| Autor: |
Iraj Hosseini, Brett Fleisher, Jennifer Getz, Jérémie Decalf, Mandy Kwong, Meric Ovacik, Travis W. Bainbridge, Christine Moussion, Gautham K. Rao, Kapil Gadkar, Amrita V. Kamath, Saroja Ramanujan |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Pharmaceutics, Vol 16, Iss 5, p 660 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
1999-4923 |
| DOI: |
10.3390/pharmaceutics16050660 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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