ArticleClinical pharmacokinetics2024
A Sequential Population Pharmacokinetic Model of Zilovertamab Vedotin in Patients with Hematologic Malignancies Extrapolated to the Pediatric Population.
Article in Clinical pharmacokinetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- Targeted therapies in pediatric oncology: A start.Molecular therapy. Oncology · 2026Review
- Review
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Authors and funding
4 authors.
Funding
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Abstract
BACKGROUND AND
objectivesRecently 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).
methodsData 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.
resultsThe 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.
conclusionsThe 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.
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