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

Wang et al . 1 (2009) and Zhang et al . 2 (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.