Dose selection based on physiologically based pharmacokinetic (PBPK) approaches

Abstract

Physiologically based pharmacokinetic (PBPK) models are built using differential equations to describe the physiology/anatomy of different biological systems. Readily available in vitro and in vivo preclinical data can be incorporated into these models to not only estimate pharmacokinetic (PK) parameters and plasma concentration-time profiles, but also to gain mechanistic insight into compound properties. They provide a mechanistic framework to understand and extrapolate PK and dose across in vitro and in vivo systems and across different species, populations and disease states. Using small molecule and large molecule examples from the literature and our own company, we have shown how PBPK techniques can be utilised for human PK and dose prediction. Such approaches have the potential to increase efficiency, reduce the need for animal studies, replace clinical trials and increase PK understanding. Given the mechanistic nature of these models, the future use of PBPK modelling in drug discovery and development is promising, however some limitations need to be addressed to realise its application and utility more broadly.

Figures

Fig. 1

Schematic of a PBPK model. Blood flow (arrow), lymph flow (broken arrow)

Fig. 2

PBPK strategy through discovery to early- and late-stage development

Fig. 3

Graphical representation of mAb kidney model (see text for details of parameters)

Fig. 4

Model predictions of target suppression. Different curves correspond to different combinations of mAb affinities and dosing. MAb distribution parameters: Inter-compartmental clearance = 0.6 L/day, clearance = 0.25 L/day. Volumes of different compartments are: plasma = extravascular space accessed by mAb = 3 L; kidney interstitium = 100 mL; proximal tubule = 30 mL. Rate of fluid transport to kidney interstitium is set at 4.5 L/day, i.e. 0.5% of plasma flow rate to kidney; 85% of which is recirculated and remaining 15% ends up as lymphatic fluid. Reflection coefficients associated with endothelial barrier are 0.9 and 0.2 (24). Target parameters: expression = 100 pM; internalisation of free target = 1 h−1; internalisation of target–mAb complex = 5 h−1. Solid line represents KD = 1 nM, dose = 1 mg/kg; dotted line represents KD = 1 nM, dose = 10 mg/kg; dashed line represents KD = 100pM, dose = 1 mg/kg; dash-dot line represents KD = 100pM, dose = 10 mg/kg