Human variability

TL;DR: This short review describes potential options to refine safety factors used in risk assessment, with particular emphasis on pathway-related uncertainty factors associated with variability in kinetics.

TL;DR: In this article, the validity of the human kinetic subfactor has been analyzed in relation to CYP1A2 metabolism using published in vivo pharmacokinetic parameters selected to reflect chronic exposure (metabolic and total clearances and area under the plasma concentration-time curve: CLm, CL and AUC) and acute exposure (the peak plasma concentration, C(max)).

TL;DR: Pathway-related uncertainty factors are presented here as derived from the result of meta-analyses of toxicokinetic variability data in humans using therapeutic drugs metabolised by a single pathway in subgroups of the population.

TL;DR: This effort sets the stage for the acquisition of critical data and further integration of polymorphism data with PBPK modeling as a means to quantitate population variability.