title: Indirect pharmacodynamic response models do not require any parametric pharmacokinetic model to be fitted to effect-time data.
abstract: Indirect response models (IRM) represent one of the possible ways to explain and quantitatively describe a delayed pharmacodynamic effect at non-steady-state conditions. The standard way to get estimates of pharmacodynamic (PD) parameters of IRM consists of two steps. First, an appropriate parametric pharmacokinetic (PK) model (compartmental, polyexponential, etc.) is to be fitted to plasma concentration-time data, and then IRM is fitted to PD data having PD model as an input. In the present work it is demonstrated that a simple piecewise function which consists in interpolation lines connecting concentration-time points can be used as a universal nonparametric PK model thereby allowing to skip the first step. MS Excel spreadsheets implementing this PK model and four known versions of IRM are presented. The usefulness of the approach is demonstrated by fitting IRMs to simulated data as well as to real PK/PD data of warfarin and terbutaline. Estimates of IRM parameters obtained with the nonparametric PK model were close to that published in the literature.
authors.affiliation: Janssen Research Foundation, Beerse, Belgium.
authors.forename: V K
authors.initials: VK
authors.lastname: Piotrovsky
mesh_terms: D008954:Models, Biological; D010599:Pharmacokinetics; D010600:Pharmacology