High interpatient variability of raltegravir CSF concentrations in HIV-positive patients: a pharmacogenetic analysis

Objectives: To analyse the determinants of raltegravir CSF penetration, including the pharmacogenetics of drug transporters located at the blood-brain barrier or blood-CSF barrier. Methods: Plasma and CSF raltegravir concentrations were determined by a validated HPLC coupled with mass spectrometry method in adults on raltegravir-based combination antiretroviral therapy undergoing a lumbar puncture. Single nucleotide polymorphisms in the genes encoding drugs transporters (ABCB1 3435, SLCO1A2, ABCC2 and SLC22A6) and the gene encoding hepatocyte nuclear factor 4 alpha (HNF4 alpha) were determined by real-time PCR. Results: In 41 patients (73.2% male, 95.1% Caucasians), the median raltegravir plasma and CSF concentrations were 165 ng/mL (83-552) and 31 ng/mL (21-56), respectively. CSF-to-plasma ratios (CPRs) ranged from 0.005 to 1.33 (median 0.20, IQR 0.04-0.36). Raltegravir trough CSF concentrations (n = 35) correlated with raltegravir plasma levels (rho = 0.395, P = 0.019); CPRs were higher in patients with blood-brain barrier damage (0.47 versus 0.18, P = 0.02). HNF4 alpha 613 CG genotype carriers had lower trough CSF concentrations (20 versus 37 ng/mL, P = 0.03) and CPRs (0.12 versus 0.27, P = 0.02). Following multivariate linear regression analysis, the CSF-to-serum albumin ratio was the only independent predictor of raltegravir penetration into the CSF. Conclusions: Raltegravir penetration into the CSF shows a large interpatient variability, although CSF concentrations were above the wild-type IC50 in all patients (and above IC95 in 28.6%). In this cohort, blood - brain barrier permeability is the only independent predictor of raltegravir CPR. The impact of single nucleotide polymorphisms in selected genes on raltegravir penetration warrants further studies.