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

• Published in: International journal of molecular sciences Vol. 23; no. 19; p. 11939
• Main Authors: Witkowski, Jakub, Polak, Sebastian, Rogulski, Zbigniew, Pawelec, Dariusz
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 08.10.2022; MDPI
• Subjects: Animal models; Animals; anticancer drugs; Cancer; Clinical trials; Dosage; drug combination; Extrapolation; Heart; In vitro methods and tests; In vivo methods and tests; Kidneys; Liver; MDM2 protein; Melanoma; Melanoma - drug therapy; Metastasis; Mice; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Modelling; Models, Biological; PBPK/PD modelling; Pharmacodynamics; Pharmacokinetics; Plasma; preclinical study; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; Schedules; Skin; Spleen; Tumors; Xenografts; drug combination; pharmacodynamics; pharmacokinetics; MEK inhibitor; PBPK/PD modelling; preclinical study; anticancer drugs; MDM2 inhibitor
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms231911939

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 results. This approach allowed us to reasonably estimate the most synergistic and efficacious dosing schedules and dose levels for combinations of siremadlin and trametinib in mice. PBPK/PD modelling is a powerful tool that allows researchers to properly estimate the in vivo efficacy of the anticancer drug combination based on the results of in vitro studies. Such an approach based on in vitro and in vivo extrapolation may help researchers determine the most efficacious dosing strategies and will allow for the extrapolation of animal PBPK/PD models into clinical settings.