Cerebrospinal Fluid Exposure of Efavirenz and Its Major Metabolites When Dosed at 400 mg and 600 mg Once Daily: A Randomized Controlled Trial

Winston, Alan, Amin, Janaki, Clarke, Amanda, Else, Laura, Amara, Alieu ORCID: 0000-0002-1137-2948, Owen, Andrew ORCID: 0000-0002-9819-7651, Barber, Tristan, Jessen, Heiko, Avinghsanon, Anchalee, Chetchotisakd, Ploenchan
et al (show 4 more authors) (2015) Cerebrospinal Fluid Exposure of Efavirenz and Its Major Metabolites When Dosed at 400 mg and 600 mg Once Daily: A Randomized Controlled Trial. CLINICAL INFECTIOUS DISEASES, 60 (7). pp. 1026-1032.

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<h4>Background</h4>The optimal penetration of antiretroviral agents into the central nervous system may be a balance between providing adequate drug exposure to inhibit human immunodeficiency virus (HIV) replication while avoiding concentrations associated with neuronal toxicities.<h4>Methods</h4>Cerebrospinal fluid (CSF) exposure of efavirenz and the metabolites 7-hydroxy (7OH) and 8-hydroxy (8OH) efavirenz were assessed after at least 12 weeks of therapy in HIV-infected subjects randomized to commence antiretroviral regimens containing efavirenz at either 400 mg or 600 mg once daily.<h4>Results</h4>Of 28 subjects (14 and 14 on efavirenz 400 mg and 600 mg, respectively), CSF HIV RNA was undetectable in all. Geometric mean CSF efavirenz, 7OH-, and 8OH-efavirenz concentrations (with 90% confidence intervals [CIs]) for the 400-mg and 600-mg dosing groups were 16.5 (13-21) and 19.5 (15-25) ng/mL; 0.6 (.4-.9) and 0.6 (.4-1) ng/mL; and 5.1 (4.0-6.4) and 3.1 (2.1-4.4) ng/mL, respectively. Efavirenz concentration in CSF was >0.51 ng/mL (proposed CSF 50% maximal inhibitory concentration for wild-type virus) in all subjects, and 8OH-efavirenz concentration in CSF was >3.3 ng/mL (a proposed toxicity threshold) in 11 of 14 and 7 of 14 subjects randomized to the 400 mg and 600 mg doses of efavirenz, respectively. Whereas CSF efavirenz concentration was significantly associated with plasma concentration (P < .001) and cytochrome P450 2B6 genotype (CSF efavirenz GG to GT/TT geometric mean ratio, 0.56 [90% CI, .42-.74]), CSF 8OH-efavirenz concentration was not (P = .242 for association and CSF 8OH-efavirenz GG to GT/TT geometric mean ratio, 1.52 [90% CI, .97-2.36]).<h4>Conclusions</h4>With both doses of efavirenz studied, CSF concentrations were considered adequate to inhibit HIV replication, although concentrations of 8OH-efavirenz were greater than those reportedly associated with neuronal toxicity. CSF exposure of 8OH-efavirenz was not dependent on plasma exposure and, as we postulate, may be subject to saturable pharmacokinetic effects.<h4>Clinical trials registration</h4>NCT01011413.

Item Type: Article
Uncontrolled Keywords: efavirenz, pharmacokinetics, pharmacogenomics, CSF, HIV
Subjects: ?? RM ??
Depositing User: Symplectic Admin
Date Deposited: 21 May 2015 15:53
Last Modified: 15 Dec 2022 11:40
DOI: 10.1093/cid/ciu976
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/2011747