主催: The Japanese Pharmacological Society, The Japanese Society of Clinical Pharmacology
会議名: WCP2018 (18th World Congress of Basic and Clinical Pharmacology)
開催地: Kyoto
開催日: 2018/07/01 - 2018/07/06
PBPK models are often used to perform inter- or intra-species scaling, to explore the underlying mechanisms responsible for observed PK characteristics and to simulate receptor occupancy or target suppression in tissues for PD analysis. The PK of macromolecular drugs is driven by mechanisms differing from their small molecule counterparts (Ferl et al. 2016). For monoclonal antibodies (MAbs), transendothelial processes (extravasation and endocytic uptake) and target kinetics are significant drivers of distribution and plasma clearance (Malik et al. 2017), whereas these processes are mostly unimportant for describing the PK of small molecules.
In the era of personalized medicine, we aim to use large molecule PBPK models to explore the PK variability associated with current dosing strategies and to advance our understanding of PK in special populations, such as children.
Rather than considering only the mean individual, virtual populations with real-world variability in physiologic characteristics can be used as inputs for population-level PBPK simulations. The output describes not only the mean PK profile, but also the resulting PK variability for the population as a function of the underlying physiologic characteristics of its individuals. Sensitivity analyses allow us to identify which of these characteristics are most influential to variability in each component of the PK profile. Where these characteristics are clinically identifiable, individualized dosing strategies can be implemented to improve safety and efficacy. Already a PBPK model has uncovered the time and disease-state dependency of PK variability for one MAb and hypotheses have been generated to link the key physiologic determinants of variability to clinically-identifiable characteristics (Malik et al. 2017).
Of interest is the scaling of MAb PK from adults to children for the planning of pediatric clinical trials. A comprehensive review of the age-dependence of the important drivers of large molecule PK and PK variability in children has been completed and will be discussed.
Ferl G, Theil FP, Wong H. 2016. Biopharmaceutics & Drug Disposition. 37: 75-92.
Malik PRV, Hamadeh A, Phipps C, Edginton AN. 2017. Journal of Pharmacokinetics and Pharmacodynamics. 44(3): 277-290.
