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

Pharm Res. 2014 Sep;31(9):2367-82. doi: 10.1007/s11095-014-1333-3. Epub 2014 Mar 13.


Purpose: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbamates / blood
  • Carbamates / pharmacokinetics*
  • Carbamates / pharmacology
  • Computer Simulation
  • Cytochrome P-450 CYP2C8 / genetics*
  • Drug Interactions
  • Genotype
  • Humans
  • Hypoglycemic Agents / blood
  • Hypoglycemic Agents / pharmacokinetics*
  • Hypoglycemic Agents / pharmacology
  • Liver-Specific Organic Anion Transporter 1
  • Models, Biological
  • Monte Carlo Method
  • Organic Anion Transporters / genetics*
  • Piperidines / blood
  • Piperidines / pharmacokinetics*
  • Piperidines / pharmacology
  • Polymorphism, Genetic
  • Prospective Studies


  • Carbamates
  • Hypoglycemic Agents
  • Liver-Specific Organic Anion Transporter 1
  • Organic Anion Transporters
  • Piperidines
  • SLCO1B1 protein, human
  • repaglinide
  • Cytochrome P-450 CYP2C8