@article{4abafac78f8748fab30af2761977cdc8,
title = "Efavirenz concentrations in CSF exceed IC50 for wild-type HIV",
abstract = "Objectives: HIV-associated neurocognitive disorders remain common despite use of potent antiretroviral therapy (ART). Ongoing viral replication due to poor distribution of antivirals into the CNS may increase risk for HIV-associated neurocognitive disorders. This study's objective was to determine penetration of a commonly prescribed antiretroviral drug, efavirenz, into CSF. Methods: CHARTER is an ongoing, North American, multicentre, observational study to determine the effects of ART on HIV-associated neurological disease. Single random plasma and CSF samples were drawn within 1h of each other from subjects taking efavirenz between September 2003 and July 2007. Samples were assayed by HPLC or HPLC/mass spectrometry with detection limits of 39ng/mL (plasma) and <0.1ng/mL (CSF). Results: Eighty participants (age 44+8 years; 79+15kg; 20 females) had samples drawn 12.5+5.4h postdose. The median efavirenz concentrations after a median of 7 months [interquartile range (IQR) 2-17] of therapy were 2145ng/mL in plasma (IQR 1384-4423) and 13.9ng/mL in CSF (IQR 4.1-21.2). The CSF/plasma concentration ratio from paired samples drawn within 1h of each other was 0.005 (IQR 0.0026-0.0076; n=69). The CSF/IC50 ratio was 26 (IQR 8-41) using the published IC50 for wild-type HIV (0.51ng/mL). Two CSF samples had concentrations below the efavirenz IC50 for wild-type HIV. Conclusions: Efavirenz concentrations in the CSF are only 0.5% of plasma concentrations but exceed the wildtype IC50 in nearly all individuals. Since CSF drug concentrations reflect those in brain interstitial fluids, efavirenz reaches therapeutic concentrations in brain tissue.",
keywords = "CNS, Non-nucleoside reverse transcriptase inhibitors, Pharmacology",
author = "Best, {Brookie M.} and Koopmans, {Peter P.} and Letendre, {Scott L.} and Capparelli, {Edmund V.} and Rossi, {Steven S.} and Clifford, {David B.} and Collier, {Ann C.} and Gelman, {Benjamin B.} and Gilbert Mbeo and McCutchan, {J. Allen} and Simpson, {David M.} and Richard Haubrich and Ronald Ellis and Igor Grant",
note = "Funding Information: B. M. B. has received past research support from Abbott Laboratories and ARK Diagnostics. P. P. K. in the past has received research grants from GlaxoSmithKline, MSD and BMS. E. V. C. has consulted or served on advisory committees for Bristol-Myers Squibb, Johnson & Johnson and Trius. S. S. R. has current or past research support from Medtronic Inc. and Raptor Pharmaceuticals. He and an immediate family member own stock in Merck & Co. D. B. C. has advisory board membership with Genzyme, Genentech, Pfizer and Millennium. He has received consultancy fees from Biogen Idec, Genentech, Pfizer, Bristol-Myers Squibb and Millennium (all ,$10000 per year). He has received a speaker fee from Glaxo-SmithKline and Millennium. He has received travel support from Biogen Idec. He has had research funding from Biogen Idec, Pfizer, Schering-Plough, Bavarian Nordic, NeuorgesX, Novartis and Tibotec. He receives research support from the NIMH, NINDS, National Institute of Allergy and Infectious Diseases and Fogarty Institute of NIH. A. C. C. has current or past research support from Merck & Co., Schering-Plough, Boehringer-Ingelheim, Gilead Sciences and Tibotec–Virco. She is a member of a Data, Safety and Monitoring Board for a Merck-sponsored study and has participated in Advisory Boards for GlaxoSmithKline, Merck & Co. and Pfizer. She and an immediate family member own stock in Abbott Laboratories and Bristol-Myers Squibb. R. H. receives research support from GlaxoSmithKline, Merck, Pfizer and Abbott Laboratories and is a consultant and/or receives an honorarium from Abbott, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Monogram, Pfizer, Roche, Tibotec and Virco. R. E. has participated in advisory boards and on speakers bureaus for GlaxoSmithKline and Abbott Laboratories. An immediate family member owns stock in Abbott Laboratories and Johnson & Johnson. I. G. has been a speaker for Abbott Laboratories. All other authors: none to declare. Funding Information: This work was supported primarily by the National Institute of Mental Health (NIMH) and the National Institute of Neurological Disorders and Stroke (NINDS) at the NIH (contract number N01 MH22005). Additional support was provided by funds from the National Institute for Child Health and Human Development (5U10 HD031318 to B. M. B., E. V. C. and S. S. R.).",
year = "2011",
month = feb,
doi = "10.1093/jac/dkq434",
language = "English (US)",
volume = "66",
pages = "354--357",
journal = "Journal of Antimicrobial Chemotherapy",
issn = "0305-7453",
publisher = "Oxford University Press",
number = "2",
}