title: Intrapatient and interpatient pharmacokinetic variability of raltegravir in the clinical setting.
abstract: BACKGROUND
  Raltegravir (RAL) is the first in class integrase inhibitor and is licensed for administration at 400 mg twice daily. RAL pharmacokinetics are characterized by high interpatient variability and recently RAL plasma exposure has been correlated with efficacy. RAL is primarily metabolized by glucuronidation via uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and UGT1A1*28 considered to be the main genetic variant associated with decreased UGT1A1 expression. This study investigated variability in RAL trough plasma concentrations (Ctrough) in the clinical setting, the effect of UGT1A1*28 and concomitant antiretrovirals.
  
  
  METHODS
  A total of 86 patients, from Turin, Italy, and Madrid, Spain, were included in the analysis. Blood samples were obtained 10-14 hours postdose. Genotyping for UGT1A1*28 was conducted by sequencing.
  
  
  RESULTS
  High interpatient and intrapatient variabilities were observed; 13 patients had ≥3 samples available, and the median coefficient of variation was 128 (64-265). Coadministration of RAL with atazanavir (ATV, n = 9) resulted in higher raltegravir Ctrough, 517 (307-2706) ng/mL when compared with patients not receiving ATV (n = 77) 223 (95-552; P = 0.02). UGT1A1*28 did not influence RAL plasma exposure.
  
  
  CONCLUSIONS
  We have documented large intersubject and intrasubject variabilities in RAL plasma concentrations and confirmed the interaction with ATV. Further studies are required to better understand the mechanisms that influence the pharmacokinetics of RAL.
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom. siccardi@liv.ac.uk
authors.forename: Marco
authors.initials: M
authors.lastname: Siccardi
authors.forename: Antonio
authors.initials: A
authors.lastname: DʼAvolio
authors.forename: Sonia
authors.initials: S
authors.lastname: Rodriguez-Novoa
authors.forename: Lorena
authors.initials: L
authors.lastname: Cuenca
authors.forename: Marco
authors.initials: M
authors.lastname: Simiele
authors.forename: Lorena
authors.initials: L
authors.lastname: Baietto
authors.forename: Andrea
authors.initials: A
authors.lastname: Calcagno
authors.forename: Darren
authors.initials: D
authors.lastname: Moss
authors.forename: Stefano
authors.initials: S
authors.lastname: Bonora
authors.forename: Vicente
authors.initials: V
authors.lastname: Soriano
authors.forename: David J
authors.initials: DJ
authors.lastname: Back
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Perri
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D000069446:Atazanavir Sulfate; D004347:Drug Interactions; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D014644:Genetic Variation; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D019428:HIV Integrase Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000493:pharmacokinetics*; D000068898:Raltegravir Potassium; D013030:Spain; D000099148:UGT1A1 Enzyme
chemical_list: D019380:Anti-HIV Agents; D000069446:Atazanavir Sulfate; D014453:Glucuronosyltransferase; D019428:HIV Integrase Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D000099148:UGT1A1 Enzyme