In Vitro/In Vivo Translation of Synergistic Combination of MDM2 and MEK Inhibitors in Melanoma Using PBPK/PD Modelling: Part II.

ABSTRACT: The development of in vitro/in vivo translational methods for synergistically acting drug combinations is needed to identify the most effective therapeutic strategies. We performed PBPK/PD modelling for siremadlin, trametinib, and their combination at various dose levels and dosing schedules in an A375 xenografted mouse model (melanoma cells). In this study, we built models based on in vitro ADME and in vivo PK/PD data determined from the literature or estimated by the Simcyp Animal simulator (V21). The developed PBPK/PD models allowed us to account for the interactions between siremadlin and trametinib at PK and PD levels. The interaction at the PK level was described by an interplay between absorption and tumour disposition levels, whereas the PD interaction was based on the in vitro res

SUBMITTER: Witkowski J 

PROVIDER: S-EPMC9570053 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature