Population Pharmacokinetics of Abacavir in Plasma and Cerebrospinal Fluid

Abstract

The distribution of abacavir into the cerebrospinal fluid (CSF) was assessed by use of a population pharmacokinetic analysis. Plasma and CSF abacavir concentrations in 54 subjects were determined. The abacavir CSF/plasma ratio averaged 36% and increased throughout the dose interval. Abacavir penetrates into the CSF in adequate concentrations to inhibit local human immunodeficiency virus replication.Nucleoside reverse transcriptase inhibitors, in combination with potent nonnucleoside reverse transcriptase inhibitors or protease inhibitors, can decrease viral replication, improve immune function, and prolong survival. Combination antiretroviral regimens may also reduce viral replication in the central nervous system (CNS). Nucleosides appear to penetrate into the CNS better than protease inhibitors and have been useful in treating patients with human immunodeficiency virus (HIV)-associated dementia (5, 12). Many of these agents are substrates for active transporter systems that effectively pump drugs out of the CNS. Cerebrospinal fluid (CSF) and plasma exhibit different viral dynamics, indicating that the CNS may serve as an independent reservoir for HIV replication (4, 6). Optimal antiretroviral concentrations in the CNS are necessary to limit local HIV replication and prevent the development of drug-resistant virus and overall treatment failure (11). A few pharmacokinetic evaluations of abacavir in primates and humans have reported limited penetration into the CNS, as characterized by CSF/plasma ratios, ranging from less than 20% to 35% (3, 8). However, most of these evaluations were derived from measurements collected early in the dose interval, which may have biased the estimates of CSF penetration (4, 5, 7). The CSF/plasma concentration ratio is a dynamic measure, and single measurements may not accurately estimate exposure in this potential sanctuary. The ratio of the areas under the CSF and plasma concentration-time curves (AUC CSF / AUC plasma ) is a better estimate of drug exposure, as it accounts for the variability over the entire dosing interval, thus giving a more accurate estimate of CNS penetration (2, 10). Since multiple CSF samples for individual AUC determinations are difficult to collect, we used sparse CSF and plasma concentrations with population pharmacokinetic analysis to estimate the population abacavir AUC CSF /AUC plasma ratio in HIV-infected patients.Plasma and CSF samples were obtained from 54 male adult HIV-infected patients receiving an abacavir-containing regimen. All subjects were consenting participants in prospective research studies conducted at the University of California San Diego HIV Neurobehavioral Research Center and approved by the University of California San Diego Institutional Review Board. Fifty-one subjects (94%) were taking abacavir according to a conventional dosing schedule, (300 mg twice daily), while three received 150 mg, 400 mg, or 600 mg twice daily, respectively. All patients were at steady state and free of opportunistic infection at the time of sample colle...

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