title: CNS effects of a CCR5 inhibitor in HIV-infected subjects: a pharmacokinetic and cerebral metabolite study.
abstract: BACKGROUND
  We conducted a pharmacokinetic and in vivo cerebral (1)H magnetic resonance spectroscopy ((1)H-MRS) study to assess CSF exposure and cerebral metabolite ratios (CMRs) following maraviroc intensification.
  
  
  METHODS
  HIV-infected neurologically asymptomatic adults receiving tenofovir, emtricitabine and lopinavir/ritonavir with plasma HIV RNA <50 copies/mL were eligible and received intensified therapy with 150 mg of maraviroc twice daily. (1)H-MRS was performed in several cerebral locations, including the right basal ganglia (RBG), to assess CMRs, including N-acetyl aspartate/creatine (NAA/Cr), at baseline and after 14 days. Subsequently, on day 15, blood samples were obtained to determine plasma concentrations of maraviroc pre-dose (C(trough)) and then paired blood and CSF samples were collected at 4 or 6 h post-dose. Associations between maraviroc exposure, clinical parameters and changes to CMRs were evaluated.
  
  
  BACKGROUND
  ClinicalTrials.gov (http://clinicaltrials.gov/ct2/show/NCT00982878).
  
  
  RESULTS
  Twelve subjects (75% male) participated with a mean (SD) CD4+ cell count of 503 (199) cells/μL. Mean (SD) maraviroc plasma concentrations at pre-dose, 4 h post-dose and 6 h post-dose were 337 (74), 842 (174) and 485 (100) ng/mL and CSF concentrations at 4 h post-dose and 6 h post-dose were 7.5 (1.3) and 5.1 (1.2) ng/mL. The mean maraviroc CSF : plasma ratio (range) was 1.01% (0.57%-1.61%). An increase of 14.8% was observed for the RBG NAA/Cr ratio, which was significantly associated with higher maraviroc plasma C(trough) (P = 0.05, r = 0.61), but not CSF concentration (P = 0.16, r = 0.46).
  
  
  CONCLUSIONS
  After 14 days of maraviroc intensification, small increases in cerebral metabolite markers of neuronal integrity (NAA/Cr ratios) were observed and are associated with maraviroc plasma C(trough).
authors: Department of Medicine,  Faculty of Medicine, Imperial College London, St Mary's Hospital Campus, Norfolk Place, London W2 1PG,  UK.
authors: Lucy
authors: L
authors: Garvey
authors: Mark
authors: M
authors: Nelson
authors: Ngaire
authors: N
authors: Latch
authors: Otto W
authors: OW
authors: Erlwein
authors: Joanna M
authors: JM
authors: Allsop
authors: Ann
authors: A
authors: Mitchell
authors: Steve
authors: S
authors: Kaye
authors: Victoria
authors: V
authors: Watson
authors: David
authors: D
authors: Back
authors: Simon D
authors: SD
authors: Taylor-Robinson
authors: Alan
authors: A
authors: Winston
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001921:Brain / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects*; D065100:CCR5 Receptor Antagonists; D002555:Cerebrospinal Fluid / Q000737:chemistry; D003510:Cyclohexanes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D000077592:Maraviroc; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D014230:Triazoles; D000077592:Maraviroc