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Antimicrobial Agents and Chemotherapy, August 2000, p. 2052-2060, Vol. 44, No. 8
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Population Pharmacokinetics and Pharmacodynamic Modeling of Abacavir (1592U89) from a Dose-Ranging, Double-Blind, Randomized Monotherapy Trial with Human Immunodeficiency Virus-Infected Subjects

Stephen Weller,* Kristine M. Radomski,dagger Yu Lou, and Daniel S. Stein

Worldwide Clinical Pharmacology, Glaxo Wellcome Inc., Research Triangle Park, North Carolina

Received 23 September 1999/Returned for modification 23 January 2000/Accepted 26 April 2000

Abacavir (formerly 1592U89) is a carbocyclic nucleoside analog with potent anti-human immunodeficiency virus (anti-HIV) activity when administered alone or in combination with other antiretroviral agents. The population pharmacokinetics and pharmacodynamics of abacavir were investigated in 41 HIV type 1 (HIV-1)-infected, antiretroviral naive adults with baseline CD4+ cell counts of >= 100/mm3 and plasma HIV-1 RNA levels of >30,000 copies/ml. Data for analysis were obtained from patients who received randomized, blinded monotherapy with abacavir at 100, 300, or 600 mg twice-daily (BID) for up to 12 weeks. Plasma abacavir concentrations from sparse 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 estimates were calculated to determine the peak concentration of abacavir in plasma (Cmax) and the area under the concentration-time curve from time zero to infinity (AUC0-infinity ) for individual subjects. The pharmacokinetics of abacavir were dose proportional over the 100- to 600-mg dose range and were unaffected by any covariates. No significant correlations were observed between the incidence of the five most common adverse events (headache, nausea, diarrhea, vomiting, and malaise or fatigue) and AUC0-infinity . A significant correlation was observed between Cmax and nausea by categorical analysis (P = 0.019), but this was of borderline significance by logistic regression (odds ratio, 1.45; 95% confidence interval, 0.95 to 2.32). The log10 time-averaged AUC0-infinity minus baseline (AAUCMB) values for HIV-1 RNA and CD4+ cell count correlated significantly with Cmax and AUC0-infinity , but with better model fits for AUC0-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. There was less than a 0.4 log10 difference over 12 weeks in the HIV-1 RNA levels with the doubling of the abacavir AUC0-infinity from 300 to 600 mg BID dosing. In conclusion, pharmacodynamic modeling supports the selection of abacavir 300 mg twice-daily dosing.

* Corresponding author. Mailing address: Division of Clinical Pharmacology, Glaxo Wellcome Inc., 5 Moore Dr., Research Triangle Park, NC 27709. Phone: (919) 483-1273. Fax: (919) 483-6380. E-mail: sw46385{at}glaxowellcome.com.

dagger Present address: Pharmaceutical Sciences Department, St. Jude Children's Research Hospital, Memphis, Tenn.

Antimicrobial Agents and Chemotherapy, August 2000, p. 2052-2060, Vol. 44, No. 8
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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