In patients with typical plasma levels of LPV, the drug is detectable in the CSF at concentrations that exceed those needed to inhibit HIV replication. Despite being > 98% bound to plasma proteins, LPV penetrates into the CNS and may contribute to the control of HIV in this potential reservoir.

Plasma and cerebrospinal fluid (CSF) indinavir concentrations were measured by high-performance liquid chromatography. The median concentration in plasma exceeded that in CSF 10-fold. The modeled CSF curve was flat at 155 nM, and the estimated ratio of the areas under the CSF and plasma concentration-time curves was 6%. We conclude that CSF indinavir concentrations are lower than levels in plasma but exceed the clinical 95% inhibitory concentration range.Combining nucleoside analogue reverse transcriptase inhibitors with protease inhibitors (PIs) can dramatically reduce viral replication, preserve immune function, and prolong survival. Combination regimens may also reduce human immunodeficiency virus (HIV) replication in the cerebrospinal fluid (CSF) (1, 6, 9, 13; M. Gisslen, L. Hagberg, B. Svennerholm, and G. Norkrans, Letter, AIDS 11:1194, 1997). However, the independent contribution of PIs to such reductions is unclear since PIs are highly protein bound and, therefore, may not reach therapeutic concentrations in the central nervous system (CNS) (1, 5). In fact, the failure of PIs to consistently control HIV replication in the CNS is supported by clinical studies (7; E. H. Gisolf, S. Juriaans, M. E. van der Ende, P. Portegies, R. Hoetelmans, and S. A. Danner, Sixth Conf. Retroviruses Opportunistic Infect., poster 403, 1999).Among the currently available PIs, indinavir (IDV) binds the least to plasma proteins (ϳ60%), which suggests that it may penetrate into the CNS well enough to be efficacious (8 1997). These studies estimated the CNS penetration of IDV by calculating the ratios of the concentrations in CSF and plasma. This method produces an estimate of drug exposure that is limited by its sensitivity to the interval between dosing and sample collection.Since the ratio of the areas under the CSF and plasma concentration curves (AUC CSF /AUC plasma ) accounts for variability over the entire dosing interval, it is a more accurate estimate of CSF penetration over time than the ratio of the concentrations in CSF and plasma (3,8,12). Martin and colleagues used pharmacokinetic modeling to support a role for active transport of IDV out of the CSF (9). In this study, we used population pharmacokinetic (PPK) methods to estimate the IDV AUC CSF /AUC plasma ratio.Twenty-two matched CSF and plasma samples from 22 adults were selected from the specimen bank of the HIV Neurobehavioral Research Center. All patients were at steady state on IDV-containing antiretroviral regimens and were free of opportunistic conditions. All 22 subjects took 800 mg of IDV orally every 8 h with either stavudine-lamivudine (3TC) (13 of 22), zidovudine-3TC (7 of 22), stavudine-dideoxycytosine (1 of 22) or 3TC alone (1 of 22).Blood and CSF samples were obtained within 2 h of each other. IDV levels were measured by high-performance liquid chromatography (HPLC) at Merck Research Laboratories (West Point, Pa.). The CSF assay was validated over the range of 2.8 to 2,800 nM and had a precision of Ͻ10% of the coefficient of variation. The plasma assa...