Etravirine in CSF is highly protein bound.
Title | Etravirine in CSF is highly protein bound. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Nguyen, A, Rossi, S, Croteau, D, Best, BM, Clifford, DB, Collier, AC, Gelman, B, Marra, C, McArthur, JC, McCutchan, JA, Morgello, S, Simpson, DM, Ellis, RJ, Grant, I, Capparelli, E, Letendre, S |
Corporate Authors | CHARTER Group |
Journal | J Antimicrob Chemother |
Volume | 68 |
Issue | 5 |
Pagination | 1161-8 |
Date Published | 2013 May |
ISSN | 1460-2091 |
Keywords | Adult, Anti-HIV Agents, Cerebrospinal Fluid, CHARTER, Chromatography, High Pressure Liquid, Cohort Studies, Female, HIV Infections, Humans, Inhibitory Concentration 50, Internal, Isotope Labeling, Male, Middle Aged, Plasma, Protein Binding, Proteins, Pyridazines, Tandem Mass Spectrometry, Ultracentrifugation |
Abstract | OBJECTIVES: Etravirine has high affinity for plasma drug-binding proteins, such as albumin and α1-acid glycoprotein, which limits the amount of unbound etravirine available to enter the CNS. The objective of this study was to compare total and unbound etravirine concentrations in CSF with plasma concentrations and the in vitro median inhibitory concentration (IC50) for wild-type HIV (0.9 ng/mL).METHODS: Total and bound etravirine concentrations were measured in 17 CSF and plasma pairs by isotope-dilution liquid chromatography tandem mass spectroscopy, radioligand displacement and ultracentrifugation. Unbound etravirine concentrations were calculated from the bound fraction. The dynamic range of the assay was 7.8-2000 (plasma) and 0.78-200 (CSF) ng/mL.RESULTS: Subjects were mostly middle-aged (median 43 years) white (78%) men (89%). All CSF etravirine concentrations were above the limit of quantification. Total and unbound median etravirine concentrations in CSF were 9.5 (IQR 6.4, 26.4) and 0.13 (IQR 0.08, 0.27) ng/mL, respectively. Etravirine was 96% (IQR 94.5, 97.2) protein bound in plasma and 98.4% (IQR 97.8, 98.8) in CSF. Total etravirine in CSF was 4.3% (IQR 3, 5.9) of total and 101% (IQR 76, 160) of unbound etravirine in plasma. There were no significant correlations between unbound etravirine concentrations and concentrations of albumin in plasma or CSF. Unbound etravirine concentrations in CSF did not reach the wild-type IC50 in any of the specimens.CONCLUSIONS: Unbound etravirine may not achieve optimal concentrations to inhibit HIV replication in the CNS. |
DOI | 10.1093/jac/dks517 |
Alternate Journal | J. Antimicrob. Chemother. |
PubMed ID | 23335197 |
PubMed Central ID | PMC3625433 |
Grant List | U54 HD071600-01 / HD / NICHD NIH HHS / United States R01 MH58076 / MH / NIMH NIH HHS / United States DA022137 / DA / NIDA NIH HHS / United States R01 MH83552 / MH / NIMH NIH HHS / United States U13 MH81676 / MH / NIMH NIH HHS / United States P30 MH62512 / MH / NIMH NIH HHS / United States MH22005 / MH / NIMH NIH HHS / United States MH058076 / MH / NIMH NIH HHS / United States P50 DA26306 / DA / NIDA NIH HHS / United States U01 NS45911-04 / NS / NINDS NIH HHS / United States P01 DA026146 / DA / NIDA NIH HHS / United States 1R01NS074409-01A1 / NS / NINDS NIH HHS / United States R01 MH78748 / MH / NIMH NIH HHS / United States U01 AI 68632 / AI / NIAID NIH HHS / United States N01MH22005 / MH / NIMH NIH HHS / United States MH79886 / MH / NIMH NIH HHS / United States R01MH83552 / MH / NIMH NIH HHS / United States U01 AI69432 / AI / NIAID NIH HHS / United States R01MH058076 / MH / NIMH NIH HHS / United States K30RR22681 / RR / NCRR NIH HHS / United States R25MH080663 / MH / NIMH NIH HHS / United States U01MH083501 / MH / NIMH NIH HHS / United States R01MH083627 / MH / NIMH NIH HHS / United States 2U01NS32228 / NS / NINDS NIH HHS / United States U01 MH83506 / MH / NIMH NIH HHS / United States U01MH83506 / MH / NIMH NIH HHS / United States NS32228 / NS / NINDS NIH HHS / United States N01 MH22005 / MH / NIMH NIH HHS / United States NS072005 / NS / NINDS NIH HHS / United States P01 DA12065 / DA / NIDA NIH HHS / United States U2G PS00623 / PS / NCHHSTP CDC HHS / United States P30MH62512 / MH / NIMH NIH HHS / United States R01 MH92225 / MH / NIMH NIH HHS / United States R01 AG15301 / AG / NIA NIH HHS / United States P50DA26306 / DA / NIDA NIH HHS / United States R01MH095621 / MH / NIMH NIH HHS / United States AI69495 / AI / NIAID NIH HHS / United States |