Allometric scaling of therapeutic monoclonal antibodies in preclinical and clinical settings

Abstract

Constant technological advancement enabled the production of therapeutic monoclonal antibodies (mAbs) and will continue to contribute to their rapid expansion. Compared to small-molecule drugs, mAbs have favorable characteristics, but also more complex pharmacokinetics (PK), e.g., target-mediated nonlinear elimination and recycling by neonatal Fc-receptor. This review briefly discusses mAb biology, similarities and differences in PK processes across species and within human, and provides a detailed overview of allometric scaling approaches for translating mAb PK from preclinical species to human and extrapolating from adults to children. The approaches described here will remain vital in mAb drug development, although more data are needed, for example, from very young patients and mAbs with nonlinear PK, to allow for more confident conclusions and contribute to further growth of this field. Improving mAb PK predictions will facilitate better planning of (pediatric) clinical studies and enable progression toward the ultimate goal of expediting drug development.

Rituximab pharmacokinetic and pharmacokinetic–pharmacodynamic evaluation based on a study in diffuse large B‐cell lymphoma: Influence of tumor size on pharmacokinetic and assessment of pharmacokinetic similarity

“…The allometric exponents we estimated for clearances and volumes of distribution were smaller than the theoretical values of, respectively, ¾ and 1. This difference is attributed to two factors: first, rituximab being a monoclonal antibody, which is frequently reported to have allometric exponent estimates that differ from the theoretical values; 38 and second, the narrow WT range in the current study in adults, which is often associated with allometric exponents being slightly underestimated. [39][40][41][42] Another possible limitation of this study is that tumor size is based on computed tomography (CT) evaluation (i.e., anatomical) and not on the joint metabolicanatomical evaluation awarded by positron emission tomography CT. 25 Despite this data limitation, the model works well, and the coefficient of variation of RUV was only 12.6%.…”

Development of a pediatric physiologically-based pharmacokinetic model to support recommended dosing of atezolizumab in children with solid tumors

“…Generally, dose recommendations in pediatric patients leverage empirical allometric scaling or mechanistic PBPK modeling ( Germovsek et al, 2021 ; Johnson and Ke, 2021 ). The former approach uses power functions to calculate the drug clearance or volume of distribution based on the normalized body weight or body surface area of a pediatric subject with respect to an adult.…”

Combatting seasonal malaria transmission using a highly potent Plasmodium falciparum transmission-blocking monoclonal antibody

“…Our study has a number of limitations. The pharmacokinetic extrapolation from healthy western adults to African populations has a solid mechanistic and empirical foundation (22,48), but dedicated studies of TB31F in African populations, including children, are needed to confirm its safety and the appropriateness of the proposed weight-based dosing regimen. These studies can confirm the pharmacokinetic properties in this population and test TB31F formulations to achieve the modelled doses by intravenous or subcutaneous administration.…”