Population pharmacokinetic meta-analysis of seven antiretroviral drugs
S. Petitprez (1), Y. Thoma (2), Y. Sutter (2), R. Hooper (2), M. Arab-Alameddine (3), T. Buclin (1), C.Csajka (1,4) and M. Guidi (1,4).
(1) Division of Clinical Pharmacology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland, (2) Reconfigurable and Embedded Digital Systems Institute, School of Business and Engineering Vaud, University of Applied Sciences Western Switzerland, Yverdon-les-Bains, (3) Merck Biopharma, Quantitative Řharmacology-global Early development, Switzerland, (4) School of Pharmacy, Department of Pharmaceutical Sciences, University of Geneva and Lausanne, Geneva Switzerland
Objectives: The giant advances in antiretroviral therapy (ART) in the last two decades have transformed HIV infection from a deadly disease into a manageable chronic condition. In this context, therapeutic drug monitoring (TDM) has acquired increasing relevance in the optimization of dosage regimens. In this study, a systematic review of available population pharmacokinetic (Pop-PK) studies was performed in order to generate meta-models of seven different ART drugs. These models will be implemented into a Bayesian TDM software which is currently under development.
Methods: A systematic literature search of Pop-PK studies on seven ART drugs was conducted. Pop-PK parameters were retrieved and normalized for a typical individual (70 kg, male, Caucasian, carrying reference allele for all influencing genetic covariates). Each model was then reduced to a one-compartment model with first-order absorption and elimination, retaining inter-patient variability on the PK parameters and proportional error models for residual variability description. Summary pharmacokinetic parameters across all studies were calculated with R using random effects models. PK percentiles for standard dosage regimens were generated (NONMEM®). The validation of the meta-models was performed by calculating bias and precision between predicted and observed ART concentrations collected within the framework of the Swiss HIV Cohort Study (SHCS), as well as visual predictive checks (VPC).
Results: This study provides a concise summary of Pop-PK models and parameters of seven ART. Clearance (CL), central volume of distribution (Vz) and absorption rate constant (Ka) values could be extracted from all the studies. Individual and summary CL and Vz values were in good accordance among the studies except for darunavir where Vz values varied between the 2 publications. Ka values showed more variability. Adequate predictions of drug concentrations were obtained in the validation process for all ART drugs.
Conclusions: This study provides Pop-PK parameters across all available studies for seven different ART drugs. Combined with the use of an user-friendly and state-of-the-art TDM computer software, these results will provide a valuable tool for optimizing antiretroviral therapy based on best available evidence.