A Guide to Rational Dosing of Monoclonal Antibodies

Background and Objective Dosing of therapeutic monoclonal antibodies (mAbs) is often based on body size, with the perception that body size-based dosing would reduce inter-subject variability in drug exposure. However, most mAbs are target specific with a relatively large therapeutic window and generally a small contribution of body size to pharmacokinetic variability. Therefore, the dosing paradigm for mAbs should be assessed in the context of these unique characteristics. The objective of this study was to review the current dosing strategy and to provide a scientific rationale for dosing of mAbs using a modelling and simulation approach. Methods In this analysis, the body weight-based or body weight-independent (fixed) dosing regimens for mAbs were systematically evaluated. A generic two-compartment first-order elimination model was developed. Individual or population pharmacokinetic profiles were simulated as a function of the body weight effects on clearance (θ bw_cl ) and on the central volume of distribution (θ bw_vl ). The variability in exposure (the area under the serum concentration-time curve [AUC], trough serum concentration [C min ] and peak serum concentration [C max ]) was compared between body weight-based dosing and fixed dosing in the entire population. The deviation of exposure for light and heavy subjects from median body weight subjects was also measured. The simulation results were then evaluated with clinical pharmacokinetic characteristics of various mAbs that were given either by body weight-based dosing or by fixed dosing in the case study. Results Results from this analysis demonstrated that exposure variability was dependent on the magnitude of the body weight effect on pharmacokinetics. In contrast to the conventional assumption, body weight-based dosing does not always offer advantages over fixed dosing in reducing exposure variability. In general, when the exponential functions of θ bw_cl and θ bw_vl in the population pharmacokinetic model are 0.5, body weight-based dosing results in less variability and less deviation than fixed dosing. In the scenarios when either θ bw_cl or θ bw_vl is >0.5, the impact on exposure variability is different for each exposure measure. The case study demonstrated that most mAbs had little effect or a moderate body weight effect (θ bw_cl and θ bw_vl