A Guide to Rational Dosing of Monoclonal Antibodies

Abstract

The analysis provided insights into the conditions under which either fixed or body weight-based dosing would be superior in reducing pharmacokinetic variability and exposure differences between light and heavy subjects across the population. The pharmacokinetic variability introduced by either dosing regimen is moderate relative to the variability generally observed in pharmacodynamics, efficacy and safety. Therefore, mAb dosing can be flexible. Given many practical advantages, fixed dosing is recommended to be the first option in first-in-human studies with mAbs. The dosing strategy in later stages of clinical development could then be determined based on combined knowledge of the body weight effect on pharmacokinetics, safety and efficacy from the early clinical trials.

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 Considerations for the Development of Immune Checkpoint Inhibitors

“…74,75 The mAbs commonly display modest interpatient variability in PK, and population PK is used to identify intrinsic and extrinsic covariates that can explain part of the observed variability. 60 The covariates chosen for investigation focused primarily on intrinsic factors such as sex and age, as well as those relating to disease state (for example, tumor type, tumor burden, and baseline parameters such as performance status, lactate dehydrogenase [LDH], and albumin), which might rationally be expected to differ between patients and so contribute to interpatient PK variability. Statistically significant covariates identified through population PK analysis for approved immune checkpoint inhibitors are shown in Table 2.…”