Physiologically Based Pharmacokinetic Modelling as a Tool for Dose Optimisation in Special Population Groups

Abstract

This thesis explores the application of physiologically based pharmacokinetic (PBPK) modelling, an approach that predicts drug disposition by integrating physiological and drug parameters. The objective is to elucidate the impact of physiological alterations within special populations on drug pharmacokinetics, aiming to identify optimal dosing that accounts for exposure differences. The initial section focuses on fluvoxamine dose optimisation in pregnant women, considering their CYP2D6 phenotypes. The study revealed that fluvoxamine maternal concentrations significantly decreased during gestation, while the foetal concentrations increased substantially in poor metabolisers (PM) but remained constant in ultra-rapid (UM) and extensive metabolisers (EM). The recommended dose for UM and EM reached 300 mg daily at gestational weeks 15 and 35, respectively. Conversely, a consistent 100 mg daily for PM is sufficient to maintain the therapeutic concentration throughout the gestation. The succeeding part discusses the imatinib dosing strategy in obese adults with cancer. Results showed significant differences in maximum concentration (Cmax) and area-under-the-curve (AUC) between obese and lean adults but not in trough concentrations (Cmin). The therapeutic drug monitoring (TDM) approach using the PBPK model demonstrated that the same TDM-guided dosing adjustment could be applied to lean, overweight, and obese adults to restore Cmin to the target concentration level. The last segment centres on the paediatric obesity population using amlodipine as a case study. Findings showed significant differences in predicted Cmax and AUC were observed across ages 2 to 18 years with a fixed dose regimen, while weight-based dosing showed no difference in Cmax from ages 2 to 9 years. Thus, a 1.25 – 1.5-fold dose increase is needed to attain the same Cmax as in non-obese children when using a fixed dose. In summary, PBPK modelling effectively assessed the influence of physiological changes in special populations on drug pharmacokinetics and ascertained the optimal dose from a pharmacokinetic perspective.