Re‐Evaluation of Fixed Dosing Versus Body Size‐Based Dosing Approaches for Large Molecule Therapeutics in Adults

(2011) recommended a fixed dosing approach for large molecule therapeutics for first-in-human (FIH) trials, based on the finding that the majority of α values (body size effect on clearance) were < 0.5 across 12 monoclonal antibodies (mAbs) and 18 therapeutic proteins (TPs) and peptides, and fixed dosing provides advantages such as convenience, reduced medical errors, and cost-effectiveness. They also recommended that the approved dosing approach should be determined by α and the therapeutic window. This review aims to re-evaluate these recommendations using a larger dataset (N = 143) of diverse molecules. Results showed 62% (78/126) of non-ADC drugs were approved with fixed dosing, and 58% (28/48) of non-ADC drugs approved with body size-based dosing had an α < 0.7 where fixed dosing would be appropriate. Therefore, only the remaining 16% (20/126) of non-ADC drugs required body size-based dosing. In addition, the FIH dosing approach had significant implications on the approved dosing approach with 68% (90/133) of drugs using the same dosing approach in FIH and approval. Lastly, of non-ADC drugs evaluated, 56% (71/126) demonstrated a relationship between α and the approved dosing approach. When α did not explain the approved dosing approach, lack of clinically meaningful differences in exposure (49%, 27/55) was the most common justification. These findings confirm Wang et al.'s and Zhang et al.'s previous conclusions, continuing to support their recommendations. Based on these insights, a decision tree is proposed for selecting the appropriate dosing approach at each stage of drug development.