title: Class-specific relative genetic contribution for key antiretroviral drugs.
abstract: OBJECTIVE
  Antiretroviral pharmacokinetics is defined by numerous factors affecting absorption, distribution, metabolism and elimination. Biological processes underpinning drug distribution are only partially characterized and multiple genetic factors generate cumulative or antagonistic interactions, which complicates the implementation of pharmacogenetic markers. The aim of this study was to assess the degree to which heredity influences pharmacokinetics through the quantification of the relative genetic contribution (rGC) for key antiretrovirals.
  
  
  METHODS
  A total of 407 patients receiving lopinavir/ritonavir, atazanavir/ritonavir, atazanavir, efavirenz, nevirapine, etravirine, maraviroc, tenofovir or raltegravir were included. Intra-patient variability (SDw) and inter-patient (SDb) variability were measured in patients with plasma concentrations available from more than two visits. The rGC was calculated using the following equation: 1 - (1 / F) where F = SDb(2) / SDw(2).
  
  
  RESULTS
  Mean (95% CI) rGC was calculated to be 0.81 (0.72-0.88) for efavirenz, 0.74 (0.61-0.84) for nevirapine, 0.67 (0.49-0.78) for etravirine, 0.65 (0.41-0.79) for tenofovir, 0.59 (0.38-0.74) for atazanavir, 0.47 (0.27-0.60) for atazanavir/ritonavir, 0.36 (0.01-0.48) for maraviroc, 0.15 (0.01-0.44) for lopinavir/ritonavir and 0 (0-0.33) for raltegravir.
  
  
  CONCLUSIONS
  The rank order for genetic contribution to variability in plasma concentrations for the study drugs was efavirenz > nevirapine > etravirine > tenofovir > atazanavir > atazanavir/ritonavir > maraviroc > lopinavir/ritonavir > raltegravir, indicating that class-specific differences exist. The rGC strategy represents a useful tool to rationalize future investigations as drugs with higher rGC scores may represent better candidates for pharmacogenetic-pharmacokinetic studies.
authors.affiliation: Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK siccardi@liverpool.ac.uk.
authors.forename: Marco
authors.initials: M
authors.lastname: Siccardi
authors.affiliation: Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Nigeria.
authors.forename: Adeniyi
authors.initials: A
authors.lastname: Olagunju
authors.affiliation: Department of Infectious Diseases, University of Torino, Amedeo di Savoia Hospital, Torino, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Simiele
authors.affiliation: Department of Infectious Diseases, University of Torino, Amedeo di Savoia Hospital, Torino, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: D'Avolio
authors.affiliation: Department of Infectious Diseases, University of Torino, Amedeo di Savoia Hospital, Torino, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Calcagno
authors.affiliation: Department of Infectious Diseases, University of Torino, Amedeo di Savoia Hospital, Torino, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Perri
authors.affiliation: Department of Infectious Diseases, University of Torino, Amedeo di Savoia Hospital, Torino, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Bonora
authors.affiliation: Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044966:Anti-Retroviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods*; D010949:Plasma / Q000737:chemistry*; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D044966:Anti-Retroviral Agents