title: Efavirenz concentrations in CSF exceed IC50 for wild-type HIV.
abstract: OBJECTIVE
  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 1 h 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 39 ng/mL (plasma) and <0.1 ng/mL (CSF).
  
  
  RESULTS
  Eighty participants (age 44 ± 8 years; 79 ± 15 kg; 20 females) had samples drawn 12.5 ± 5.4 h post-dose. The median efavirenz concentrations after a median of 7 months [interquartile range (IQR) 2-17] of therapy were 2145 ng/mL in plasma (IQR 1384-4423) and 13.9 ng/mL in CSF (IQR 4.1-21.2). The CSF/plasma concentration ratio from paired samples drawn within 1 h of each other was 0.005 (IQR 0.0026-0.0076; n = 69). The CSF/IC(50) ratio was 26 (IQR 8-41) using the published IC(50) for wild-type HIV (0.51 ng/mL). Two CSF samples had concentrations below the efavirenz IC(50) for wild-type HIV.
  
  
  CONCLUSIONS
  Efavirenz concentrations in the CSF are only 0.5% of plasma concentrations but exceed the wild-type IC(50) in nearly all individuals. Since CSF drug concentrations reflect those in brain interstitial fluids, efavirenz reaches therapeutic concentrations in brain tissue.
authors.affiliation: University of California San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, San Diego, CA, USA.
authors.forename: Brookie M
authors.initials: BM
authors.lastname: Best
authors.forename: Peter P
authors.initials: PP
authors.lastname: Koopmans
authors.forename: Scott L
authors.initials: SL
authors.lastname: Letendre
authors.forename: Edmund V
authors.initials: EV
authors.lastname: Capparelli
authors.forename: Steven S
authors.initials: SS
authors.lastname: Rossi
authors.forename: David B
authors.initials: DB
authors.lastname: Clifford
authors.forename: Ann C
authors.initials: AC
authors.lastname: Collier
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Gelman
authors.forename: Gilbert
authors.initials: G
authors.lastname: Mbeo
authors.forename: J Allen
authors.initials: JA
authors.lastname: McCutchan
authors.forename: David M
authors.initials: DM
authors.lastname: Simpson
authors.forename: Richard
authors.initials: R
authors.lastname: Haubrich
authors.forename: Ronald
authors.initials: R
authors.lastname: Ellis
authors.forename: Igor
authors.initials: I
authors.lastname: Grant
mesh_terms: D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000097:blood / Q000134:cerebrospinal fluid* / Q000627:therapeutic use; D048588:Benzoxazines / Q000097:blood / Q000134:cerebrospinal fluid* / Q000627:therapeutic use; D001921:Brain; D002851:Chromatography, High Pressure Liquid; D003521:Cyclopropanes; D005260:Female; D015658:HIV Infections / Q000134:cerebrospinal fluid* / Q000150:complications / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008875:Middle Aged; D009422:Nervous System Diseases / Q000134:cerebrospinal fluid* / Q000188:drug therapy* / Q000821:virology; D011897:Random Allocation; D019562:Viral Load
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; C098320:efavirenz