Therapeutic DRV and ETR concentrations in CSF.

Type: Poster
Title: Therapeutic DRV and ETR concentrations in CSF.
Authors: Best B, Letendre S, Croteau D, Capparelli E, Clifford D, Gelman B, Marra C, McArthur J, Simpson D, Grant I, and the CHARTER Group
Date: 02-28-2011
Abstract:Background: Antiretroviral therapy (ART) that reaches higher levels in cerebrospinal fluid (CSF) is associated with better control of HIV. The objective was to measure total and unbound darunavir (DRV) or etravirine (ETR) in CSF and compare findings to relevant plasma and inhibitory concentrations. This abstract combines data from two projects at the request of reviewers. Methods: Isotope-dilution LC/MS/MS was used to measure total DRV in 29 CSF and plasma pairs from 16 HIV+ participants (pts) and total ETR in 17 CSF and plasma pairs from 9 HIV+ pts. DRV and ETR were extracted with methyl-tert-butyl ether after addition of relevant internal standard. Unbound drug was measured by LC/MS/MS analysis of 10 kDa cut-off ultrafiltrates. Protein binding was determined by equilibrating bound drug in matrix via competitive exchange with radiolabeled drug and subsequent measurement of radiolabeled drug in the <30 kDa MW ultrafiltrate of matrix. Recovery from all matrices was ≥ 96% but non-specific binding of ETR during ultrafiltration precluded accurate calculation of unbound concentrations. Dynamic ranges of assays were 3.9 to 2,000 (plasma DRV or ETR) and 0.39 to 200 ng/mL (ultrafiltrate and CSF DRV or ETR). Levels in CSF were compared to the 50% inhibitory concentration (IC50) for wild-type HIV (DRV: 2.75 ng/mL, ETR: 0.696 ng/mL). Results: Median treatment durations were 7.3 (DRV) and 8.3 (ETR) months. CSF was sampled a median of 7.6 (DRV) and 4.9 hours (ETR) post-dose. Drug was detected in all CSF specimens: median concentrations 55.8 (DRV) and 9.5 ng/mL (ETR). 87% of DRV in plasma and 6.8% in CSF were protein-bound. Median CSF-to-total plasma ratios were 0.014 (DRV) and 0.042 (ETR). CSF levels correlated with total (ETR: r = 0.76, p < 0.001, DRV: r = 0.55, p = 0.002) and unbound (DRV: r = 0.64, p < 0.001) levels in plasma. CSF concentrations exceeded the IC50 of wild-type HIV (unbound DRV: median 18.9-fold, total ETR: 13.6-fold). Conclusions: DRV and ETR are present in CSF and exceed the wild-type IC50 in all pts. Negligible protein binding of DRV occurs in CSF. ETR concentrations in CSF were higher than estimated by physicochemical characteristics. DRV and ETR should contribute to control of HIV replication in the nervous system as components of effective ART