Population pharmacokinetics and pharmacodynamic modeling of abacavir (1592U89) from a dose-ranging, double-blind, randomized monotherapy trial with human immunodeficiency virus-infected subjects

Abacavir (formerly 1592U89) is a carbocyclic nucleoside analog with potent anti-human immunodeficiency virus (anti HIV) activity when administered alo ne or in combination with other antiretroviral agents. The population pharm acokinetics and pharmacodynamics of abacavir were investigated in 41 HIV ty pe 1 (HIV-1)-infected, antiretroviral naive adults,vith baseline CD4(+) cel l counts of greater than or equal to 100/mm(3) and plasma HIV-1 RNA levels of >30,000 copies/ml, Data for analysis were obtained from patients who rec eived randomized, blinded monotherapy with abacavir at 100, 300, or 600 mg twice daily (BID) for up to 12 weeks. Plasma abacavir concentrations from s parse sampling were analyzed by standard population pharmacokinetic methods , and the effects of dose, combination therapy, gender, weight, and age on parameter estimates were investigated. Bayesian pharmacokinetic parameter e stimates were calculated to determine the peak concentration of abacavir in plasma (C-max) and the area under the concentration-time curve from time z ero to infinity (AUC(0=infinity)) for individual subjects. The pharmacokine tics of abacavir were dose proportional over the 100- to 600-mg dose range and were unaffected by any covariates. No significant correlations were obs erved between the incidence of the five most common adverse events (headach e, nausea, diarrhea, vomiting, and malaise or fatigue) and AUC(0-infinity). A significant correlation was observed between C-max and nausea by categor ical analysis (P = 0.019), but this was of borderline significance by logis tic regression (odds ratio, 1.45; 95% confidence interval, 0.95 to 232), Th e log(10) time averaged AUC(0-infinity) minus baseline (AAUCMB) values for HIV-1 RNA and CD4+ cell count correlated significantly with C-max and AUC(0 -infinity), but,vith better model fits for AUC(0-infinity), The increase in AAUCMB values for CD4+ cell count plateaued early for drug exposures that were associated with little change in AAUCMB values for plasma HIV-1 RNA. T here was less than a 0.4 log(10) difference over 12 weeks in the HIV-1 RNA levels with the doubling of the abacavir AUC(0-infinity) from 300 to 600 mg BID dosing. In conclusion, pharmacodynamic modeling supports the selection of abacavir 300 mg twice-daily dosing.