title: Cerebrospinal fluid exposure of efavirenz and its major metabolites when dosed at 400 mg and 600 mg once daily: a randomized controlled trial.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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]).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  NCT01011413.
authors.affiliation: Section of Infectious Diseases, Imperial College London, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Winston
authors.affiliation: Kirby Institute, University of New South Wales, Sydney, Australia.
authors.forename: Janaki
authors.initials: J
authors.lastname: Amin
authors.affiliation: Thai Red Cross AIDS Research Centre, Bangkok, Thailand.
authors.forename: Amanda
authors.initials: A
authors.lastname: Clarke
authors.affiliation: Department of Pharmacology, University of Liverpool.
authors.forename: Laura
authors.initials: L
authors.lastname: Else
authors.affiliation: Department of Pharmacology, University of Liverpool.
authors.forename: Alieu
authors.initials: A
authors.lastname: Amara
authors.affiliation: Department of Pharmacology, University of Liverpool.
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
authors.affiliation: Chelsea and Westminster NHS Foundation Trust, London, United Kingdom.
authors.forename: Tristan
authors.initials: T
authors.lastname: Barber
authors.affiliation: Medical Group Practice, Berlin, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Jessen
authors.forename: Anchalee
authors.initials: A
authors.lastname: Avihingsanon
authors.affiliation: Thai Red Cross AIDS Research Centre, Bangkok, Thailand.
authors.forename: Anchalee
authors.initials: A
authors.lastname: Avinghsanon
authors.affiliation: Srinagarind Hospital, Khon Kaen University, Thailand.
authors.forename: Ploenchan
authors.initials: P
authors.lastname: Chetchotisakd
authors.affiliation: Department of Pharmacology, University of Liverpool.
authors.forename: Saye
authors.initials: S
authors.lastname: Khoo
authors.affiliation: Kirby Institute, University of New South Wales, Sydney, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Cooper
authors.affiliation: Kirby Institute, University of New South Wales, Sydney, Australia.
authors.forename: Sean
authors.initials: S
authors.lastname: Emery
authors.affiliation: Kirby Institute, University of New South Wales, Sydney, Australia.
authors.forename: Rebekah
authors.initials: R
authors.lastname: Puls
mesh_terms: D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D048588:Benzoxazines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002555:Cerebrospinal Fluid / Q000737:chemistry*; D003521:Cyclopropanes; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; C098320:efavirenz
keywords: CSF; HIV; efavirenz; pharmacogenomics; pharmacokinetics