Fixed Dosing Versus Body Size—Based Dosing of Monoclonal Antibodies in Adult Clinical Trials

Abstract

Although without clear scientific rationale, body size-based dosing is often used for administering monoclonal antibodies (mAbs). This simulation study compared the performance of body size-based and fixed dosing in reducing pharmacokinetic (PK) and/or pharmacodynamic (PD) variability in adults for 12 mAbs with published population PK and/or PD models. At the population level, 95th percentile intervals of concentration-time profiles, distribution, and variability of exposure for 1000 subjects after both dosing approaches were examined. At the individual level, the difference between the exposures of patients with extreme body sizes from the typical exposure following both approaches was compared. The results show that the 2 dosing approaches perform similarly across the mAbs investigated with fixed dosing being better for some mAbs and body size-based dosing being better for the others. Based on this finding, we recommend using fixed dosing in first-in-human (FIH) adult studies because it offers other advantages. When sufficient data become available, a full assessment of body size effect on PK/PD should be conducted to determine the optimal dosing approach for phase 3 trials. Other factors that may affect the selection of dosing approach were also discussed. Dosing approach for mAbs in the pediatric population is out of the scope of this study.

Population pharmacokinetic and pharmacodynamic analysis of BIIB023, an anti‐TNF‐like weak inducer of apoptosis (anti‐TWEAK) monoclonal antibody

“…The values obtained for V, V 2 , CL and CL 2 are in congruence with the noncompartmental analysis parameters in Table 3 and are comparable to those reported for other human and humanized monoclonal antibodies [21][22][23][24][25][26]. Body weight is also commonly found to be a covariate of monoclonal antibody pharmacokinetics [27,28].…”

Linear pharmacokinetic parameters for monoclonal antibodies are similar within a species and across different pharmacological targets: A comparison between human, cynomolgus monkey and hFcRn Tg32 transgenic mouse using a population-modeling approach

“…PopPK analysis is often used to study the inter-subject variability of mAb PK and to explore covariates of this variability. Body weight/ surface area are the most commonly identified covariates found to influence the PK of mAbs 9 , 19 , 26 , 27 . The effects of other demographic factors, including age, sex, ethnicity, body size, genetic polymorphisms, concomitant medications, immune status and multiple other patient-specific details, have also been considered 28 …”

Clinical Pharmacology Tools and Evaluations to Facilitate Comprehensive Dose Finding in Oncology: A Continuous Risk‐Benefit Approach

“…The impact of body weight on PK parameters has been well described by Wang et al 36 as well as Zhang et al 37 In their initial review Wang et al found that fixed dosing performed similarly to body weight-based dosing in reducing intersubject variability in drug exposure across the therapeutic proteins studied. Zhang et al expanded the evaluation to other therapeutic proteins and peptides and included 18 therapeutic proteins and peptides with published population PK and/or PD models to evaluate the 2 dosing approaches: flat fixed vs body weight-based dose (see Figure 2).…”