Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

Abstract

Abstract. The advancement of therapeutic monoclonal antibodies during various stages of the drug development process can be effectively streamlined when appropriate translational strategies are applied. Design of successful translational strategies for development of monoclonal antibodies should allow for understanding of the dose-and concentration-response relationships with respect to both beneficial and toxic effects from early phases of drug development. Evaluation of relevant biomarkers during early stages of drug development should facilitate the successful design of safe and effective dosing strategies. Moreover, application of quantitative pharmacology is critical for translation of exposure-response relationships early on.

Antibody Drug Conjugates: Application of Quantitative Pharmacology in Modality Design and Target Selection

“…1). Critical target-related properties are (a) expression profile, and density (receptor copy number), (b) target internalization and turnover rate, and (c) functional relevance to human disease (18)(19)(20). An ideal target should demonstrate a specific expression profile at the relevant site of action (typically tumor cells) with little to no expression in other healthy tissues (18,19).…”

“…The two key target-related parameters affecting drug concentration at the intracellular site are expression density of the target receptor and its internalization or turnover rate which define the target capacity (20). Understanding the t a r g e t c a p a c i t y -t h e i n t e r p l a y b e t w e e n t h e s e parameters-provides a rational approach for target selection.…”

Compartmental Tissue Distribution of Antibody Therapeutics: Experimental Approaches and Interpretations

“…boswell.charles@gene.com) ABBREVIATIONS: ADME, Adsorption distribution, metabolism, and excretion; Fc, Crystallizable fragment; DTPA, Diethylenetriaminepentaacetic acid; DOTA, 1,4,7,20- Although nonradioactive, bioanalytical methods are still regarded as the industry standard (13), the use of radionuclides in the quantitative pharmacology of antibodies boasts extremely high sensitivity and well-established methods for incorporation and detection (14). But perhaps the most important advantage lies in the facile detection of radionuclides in tissues for biodistribution studies (15,16).…”

Mathematical analysis of the pharmacokinetic–pharmacodynamic (PKPD) behaviour of monoclonal antibodies: Predicting in vivo potency

“…The increasing interest in biologicals in general, and mAbs in particular, is partly due to their high success rate during preclinical and clinical development [1]. It has been suggested that an important element that has contributed to this success is the fact that, compared to small molecules, the pharmacokinetic-pharmacodynamic (PKPD) properties of mAbs are more amenable to quantitative, mechanistic modelling and simulation (M&S)-based translation approaches across preclinical and clinical research [2,3,4,5]. A specific example of this is the implementation of the principles of target-mediated drug disposition (TMDD) into quantitative pharmacological models to describe and predict PKPD behaviour of mAbs.…”

“…PK and PD become interdependent. Mager and Jusko [7] were the first to propose a general PK model for drugs exhibiting TMDD, which has provided the basis for extensive further studies and development (see for example [8,9,10,11,5]). Experimental confirmation of TMDD model predictions was provided in a recent elegant study by Abraham et al [12], who showed marked differences in interferon (INF)-β PK in wild-type and type-1 INF α/β receptor knockout mice.…”