Physiologically based pharmacokinetic modeling to predict human pharmacokinetics of a novel mithramycin analog for Ewing sarcoma.

PURPOSE: To develop and qualify a physiologically based pharmacokinetic (PBPK) modeling strategy for mithramycin (MTM) and its analog, MTMSA-Trp, with the aim of projecting first-in-human plasma pharmacokinetics and supporting the translational development of MTMSA-Trp for Ewing sarcoma treatment.

METHODS

PBPK models were created in GastroPlus® using a middle-out approach, incorporating preclinical pharmacokinetic data from mice, rats, and cynomolgus monkeys. Human clearance was estimated through three methods: an additional clearance approach, allometric scaling, and single-species scaling from monkeys. The model was evaluated using clinical MTM plasma PK data and then employed to project human MTMSA-Trp plasma PK, with tissue predictions considered exploratory to contextualize hepatotoxicity risk.

RESULTS

The additional clearance approach provided the most accurate prediction of human MTM plasma PK. Across all clearance prediction methods, MTMSA-Trp was predicted to achieve 8- to 15-fold higher human plasma exposure than MTM at the same dose. Model-derived liver exposures were 2- to 4-fold higher, with a lower predicted liver partition for MTMSA-Trp; however, these tissue predictions remained sensitive to distribution assumptions. Parameter sensitivity analysis identified the blood-to-plasma ratio as the most influential parameter among those examined.

CONCLUSION

PBPK modeling supports the projection that MTMSA-Trp will achieve substantially higher plasma exposure than MTM in humans. This empirically developed workflow may inform translational efforts for the first-in-human development of MTMSA-Trp.