An in vivo Pharmacokinetic/Pharmacodynamic Model for Antiretroviral Combination

Abstract

Purpose: The objective of this study was to investigate the pharmacokinetic/pharmacodynamic properties of an antiretroviral therapy in HIV-infected patients. Method: Eight HIV-infected patients received zidovudine, lamivudine, and indinavir as their first antiretroviral treatment. Pharmacokinetic data were analyzed separately using a one-compartmental model with first-order absorption, and the individual estimates were used to simulate drug concentrations. To determine the relationship between drug concentrations and the antiviral effect, an in vitro E_max model was tested. Alternatively, a dynamic model was built describing the viral and cellular pathophysiology, including the turnover of viral replication in infected cells and the production of virus under treatment. Result: The E_max model fit poorly the experimental data. The complex model was not identifiable with the data available in this study, however a simplified model allowed us to estimate the pharmacodynamic parameters reflecting the decrease of both infected cells and viral load under antiretroviral treatment. Conclusion: Using potent highly active antiretroviral therapy, the treatment was so effective that it was not possible to estimate the parameters of the relationship between drug concentrations and the reduction of viral load. Even if the relationship does exist, the direct response model of antiretroviral agents cannot be demonstrated, however the simplified model provides an understanding of the synergy of such a combination and offers suggestions as how to prevent the emergence of viral resistant strains.