Background and objectives: Recently a number of antibody-drug conjugate (ADC) pharmacometric models have been reported in the literature, describing one or two ADC-related analytes. The objective of this analysis was to build a population pharmacokinetic (popPK) three-analyte ADC model to describe efficacy and safety of zilovertamab vedotin, an ROR1-targeting ADC conjugated to monomethyl auristatin E (MMAE).
Methods: Data from a phase 1 study of zilovertamab vedotin in subjects with hematologic malignancies was used in a stepwise ADC modeling strategy based on the simplified ADC popPK model proposed by Gibiansky. This choice provided opportunity to model three analytes: conjugated monomethyl auristatin E (acMMAE), total monoclonal antibody (total mAb), and free MMAE. The model was extrapolated to the pediatric population using a clearance maturation function and accounting for weight dependent pharmacokinetic (PK) changes.
Results: The simplified model provided a good structure to fit the adult acMMAE, total mAb, and free MMAE data. Analysis showed that MMAE was released through deconjugation of the payload and full proteolytic degradation of the acMMAE. Deconjugation was associated with an immediate release of MMAE, proteolytic clearance introduced a delay in the release of MMAE. Simulation of the model extrapolated to the pediatric population was the basis for pediatric dosing strategies for zilovertamab vedotin that were approved in the United States and European Union.
Conclusions: The total mAb, acMMAE, and free MMAE model showed a good fit to the data. The pediatric population can match the acMMAE adult exposure at the same weight-based dose regimen without concerns that the toxic MMAE concentration will reach higher levels than found in adults.
© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.