A Minimal PBPK/PD Model with Expansion-Enhanced Target-Mediated Drug Disposition to Support a First-in-Human Clinical Study Design for a FLT3L-Fc Molecule

• Main Authors: Iraj Hosseini (Author), Brett Fleisher (Author), Jennifer Getz (Author), Jérémie Decalf (Author), Mandy Kwong (Author), Meric Ovacik (Author), Travis W. Bainbridge (Author), Christine Moussion (Author), Gautham K. Rao (Author), Kapil Gadkar (Author), Amrita V. Kamath (Author), Saroja Ramanujan (Author)
• Format: Book
• Published: MDPI AG, 2024-05-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

FLT3L-Fc is a half-life extended, effectorless Fc-fusion of the native human FLT3-ligand. In cynomolgus monkeys, treatment with FLT3L-Fc leads to a complex pharmacokinetic/pharmacodynamic (PK/PD) relationship, with observed nonlinear PK and expansion of different immune cell types across different dose levels. A minimal physiologically based PK/PD model with expansion-enhanced target-mediated drug disposition (TMDD) was developed to integrate the molecule's mechanism of action, as well as the complex preclinical and clinical PK/PD data, to support the preclinical-to-clinical translation of FLT3L-Fc. In addition to the preclinical PK data of FLT3L-Fc in cynomolgus monkeys, clinical PK and PD data from other FLT3-agonist molecules (GS-3583 and CDX-301) were used to inform the model and project the expansion profiles of conventional DC1s (cDC1s) and total DCs in peripheral blood. This work constitutes an essential part of our model-informed drug development (MIDD) strategy for clinical development of FLT3L-Fc by projecting PK/PD in healthy volunteers, determining the first-in-human (FIH) dose, and informing the efficacious dose in clinical settings. Model-generated results were incorporated in regulatory filings to support the rationale for the FIH dose selection.

Item Description

10.3390/pharmaceutics16050660
1999-4923