Physiologically based and population PK modeling in optimizing drug development: A predict-learn-confirm analysis

Clin Pharmacol Ther. 2015 Sep;98(3):336-44. doi: 10.1002/cpt.155. Epub 2015 Jul 14.


Physiologically based pharmacokinetic (PBPK) modeling and classical population pharmacokinetic (PK) model-based simulations are increasingly used to answer various drug development questions. In this study, we propose a methodology to optimize the development of drugs, primarily cleared by the kidney, using model-based approaches to determine the need for a dedicated renal impairment (RI) study. First, the impact of RI on drug exposure is simulated via PBPK modeling and then confirmed using classical population PK modeling of phase 2/3 data. This methodology was successfully evaluated and applied to an investigational agent, orteronel (nonsteroidal, reversible, selective 17,20-lyase inhibitor). A phase 1 RI study confirmed the accuracy of model-based predictions. Hence, for drugs eliminated primarily via renal clearance, this modeling approach can enable inclusion of patients with RI in phase 3 trials at appropriate doses, which may be an alternative to a dedicated RI study, or suggest that only a reduced-size study in severe RI may be sufficient.

Trial registration: NCT01193244 NCT01193257.

MeSH terms

  • Clinical Trials, Phase I as Topic
  • Clinical Trials, Phase III as Topic
  • Computer Simulation*
  • Cytochrome P-450 Enzyme Inhibitors / administration & dosage
  • Cytochrome P-450 Enzyme Inhibitors / pharmacokinetics*
  • Drug Discovery / methods*
  • Drug Dosage Calculations
  • Humans
  • Imidazoles / administration & dosage
  • Imidazoles / pharmacokinetics*
  • Kidney / metabolism*
  • Kidney / physiopathology
  • Kidney Diseases / metabolism*
  • Kidney Diseases / physiopathology
  • Models, Biological*
  • Naphthalenes / administration & dosage
  • Naphthalenes / pharmacokinetics*
  • Nonlinear Dynamics
  • Renal Elimination
  • Reproducibility of Results
  • Steroid 17-alpha-Hydroxylase / antagonists & inhibitors
  • Steroid 17-alpha-Hydroxylase / metabolism


  • Cytochrome P-450 Enzyme Inhibitors
  • Imidazoles
  • Naphthalenes
  • Steroid 17-alpha-Hydroxylase
  • orteronel

Associated data