Modelling the delay between pharmacokinetics and EEG effects of morphine in rats: binding kinetic versus effect compartment models

Wilhelmus E A De Witte,Elizabeth C M De Lange,Vivi Rottschäfer,Piet H Van Der Graaf,Meindert Danhof,Lambertus A Peletier

doi:10.1007/s10928-018-9593-x

Wilhelmus E A De Witte, Elizabeth C M De Lange + Show 4 more

Open Access

https://doi.org/10.1007/s10928-018-9593-x

Copy DOI

Abstract

Drug–target binding kinetics (as determined by association and dissociation rate constants, kon and koff) can be an important determinant of the kinetics of drug action. However, the effect compartment model is used most frequently instead of a target binding model to describe hysteresis. Here we investigate when the drug–target binding model should be used in lieu of the effect compartment model. The utility of the effect compartment (EC), the target binding kinetics (TB) and the combined effect compartment–target binding kinetics (EC–TB) model were tested on either plasma (ECPL, TBPL and EC–TBPL) or brain extracellular fluid (ECF) (ECECF, TBECF and EC–TBECF) morphine concentrations and EEG amplitude in rats. It was also analyzed when a significant shift in the time to maximal target occupancy (TmaxTO) with increasing dose, the discriminating feature between the TB and EC model, occurs in the TB model. All TB models assumed a linear relationship between target occupancy and drug effect on the EEG amplitude. All three model types performed similarly in describing the morphine pharmacodynamics data, although the EC model provided the best statistical result. The analysis of the shift in TmaxTO (∆TmaxTO) as a result of increasing dose revealed that ∆TmaxTO is decreasing towards zero if the koff is much smaller than the elimination rate constant or if the target concentration is larger than the initial morphine concentration. The results for the morphine PKPD modelling and the analysis of ∆TmaxTO indicate that the EC and TB models do not necessarily lead to different drug effect versus time curves for different doses if a delay between drug concentrations and drug effect (hysteresis) is described. Drawing mechanistic conclusions from successfully fitting one of these two models should therefore be avoided. Since the TB model can be informed by in vitro measurements of kon and koff, a target binding model should be considered more often for mechanistic modelling purposes.

Highlights

Drug–target binding kinetics is an important criterion in the selection of drug candidates, as it can be a determinant of the time course and the selectivity of drug effect [1,2,3,4].the in vivo time course of drug action is influenced by multiple factors including plasma pharmacokinetics, target site distribution, target binding kinetics, competition with endogenous ligands, turnover of the target, signal transduction kinetics and the kinetics of homeostatic feedback
effect compartment (EC) and target binding kinetics (TB) models have been applied to the morphine data to describe the relationship between the observed plasma concentrations and EEG amplitude and direct effect (DE), indirect effect (IE), EC and TB models have been applied to brain extracellular fluid (ECF) and EEG amplitude data
The originally published ECPL model structure was optimized by adding a slope-parameter, which describes the linear decline of EEG amplitude over time during the experiment independently of the drug effect, and by including IIV on the baseline EEG amplitude only

Summary

Introduction

Drug–target binding kinetics is an important criterion in the selection of drug candidates, as it can be a determinant of the time course and the selectivity of drug effect [1,2,3,4]. The in vivo time course of drug action is influenced by multiple factors including plasma pharmacokinetics, target site distribution, target binding kinetics, competition with endogenous ligands, turnover of the target, signal transduction kinetics and the kinetics of homeostatic feedback. One of the arguments against an important role of binding kinetics for in vivo drug action is that binding kinetics are most often not required to get a good fitting PKPD model for small molecules. The sparsity of target binding PKPD models for small molecules can be explained by the relatively fast binding kinetics of many drugs currently on the market, compared to their pharmacokinetics [3]. When a delay between drug concentrations and effect is observed, this delay is often described by an effect compartment or indirect response model [18, 19]

Objectives

Methods

Results

Discussion

Conclusion