Eenvoudige allometrische schaling voorspelt farmacokinetiek en doseringskeuze van ADC's in de mens

Antibody-drug conjugates (ADCs) have emerged as promising cancer therapeutics; however, predicting their pharmacokinetics (PK) in humans remains challenging, particularly during early development. Therefore, we aimed to develop a practical translational approach to estimate the human PK profiles of ADCs and their cytotoxic payloads using nonclinical data. PK data from nine FDA and PMDA approved ADCs were analyzed. Allometric scaling (exponent = 1.0) was applied to the PK parameters in monkeys to predict the clearance and volume of distribution in humans, which had a high accuracy (within two-fold of the observed clinical values). Subsequently, compartment models were constructed for four ADCs, and the payload release rate constant (krel) was estimated by fitting the monkey ADC and payload concentration-time profiles. The estimated krel values were then directly applied to simulate human payload concentration-time profiles. The predicted human payload exposures were mostly within three-fold of the clinical data, regardless of differences in the linker type. In conclusion, this study demonstrates the use of a simple, single species scaling method using direct antibody measurements for the robust prediction of ADC and payload PK in humans. Our approach provides novel and efficient dose selection and risk assessment with minimal preclinical data.