations (C), and between mean plasma 3TC concentrations and mean intracellular 3TC-TP concentrations (D).

Fig. 4.

Relationships between mean plasma AZT concentrations and the gender covariate (left) and between mean intracellular AZT-TP concentrations and the gender covariate (right).

Fig. 5.

Predicted plasma AZT concentrations (left) and intracellular AZT-TP concentrations (right) at steady state for AZT at 600 mg/day (q.d) (gray line) and 300 mg b.i.d. (A) and plasma 3TC concentrations (left) and intracellular 3TC-TP concentrations (right) at steady state for 3TC at 300 mg/day (black line) and 150 mg b.i.d. (B). The dashed and solid lines represent the 90% prediction intervals and median predictions, respectively, obtained by Monte Carlo simulation with 3,000 individuals using the parameters presented in Tables 2 and 3.