Background: Lamivudine (3TC) and zidovudine (AZT) are potent selective inhibitors of HIV reverse transcriptase and, due to their synergistic effect, are available as a fixed dose combination (FDC) tablet for use in antiretroviral therapy (ART). The absorption and exposure of AZT and 3TC from single component and fixed-dose combination formulations are considered to be comparable. The aim of our analysis was to determine if the absorption of 3TC and AZT is correlated when administered as a fixed-dose combination tablet.
Methods: Log-transformed 3TC and AZT concentration-time data from 25 healthy volunteers were analysed separately and simultaneously using nonlinear mixed effects modelling. Two compartment disposition models with exponential between-subject variability and proportional residual variability were evaluated. Typical population values were estimated using the FOCE INTER method in NONMEM 6.2. The final model was evaluated using the nonparametric bootstrap and visual predictive check tools of PsN. Correlations were calculated using estimates of the variances and covariances of the random effects.
Results: The absorption of AZT and 3TC was highly variable. The BSV (CV%) in the absorption rate constants (Ka) was 170% and 91%, respectively, and highly correlated (correlation = 0.93). Population pharmacokinetic parameters for AZT were similar whether analysed separately or simultaneously with 3TC. During simultaneous analysis, estimates of 3TC CL/F and 3TC V2/F became unreliable (16.5 L/h and 418 L vs 0.986 L/h and 3150 L, respectively). The addition of correlation between BSV in Ka of AZT and 3TC significantly improved the model fit.
Conclusion: The absorption of AZT and 3TC was highly variable. The BSV (CV%) in the absorption rate constant (Ka) was 170% and 91%, respectively, and highly correlated (correlation = 0.93).