Physiologically-Based PK/PD Modelling of Therapeutic Macromolecules

Abstract

Therapeutic proteins are a diverse class of drugs consisting of naturally occurring or modified proteins, and due to their size and physico-chemical properties, they can pose challenges for the pharmacokinetic and pharmacodynamic studies. Physiologically-based pharmacokinetics (PBPK) modelling has been effective for early in silico prediction of pharmacokinetic properties of new drugs. The aim of the present workshop was to discuss the feasibility of PBPK modelling of macromolecules. The classical PBPK approach was discussed with a presentation of the successful example of PBPK modelling of cyclosporine A. PBPK model was performed with transport of the cyclosporine across cell membranes, affinity to plasma proteins and active membrane transporters included to describe drug transport between physiological compartments. For macromolecules, complex PBPK modelling or permeability-limited and/or target-mediated distribution was discussed. It was generally agreed that PBPK modelling was feasible and desirable. The role of the lymphatic system should be considered when absorption after extravascular administration is modelled. Target-mediated drug disposition was regarded as an important feature for generation of PK models. Complex PK-models may not be necessary when a limited number of organs are affected. More mechanistic PK/PD models will be relevant when adverse events/toxicity are included in the PK/PD modelling.

Clinical pharmacology considerations in biologics development

“…In a PBPK model, a flow balance is kept by ensuring that the sum of input flows (ie, blood+lymphatic flow) is equal to the sum of output flows for each compartment. A schematic chart of a PBPK model can be found in many publica tions [12,30,31] . Overall, model-based drug development takes advantage of a series of quantitative approaches, such as mechanism-based PK, PBPK, PK-PD, exposure-response, and PK-PD-clinical response models.…”

Pharmacokinetic Analysis of Continuous Erythropoietin Receptor Activator Disposition in Adult Sheep Using a Target-Mediated, Physiologic Recirculation Model and a Tracer Interaction Methodology

“…However, physiologically based PK (PBPK) models have become a powerful alternative to classic compartmental models because they provide a mechanistic approach that 1) relates drug disposition to various physiological, anatomical, and physicochemical factors (Thygesen et al, 2009) and 2) offers a strong basis for interspecies, tissue, route, and drug extrapolations (Nestorov, 2003).…”

Modeling, Simulation, and Translation Framework for the Preclinical Development of Monoclonal Antibodies

“…A recent review of PBPK modeling for macromolecules can be found in Thygesen et al (16). Once the target is selected and validated, the emphasis may then be to optimize the mAb's properties, albeit some of this effort may have already been underway or happening in parallel.…”

“…During the SB/SP phases ( Fig. 1), beyond the basic assessment of PK, time may be afforded to build a PBPK model to gain a better understanding of the mAb's tissue distribution characteristics (16)(17)(18). Such a model could assist in determining whether the mAb is adequately exposed to the intended tissue or site of action.…”