title: Estimation of the effect of SLCO1B1 polymorphisms on lopinavir plasma concentration in HIV-infected adults.
abstract: BACKGROUND
  The organic anion transporting polypeptides (OATP)/SLCO family represents an important class of hepatic drug uptake transporters that mediate the sodium independent transport of a diverse range of amphipathic organic compounds, including the protease inhibitors. The SLCO1B1 521T>C (rs4149056) single nucleotide polymorphism (SNP) has been consistently associated with reduced transport activity in vivo, and we previously showed an association of this polymorphism with lopinavir plasma concentrations. The aim of this study was to develop a population pharmacokinetic (PK) model to quantify the impact of 521T>C.
  
  
  METHODS
  A population PK analysis was performed with 594 plasma samples from 375 patients receiving lopinavir/ritonavir. Non-linear mixed effects modelling was applied to explore the effects of SLCO1B1 521T>C and patient demographics. Simulations of the lopinavir concentration profile were performed with different dosing regimens considering the different alleles.
  
  
  RESULTS
  A one-compartment model with first-order absorption best described the data. Population clearance was 5.67 l/h with inter-patient variability of 37%. Body weight was the only demographic factor influencing clearance, which increased 0.5 l/h for every 10 kg increase. Homozygosity for the C allele was associated with a 37% lower clearance, and 14% for heterozygosity, which were statistically significant.
  
  
  CONCLUSIONS
  These data show an association between SLCO1B1 521T>C and lopinavir clearance. The association is likely to be mediated through reduced uptake by hepatocytes leading to higher plasma concentrations of lopinavir. Further studies are now required to confirm the association and to assess the influence of other polymorphisms in the SLCO family on lopinavir PK.
authors.affiliation: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Schipani
authors.forename: Deirdre
authors.initials: D
authors.lastname: Egan
authors.forename: Laura
authors.initials: L
authors.lastname: Dickinson
authors.forename: Gerry
authors.initials: G
authors.lastname: Davies
authors.forename: Marta
authors.initials: M
authors.lastname: Boffito
authors.forename: Mike
authors.initials: M
authors.lastname: Youle
authors.forename: Saye H
authors.initials: SH
authors.lastname: Khoo
authors.forename: David J
authors.initials: DJ
authors.lastname: Back
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
mesh_terms: D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D003198:Computer Simulation; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D061466:Lopinavir / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D027361:Organic Anion Transporters / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D061466:Lopinavir