Population pharmacokinetic analysis of anti-retroviral therapies

The basic tenet of clinical pharmacokinetics is that the magnitudes of both the desired response and toxicity are functions of drug concentrations at the site(s) of action. Utilizing population pharmacokinetic models drug therapy can be prospectively individualized to achieve a target systemic exposure. This dissertation is the application of population pharmacokinetic modeling to quantitate the pharmacological relationship between drug exposure and response, and to investigate the sources of variation between individuals to selected antiretroviral regimens.;The first objective was to develop a model to characterize the plasma and intracellular pharmacokinetics of TFV (tenofovir) and TFV-DP (tenofovir diphosphate). Since the relationships among the TDF dose given to patients, the plasma concentrations of TFV and the intracellular concentrations of TFV-DP remain poorly understood. The developed model was able to describe for the first time the plasma pharmacokinetic of TFV and links by way of an indirect response model these plasma concentrations to the formation of the intracellular, pharmacologically-active moiety, TFV-DP. The applicability of the model was tested by investigating and showing differences in TFV and TFV-DP pharmacokinetics by age. This linked plasma and intracellular model should facilitate more informed investigations of the clinical pharmacology of TFV through an ability to predict intracellular concentrations based on knowledge of plasma concentrations.;The second objective was to use results from a randomized clinical trial to estimate the pharmacokinetic characteristics of atazanavir (ATV) and efavirenz (EFV) separately and characterize interpatient variability and identify patient covariates influencing the pharmacokinetics of ATV and EFV by using population techniques. The results from these analyses show that with sparse one observation per patient data, using population pharmacokinetic approach the mixture model was able to estimate and satisfactory describe ATV and EFV pharmacokinetic estimates including effects of known covariates which were comparable with previously published studies. The results were also able to provide an explanation for the reason for failure of ATV arm when compared with EFV arm.