title: Reduced physiologically-based pharmacokinetic model of repaglinide: impact of OATP1B1 and CYP2C8 genotype and source of in vitro data on the prediction of drug-drug interaction risk.
abstract: OBJECTIVE
  To investigate the effect of OATP1B1 genotype as a covariate on repaglinide pharmacokinetics and drug-drug interaction (DDIs) risk using a reduced physiologically-based pharmacokinetic (PBPK) model.
  
  
  METHODS
  Twenty nine mean plasma concentration-time profiles for SLCO1B1 c.521T>C were used to estimate hepatic uptake clearance (CLuptake) in different genotype groups applying a population approach in NONMEM v.7.2.
  
  
  RESULTS
  Estimated repaglinide CLuptake corresponded to 217 and 113 μL/min/10(6) cells for SLCO1B1 c.521TT/TC and CC, respectively. A significant effect of OATP1B1 genotype was seen on CLuptake (48% reduction for CC relative to wild type). Sensitivity analysis highlighted the impact of CLmet and CLdiff uncertainty on the CLuptake optimization using plasma data. Propagation of this uncertainty had a marginal effect on the prediction of repaglinide OATP1B1-mediated DDI with cyclosporine; however, sensitivity of the predicted magnitude of repaglinide metabolic DDI was high. In addition, the reduced PBPK model was used to assess the effect of both CYP2C8*3 and SLCO1B1 c.521T>C on repaglinide exposure by simulations; power calculations were performed to guide prospective DDI and pharmacogenetic studies.
  
  
  CONCLUSIONS
  The application of reduced PBPK model for parameter optimization and limitations of this process associated with the use of plasma rather than tissue profiles are illustrated.
authors.affiliation: Centre for Applied Pharmacokinetic Research Manchester Pharmacy School, The University of Manchester, Oxford Road, M13 9PT, Manchester, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Gertz
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Tsamandouras
authors.forename: Carolina
authors.initials: C
authors.lastname: Säll
authors.forename: J Brian
authors.initials: JB
authors.lastname: Houston
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Galetin
mesh_terms: D002219:Carbamates / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D003198:Computer Simulation; D065727:Cytochrome P-450 CYP2C8 / Q000235:genetics*; D004347:Drug Interactions; D005838:Genotype; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D027381:Liver-Specific Organic Anion Transporter 1; D008954:Models, Biological; D009010:Monte Carlo Method; D027361:Organic Anion Transporters / Q000235:genetics*; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D011110:Polymorphism, Genetic; D011446:Prospective Studies
chemical_list: D002219:Carbamates; D007004:Hypoglycemic Agents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D010880:Piperidines; C503999:SLCO1B1 protein, human; C072379:repaglinide; D065727:Cytochrome P-450 CYP2C8