A general model-based design of experiments approach to achieve practical identifiability of pharmacokinetic and pharmacodynamic models

J Pharmacokinet Pharmacodyn. 2013 Aug;40(4):451-67. doi: 10.1007/s10928-013-9321-5. Epub 2013 Jun 4.

Abstract

The use of pharmacokinetic (PK) and pharmacodynamic (PD) models is a common and widespread practice in the preliminary stages of drug development. However, PK-PD models may be affected by structural identifiability issues intrinsically related to their mathematical formulation. A preliminary structural identifiability analysis is usually carried out to check if the set of model parameters can be uniquely determined from experimental observations under the ideal assumptions of noise-free data and no model uncertainty. However, even for structurally identifiable models, real-life experimental conditions and model uncertainty may strongly affect the practical possibility to estimate the model parameters in a statistically sound way. A systematic procedure coupling the numerical assessment of structural identifiability with advanced model-based design of experiments formulations is presented in this paper. The objective is to propose a general approach to design experiments in an optimal way, detecting a proper set of experimental settings that ensure the practical identifiability of PK-PD models. Two simulated case studies based on in vitro bacterial growth and killing models are presented to demonstrate the applicability and generality of the methodology to tackle model identifiability issues effectively, through the design of feasible and highly informative experiments.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Computer Simulation
  • Drug Discovery*
  • Models, Biological*
  • Pharmacokinetics*
  • Research Design