Objective: To study the pharmacokinetic properties and clinical efficacy of the HIV-1 protease inhibitor (PI) indinavir in the central nervous system (CNS).
Design: Twenty-five consecutive HIV-1 infected patients on combination therapy that included indinavir, had cerebrospinal fluid (CSF) and plasma samples taken on 32 different occasions, at different times after indinavir administration. CSF and viral load data obtained from these treated patients were compared with those from 36 untreated HIV-1 infected patients of similar immunological and demographic pre-treatment status.
Methods: Concentrations of indinavir were measured in CSF and plasma by high-pressure liquid chromatography with ultraviolet light detection and the data were used in pharmacokinetic modelling.
Results: The concentration of indinavir in plasma varied with time over a dose interval by about two orders of magnitude, whereas the concentration in CSF was relatively stable. The median concentration of indinavir in CSF was 210 nmol/l, which is above the 95% inhibitory concentration in vitro. Findings from the pharmacokinetic modelling indicate that indinavir is actively transported out of the CSF (P <0.001 compared with a passive transport-only model). In the PI-treated group there was a reduction in viral load to below 50 copies/ml in most subjects and a normalization of the CSF cell content and IgG-index.
Conclusions: This study has shown that one PI, indinavir, is present in the CSF at therapeutic concentrations, and is likely to contribute to the antiretroviral activities observed within the CNS.