@article{e5737a33dcbf4a48ac64d2693fe3a8d7,
title = "Etravirine in CSF is highly protein bound",
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 IC. 50 in any of the specimens. Conclusions: Unbound etravirine may not achieve optimal concentrations to inhibit HIV replication in the CNS.",
keywords = "Antiretroviral therapy, CNS, CSF, Central nervous system, HIV, Protein binding",
author = "Anh Nguyen and Steven Rossi and David Croteau and Best, {Brookie M.} and David Clifford and Collier, {Ann C.} and Benjamin Gelman and Christina Marra and Justin Mcarthur and Mccutchan, {J. Allen} and Susan Morgello and David Simpson and Ellis, {Ronald J.} and Igor Grant and Edmund Capparelli and Scott Letendre and Ian Abramson and Muhammad Al-lozi and Atkinson, {J. Hampton} and Christine Fennema-notestine and Gamst, {Anthony C.} and Heaton, {Robert K.} and Marcotte, {Thomas D.} and Smith, {Davey M.} and Taylor, {Michael J.} and Rebecca Theilmann and Florin Vaida and {Paul woods}, Steven and Clint Cushman and Matthew Dawson and Donald Franklin and Trudy Jones and Kristen Lewis and Letty Mintz and Mengesha Teshome and Will Toperoff",
note = "Funding Information: I. G. receives ongoing research support from NIH P30 MH62512, NIH P50 DA26306, NIH P01 DA12065, NIH N01 MH22005, NIH U01 MH83506, NIH R01 MH78748, NIH R01 AG15301, NIH R01 MH83552 and NIH/University of Nebraska P01 DA026146. He has also received honoraria from Abbott Pharmaceuticals as part of their Educational Speaker Program. Funding Information: S. M. receives support from NIH grants U01MH083501, R25MH080663 and R01MH083627. Funding Information: C. M. receives research support from the NIH (NINDS and NIMH). She has received research support from Cempra Pharmaceuticals and from the CDC. She receives royalties from Lippincott Williams and Wilkins and from UptoDate. J. M. receives support from N01 MH22005. Funding Information: E. C. receives support from NIH grants NIAID U01 AI 68632, NICHD U54 HD071600-01, NINDS U01 NS45911-04, NICHD CRMC-2010-02 and NINDS 1R01NS074409—01A1, and consulting income from Trius Pharmaceuticals, Cerexa Pharmaceuticals and Abbott Pharmaceuticals. Funding Information: D. Clifford is supported by NIH grants NS32228, AI69495, MH22005, DA022137, MH058076 and 3857–53187. He has also received support from Pfizer, NeurogesX and Biogen. In addition, he has provided scientific advisory or consulting to Biogen Idec, Elan, Roche, Genentech, Glaxo-SmithKline, Janssen, Millennium, Bristol-Myers Squibb, Genzyme, Wyeth and Pfizer. Funding Information: R. J. E. received consultant fees from NeurogesX and is funded by NIH grants R01MH058076, U01MH83506, P30MH62512, R01MH83552, P50DA26306, R01MH095621 and 2U01NS32228. Funding Information: J. A. M. authors chapters on HIV for the Merck Manual and receives related research funding from NIH P30 MH62512, NIH U01 MH83506, NIH/CDC U2G PS00623, NIH U01 AI69432, NIH N01 MH22005, NIH K30 RR22681, NIH R01 MH58076 and NIH U13 MH81676. Funding Information: D. S. receives research support from the NIH (NINDS and NIMH). He provided consultancy to GlaxoSmithKline and Gilead. Funding Information: The salary of S. L. was funded by NIH research awards, including N01 MH22005, R01 MH58076, R01 MH92225, P50 DA26306 and P30 MH62512. He has received support for research projects from Abbott, Merck, Tibotec and GlaxoSmithKline. He has consulted for Gilead Sciences, GlaxoSmithKline, Merck and Tibotec, and has received lecture honoraria from Abbott and Boehringer-Ingelheim. A. N., S. R., D. Croteau and B. M. B.: none to declare. Funding Information: A. C. C. had the following disclosures: research support from Merck & Company (current) and Schering-Plough (past); former member of a Data, Safety and Monitoring Board for a Merck-sponsored study; and past stock ownership (personal/immediate family member) with Abbott Laboratories, Bristol-Myers Squibb, Johnson and Johnson, and Pfizer. B. G. receives support from NIH grants NS072005 and MH79886. Funding Information: This work was supported by an investigator-initiated research grant from Tibotec and by the National Institutes of Health via the following award: N01 MH22005.",
year = "2013",
month = may,
doi = "10.1093/jac/dks517",
language = "English (US)",
volume = "68",
pages = "1161--1168",
journal = "Journal of Antimicrobial Chemotherapy",
issn = "0305-7453",
publisher = "Oxford University Press",
number = "5",
}