Optimizing Body Size-Based Dosing Approaches for Antibody-Drug Conjugates

Optimized dosing precision of antibody-drug conjugates (ADCs) remains challenging due to narrow therapeutic indices, efficacious doses near the maximum tolerated dose, and substantial interindividual variability in exposure. Body size-based dosing can reduce exposure variability when the allometric scaling exponent for clearance α = 1 but may over- or underexpose patients with extreme body size when α ≠ 1. A recent review found α based on body weight (BW) was less than 0.7 for 8 of 10 approved ADCs,¹ indicating room for improvement. This follow-up article outlines the strategy for dosing approach selection to enhance ADC dosing precision. To assess the performance of different body size metrics, α was re-estimated to BW, body surface area (BSA), ideal body weight (IBW), and adjusted IBW (AIBW). Simulations were conducted to evaluate the performance of dose capping. Results showed that all 15 approved ADCs used body size-based dosing, with seven using an upper dose cap, even when α < 0.5. AIBW and BSA commonly had an α closer to 1 compared with BW while IBW performed poorly due to lack of BW consideration. Simulations showed that when α was not close enough to 0 or 1 (e.g., 0.4 ≤ α ≤ 0.7), dose capping helped maintain percent AUC difference between patients extreme and normal body size within the desired range (e.g., 20%) with an upper dose cap when α ≥ 0.5 or a lower dose cap when α ≤ 0.5. Based on these findings, a decision tree is proposed to guide dosing strategy selection across drug development stages, by implementing model-informed approaches to improve ADC therapeutic outcomes.