Impact of pharmacokinetic variability on a mechanistic physiological pharmacokinetic/pharmacodynamic model: A case study of neutrophil development, PM00104, and filgrastim

Abstract

Interindividual variability (IIV) is considered a crucial factor for the general use of mathematical modelling in physiology. However, mechanistic models of physiological systems are commonly built for an average patient, raising the question of their applicability at the population level. Using our previously developed physiological model of neutrophil regulation, which accounts for the detailed hematopoietic mechanisms as well as the pharmacokinetics (PKs) of a chemotherapeutic agent (PM00104) and a granulostimulant (filgrastim), we incorporated the reported population pharmacokinetic (PopPK) models of each drug to investigate the impact of PK variability on fully mechanistic models. A variety of scenarios, including multiple doses of PM00104, were simulated for cohorts of 500 in silico patients to analyse the model’s predictability in terms of several pharmacological indicators, such as the time to neutrophil nadir, the value of the nadir, and the area under the effect curve. Our results indicate the robustness of our model’s predictions in all considered scenarios. Based on our findings, we conclude that for drugs with short-lived PKs in comparison with their pharmacodynamics (PDs), models that “sufficiently” account for physiological mechanisms inherently assimilate PK deviations, making the further inclusion of PK variability unnecessary.