Merck Advances Pediatric Oncology with Innovative ADC Modeling

In late 2021, Merck & Co., Inc. partnered with Certara to solve a critical challenge in pediatric oncology: how to extend an innovative antibody–drug conjugate (ADC) therapy, originally approved for large B-cell lymphoma in adults to children with B-cell acute lymphoblastic leukemia, neuroblastoma, and Ewing sarcoma.

A key regulatory question centered on the pediatric dosing strategy. The FDA requested justification for whether body surface area (BSA)–based dosing would offer advantages over weight-based dosing in children. Determining the optimal approach required robust ADC modeling capable of supporting pediatric ADC dose optimization.

ADC pharmacokinetics are inherently complex, involving large and small molecular components, deconjugation processes, variable drug-to-antibody ratios (DARs), and limited pediatric data, making traditional modeling approaches insufficient for accurate pediatric ADC dosing predictions.

Certara collaborated with Merck to develop and validate a population PK (popPK) model for the ADC therapy using Phase I adult data. The ADC modeling framework included:

• Total antibody
• Antibody-conjugated payload
• Naked payload – This three-analyte structure allowed detailed characterization of:
  • Proteolytic degradation
  • Deconjugation pathways

When initial assay data did not meet modeling requirements, Certara partnered with Merck’s teams to troubleshoot discrepancies. Instead of relying on derived ADC metrics assuming a fixed DAR, analysts used raw analyte data to improve accuracy, stability, and predictive power.

To support pediatric ADC dose optimization, the model simulated exposures across ages 6 months to 18 years. Developmental biology, such as enzyme maturation and physiologic scaling, was integrated to improve predictions and strengthen justification for pediatric ADC dosing strategies.

Certara’s work supported FDA acceptance of Merck’s weight-based dosing strategy, enabling approval of the pediatric investigational plan (PIP) and advancement to Phase III.

The project successfully modeled a highly complex ADC with three analytes, an uncommon and technically challenging achievement, marking a milestone in applying ADC modeling to pediatric oncology.

Addressing FDA concerns early helped Merck avoid potential regulatory delays and maintain development momentum.

Close scientific alignment ensured accurate assumptions and model credibility, even with limited pediatric data.

This work established a scalable framework for future pediatric ADC programs and reinforced Merck’s confidence in Certara’s pharmacometrics leadership.