In vivo effect of alpha(1)-acid glycoprotein on pharmacokinetics of amprenavir, a human immunodeficiency virus protease inhibitor

Observations from early clinical pharmacology studies of amprenavir, an inh ibitor of human immunodeficiency virus type 1 (HIV-1) protease that is high ly bound to human plasma proteins (similar to 90%), showed the single-dose pharmacokinetics of amprenavir to be variable between and within individual s. A cross-study analysis of various demographic, laboratory, and clinical covariates was therefore performed. Differences in amprenavir pharmacokinet ics could be due to variable concentrations in alpha (1)-acid glycoprotein (AAG), the predominant plasma protein to which amprenavir binds. Therefore, AAG was considered an important factor to study since the literature sugge sted that AAG levels vary by race, age, and weight and following trauma or infection, including HIV disease, Pooled data from three single-dose studie s analyzed by stepwise linear regression indicated that AAG concentrations significantly correlated with age and race and that only AAG concentrations were a significant predictor of amprenavir apparent total clearance (CL/F) , A significant inverse linear relationship was found between AAG and ampre navir CL/F, Compared to white subjects, black subjects had significantly lo wer AAG concentrations and therefore significantly higher amprenavir CL/F, Although AAG has a significant influence on the variability of total drug p harmacokinetics, unbound, or free, drug concentrations are not affected by AAG concentrations. Incorrect conclusions could be drawn on the pharmacokin etics of highly protein-bound drugs if AAG concentration is not included in the analysis.