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

Area of Science:

• Pharmacology
• Oncology
• Drug Development

Background:

• Antibody-drug conjugate (ADC) dosing precision is challenging due to narrow therapeutic indices and interindividual variability.
• Body size-based dosing is common but can lead to over- or underexposure if scaling exponents differ from one.
• Existing ADC dosing strategies may not fully account for allometric scaling characteristics.

Purpose of the Study:

• To outline a strategy for selecting optimal dosing approaches to enhance ADC dosing precision.
• To evaluate the performance of different body size metrics (body weight, BSA, IBW, AIBW) for ADC dosing.
• To assess the effectiveness of dose capping strategies in mitigating exposure variability.

Main Methods:

• Re-estimated allometric scaling exponent (α) for clearance relative to body weight (BW), body surface area (BSA), ideal body weight (IBW), and adjusted ideal body weight (AIBW).
• Conducted simulations to evaluate dose capping performance across various α values.
• Analyzed dosing strategies of 15 approved ADCs.

Main Results:

• All 15 approved ADCs utilize body size-based dosing, with seven employing dose caps.
• Adjusted ideal body weight (AIBW) and BSA often showed an allometric scaling exponent (α) closer to 1 than body weight (BW).
• Dose capping effectively maintained the percentage area under the curve (AUC) difference within a 20% range for extreme body sizes when α was between 0.4 and 0.7.

Conclusions:

• AIBW and BSA are superior body size metrics for ADC dosing compared to BW or IBW when α is not equal to 1.
• Dose capping is a valuable strategy to improve ADC dosing precision, particularly when allometric scaling is suboptimal.
• A decision tree is proposed to guide dosing strategy selection throughout drug development for improved ADC therapeutic outcomes.