title: Genetic and non-genetic determinants of raltegravir penetration into cerebrospinal fluid: a single arm pharmacokinetic study.
abstract: BACKGROUND
  Antiretroviral drugs vary in their central nervous system penetration, with better penetration possibly conferring neurocognitive benefit during human immunodeficiency virus (HIV) therapy. The efflux transporter gene ABCB1 is expressed in the blood-brain barrier, and an ABCB1 variant (3435C → T) has been reported to affect ABCB1 expression. The integrase inhibitor raltegravir is a substrate for ABCB1. We examined whether ABCB1 3435C → T affects raltegravir disposition into cerebrospinal fluid (CSF), and explored associations with polymorphisms in other membrane transporter genes expressed in the blood-brain barrier.
  
  
  METHODS
  Forty healthy, HIV-negative adults of European descent (20 homozygous for ABCB1 3435 C/C, 20 homozygous for 3435 T/T, each group divided equally between males and females) were given raltegravir 400 mg twice daily for 7 days. With the final dose, plasma was collected for pharmacokinetic analysis at 9 timepoints over 12 hours, and CSF collected 4 hours post dose.
  
  
  RESULTS
  The 4-hour CSF concentration correlated more strongly with 2-hour (r(2)=0.76, P=1.12 x 10(-11)) than 4-hour (r(2)=0.47, P=6.89 x 10(-6)) single timepoint plasma concentration, and correlated strongly with partial plasma area-under-the-curve values (AUC0-4h r(2)=0.86, P=5.15 x 10(-16)). There was no significant association between ABCB1 3435C → T and ratios of CSF-to-plasma AUC or concentration (p>0.05 for each comparison). In exploratory analyses, CSF-to-plasma ratios were not associated with 276 polymorphisms across 16 membrane transporter genes.
  
  
  CONCLUSIONS
  Among HIV-negative adults, CSF raltegravir concentrations do not differ by ABCB1 3435C → T genotype but strongly correlate with plasma exposure.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00729924 http://clinicaltrials.gov/show/NCT00729924.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Johnson
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Deborah
authors.initials: D
authors.lastname: Sutherland
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Edward P
authors.initials: EP
authors.lastname: Acosta
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Husamettin
authors.initials: H
authors.lastname: Erdem
authors.affiliation: Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Danielle
authors.initials: D
authors.lastname: Richardson
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America ; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America ; Department of Pathology, Microbiology & Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America ; Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: David W
authors.initials: DW
authors.lastname: Haas
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000328:Adult; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D005260:Female; D056726:Genetic Association Studies; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D010539:Permeability; D020641:Polymorphism, Single Nucleotide; D011760:Pyrrolidinones / Q000493:pharmacokinetics*; D000068898:Raltegravir Potassium; D012307:Risk Factors
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019380:Anti-HIV Agents; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium