title: High interpatient variability of raltegravir CSF concentrations in HIV-positive patients: a pharmacogenetic analysis.
abstract: OBJECTIVE
  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 α (HNF4α) 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 (ρ = 0.395, P = 0.019); CPRs were higher in patients with blood-brain barrier damage (0.47 versus 0.18, P = 0.02). HNF4α 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.
authors: Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Torino, Italy.
authors: Andrea
authors: A
authors: Calcagno
authors: Jessica
authors: J
authors: Cusato
authors: Marco
authors: M
authors: Simiele
authors: Ilaria
authors: I
authors: Motta
authors: Sabrina
authors: S
authors: Audagnotto
authors: Margherita
authors: M
authors: Bracchi
authors: Antonio
authors: A
authors: D'Avolio
authors: Giovanni
authors: G
authors: Di Perri
authors: Stefano
authors: S
authors: Bonora
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier; D002555:Cerebrospinal Fluid / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D010597:Pharmacogenetics; D010949:Plasma / Q000737:chemistry; D020641:Polymorphism, Single Nucleotide; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000068898:Raltegravir Potassium
chemical_list: C000715087:ABCC2 protein, human; D019380:Anti-HIV Agents; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium
keywords: P-glycoprotein; antiretrovirals; blood–brain barrier; hepatocyte nuclear factor 4 α; pharmacokinetics