Population PK-PD Modelling of Wheal and Flare Area in a First-Time-in-Human Study
C. Ambery(1), M. Beerahee(1)
(1) Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Greenford, Middlesex, United Kingdom
Objectives: To characterise the pharmacokinetic wheal and flare area relationship of a novel anti-histamine in healthy male subjects in a single ascending dose first-time-in-human study. The pharmacodynamic wheal and flare inhibition was estimated by assessment of the histamine induced cutaneous reaction (wheal and flare response). The purpose of the modelling work was to establish the concentration-effect relationship to inform dose selection in subsequent clinical studies.
Methods: A randomised, double-blind, placebo-controlled, cross-over single oral dose study was conducted in healthy male subjects over the dose-range 10-100 mg. The population pharmacokinetic-pharmacodynamic (PK-PD) analysis was performed using NONMEM VI utilising all data obtained in the study. A two-step sequential PK-PD methodology was employed. In the first step various compartmental pharmacokinetic models were fitted to the population data. In the second step an inhibitory pharmacodynamic model was fitted to the wheal and flare area population data accounting for the relationship between drug concentration and effect.
Results: A one-compartment pharmacokinetic model with first-order absorption which was allowed to change rate over time was selected and adequately described the pharmacokinetic time course. The inhibitory pharmacodynamic model adequately described the pharmacodynamic time course and accounted for baseline and placebo effect. Diagnostic methods and posterior predictive checks showed the goodness of fit of these models to the data.
Conclusions: A population PK-PD model of wheal and flare area response of a novel anti-histamine was developed from data obtained from healthy male subjects in a single ascending dose first-time-in-human study. The pharmacokinetic-pharmacodynamic model developed has been used to simulate repeat dose scenarios and to inform dose selection in subsequent clinical studies.