Pharmacokinetic–Pharmacodynamic Modelling: History and Perspectives

Abstract

A major goal in clinical pharmacology is the quantitative prediction of drug effects. The field of pharmacokinetic-pharmacodynamic (PK/PD) modelling has made many advances from the basic concept of the dose-response relationship to extended mechanism-based models. The purpose of this article is to review, from a historical perspective, the progression of the modelling of the concentration-response relationship from the first classic models developed in the mid-1960s to some of the more sophisticated current approaches. The emphasis is on general models describing key PD relationships, such as: simple models relating drug dose or concentration in plasma to effect, biophase distribution models and in particular effect compartment models, models for indirect mechanism of action that involve primarily the modulation of endogenous factors, models for cell trafficking and transduction systems. We show the evolution of tolerance and time-variant models, non- and semi-parametric models, and briefly discuss population PK/PD modelling, together with some example of more recent and complex pharmacodynamic models for control system and nonlinear HIV-1 dynamics. We also discuss some future possible directions for PK/PD modelling, report equations for general classes of novel semi-parametric models, as well as describing two new classes, additive or set-point, of regulatory, additive feedback models in their direct and indirect action variants.

An integrated pharmacokinetic and pharmacodynamic study of a new drug of abuse, methylone, a synthetic cathinone sold as “bath salts”

“…In this study the presence of some metabolites of methylone, similar to active metabolites of MDMA (De la Torre and Farre, 2004), strongly suggests their participation in the overall locomotor activity, but other possibilities cannot be discarded (Csajka and Verotta, 2006). Further studies with individual metabolites will determine which structural species have the highest likelihood of contributing to the locomotor activity caused by methylone.…”

Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics

“…administration, the change in response was directly interpretable as function of mephedrone concentration with the use of a sigmoidal E max model (Csajka and Verotta 2006). After oral dosage, plots of mephedrone effect versus observed plasma mephedrone concentrations revealed a clockwise hysteresis loop in both oral dosages.…”

Pharmacotherapy in pediatric epilepsy: from trial and error to rational drug and dose selection – a long way to go

“…Such parameterization also allows one to quantify the impact of influential factors on parameter values and describe them as covariates. The incorporation of covariates into a PKPD or disease model has an important advantage in that it enhances the prediction of response for specific groups of patients [94][95][96]. In conjunction with clinical trial simulations, model-based techniques offer an excellent opportunity for the evaluation of novel therapies [97] as well as personalization of the dosing regimen for children [98].…”