Pharmacokinetic/pharmacodynamic Modeling to optimize efavirenz dosing in HIV/AIDs infected children from Sub-Saharan Africa.

Abstract

Aim:Using a model‐based approach, the efavirenz steady‐state pharmacokinetics in Sub-Saharan African children is characterized, quantifying demographic and genotypic effects on the drug's disposition. Simulations are also conducted allowing the prediction of optimized doses of efavirenz in this population. Methods: We modeled the steady‐state population pharmacokinetics of efavirenz in Ugandan and Ethiopia children using nonlinear mixed‐effects modeling. Individual mid‐dose efavirenz concentrations were derived and simulations explored weight‐based dose optimization strategies. Results: A one-compartment model with linear elimination described the data. 13.5% of the concentrations were <1mg/L, 46.7% between 1 and 4 mg/L, and 39.8% > 4 mg/L. Clearance was affected by the CYP3A5*3 genotype using population pharmacokinetics analysis. Wild-type individuals had lower odds of virological failures. Simulations showed that individuals were slow metabolizers and hence highly exposed. Conclusion: Dosage guidelines for African children should take into consideration the weight band-based dose reduction.