CNS effects of a CCR5 inhibitor in HIV-infected subjects: A pharmacokinetic and cerebral metabolite study: A pharmacokinetic and cerebral metabolite study

Background: We conducted a pharmacokinetic and in vivo cerebral 1H magnetic resonance spectroscopy (1H-MRS) study to assess CSF exposure and cerebral metaboliteratios (CMRs) following maraviroc intensification. Methods: HIV-infected nurologically 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. 1H-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 (Ctrough) and then paired blood and CSF samples were collected at 4 or 6 h postdose. Associaons between maraviroc exposure, clinical parameters and changes to CMRs were evaluated.Trial registry: 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/mL.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 Ctrough (P=0.05, r=0.61), but not CSF concentration (P=0.16, r=0.46). Conclusions: After 14 days ofmaraviroc intensification, small increases in cerebral metabolite markers of neuronal integrity (NAA/Cr ratios) were observed and are associated with maraviroc plasmaCtrough.