An Approach for Identifiability of Population Pharmacokinetic–Pharmacodynamic Models

Abstract

Mathematical models are routinely used in clinical pharmacology to study the pharmacokinetic and pharmacodynamic properties of a drug in the body. Identifiability of these models is an important requirement for the success of these clinical studies. Identifiability is classified into two types, structural identifiability related to the structure of the mathematical model and deterministic identifiability which is related to the study design. There are existing approaches for assessment of structural identifiability of fixed-effects models, although their use appears uncommon in the literature. In this study, we develop an informal unified approach for simultaneous assessment of structural and deterministic identifiability for fixed and mixed-effects pharmacokinetic or pharmacokinetic–pharmacodynamic models. This approach uses an information theoretic framework. The method is applied both to simple examples to explore known identifiability properties and to a more complex example to illustrate its utility.

Automated Scale Reduction of Nonlinear QSP Models With an Illustrative Application to a Bone Biology System

“…Identifiability analysis was performed using an information approach that evaluated structural and deterministic identifiability . In addition, an informal heuristic approach was used to evaluate whether further parameters could be estimated by using a sensitivity analysis.…”

Scale Reduction of a Systems Coagulation Model With an Application to Modeling Pharmacokinetic–Pharmacodynamic Data

“…The structural identifiability of the extracted input–output model was assessed using an Information Theoretic Approach 23 . POPT design software was used to carry out the structural identifiability analysis.…”

“…An informal, unified approach using an information theoretic framework has recently been developed for simultaneous assessment of structural and deterministic identifiability for fixed‐ and mixed‐effects pharmacokinetic–pharmacodynamic (PKPD) models. The approach has been applied to Bateman and Dost 22 models and to a combined parent‐metabolite model describing the pharmacokinetics of ivabradine and its N‐desmethylated metabolite, S‐18982 23 …”

Children in clinical trials: towards evidence-based pediatric pharmacotherapy using pharmacokinetic-pharmacodynamic modeling

“…Numerical identifiability relates to the informativeness of the data and can be improved by the optimization of study design and its execution (55). The impact of the study design on the precision and bias of the estimated parameters of a population model in adults is well established (56)(57)(58)(59)(60).…”