Low Atazanavir concentrations in cerebrospinal fluid.

Type: Poster
Title: Low Atazanavir concentrations in cerebrospinal fluid.
Authors: Best BM, Letendre S, Patel P, Clifford D, Collier A, Gelman B, McArthur J, McCutchan J, Simpson D, Capparelli E
Date: 02-05-2006
Abstract:BACKGROUND. HIV Neurocognitive Impairment (HNCI) is prevalent despite the use of combination antiretroviral therapy. Protease inhibitors (PIs) are potent antiretrovirals but may not penetrate into the central nervous system (CNS) in therapeutic concentrations, which may allow ongoing replication and injury. Atazanavir (ATV) is a commonly used PI, 14% of which is unbound to plasma proteins and therefore available to penetrate into the CNS. The objective of this study was to determine the penetration of ATV into cerebrospinal fluid (CSF). METHODS. CHARTER is an on-going, multi-center, observational study to determine the effects of potent antiretroviral therapy on HIV-associated neurological disease. Single random plasma and CSF samples were drawn within an hour of each other from subjects taking ATV-ritonavir between October 2003 and October 2005. Plasma samples were assayed by HPLC and immunoassay; lower limit of detection 45 ng/mL. CSF samples were assayed by immunoassay (ARK ATV-Test); lower limit of detection 5 ng/mL. Data were analyzed using summary statistics and linear regression. RESULTS. 57 participants (age 43 ± 8 years; 80 ± 13 kg; 6 females; 26 White, 23 Black, 6 Hispanic) had paired samples drawn 12 ± 6 hours post-dose. In those taking ritonavir, the median plasma and CSF ATV concentrations after 8 months of therapy (median) were 1,510 ng/mL (range BQL – 5,295) and 10.3 ng/mL (range BQL – 38.4). The median CSF/plasma concentration ratio was 0.007. 42/76 (55%) CSF samples were below 11 ng/mL, the ATV wild-type IC50. Nine paired CSF and plasma samples were below detection. Eleven additional patients with plasma concentrations below 600 ng/mL had CSF samples below detection, as expected based on the observed CSF/plasma ratio. Plasma concentrations correlated with CSF concentrations (r2=0.68). Plasma and CSF viral loads at the time of sampling were 2.5 ± 1.1 and 1.9 ± 0.4 log10 copies/mL. CONCLUSIONS. ATV concentrations in CSF are highly variable and are 100-fold lower than plasma concentrations, even with ritonavir-boosting. Observed CSF concentrations were less than the estimated free concentration in plasma (~140 ng/mL), suggesting active transport out of the CSF. Increasing plasma exposure to ATV may increase ATV CSF penetration. CSF concentrations of ATV do not consistently exceed the wild-type IC50 of ATV, and may not afford protection against HIV replication in the CSF