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

Translation of the synergy between the Siremadlin (MDM2 inhibitor) and Trametinib (MEK inhibitor) combination observed in vitro into in vivo synergistic efficacy in melanoma requires estimation of the interaction between these molecules at the pharmacokinetic (PK) and pharmacodynamic (PD) levels. Th...

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Published inInternational journal of molecular sciences Vol. 23; no. 21; p. 12984
Main Authors Witkowski, Jakub, Polak, Sebastian, Rogulski, Zbigniew, Pawelec, Dariusz
Format Journal Article
LanguageEnglish
Published Switzerland MDPI AG 26.10.2022
MDPI
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Summary:Translation of the synergy between the Siremadlin (MDM2 inhibitor) and Trametinib (MEK inhibitor) combination observed in vitro into in vivo synergistic efficacy in melanoma requires estimation of the interaction between these molecules at the pharmacokinetic (PK) and pharmacodynamic (PD) levels. The cytotoxicity of the Siremadlin and Trametinib combination was evaluated in vitro in melanoma A375 cells with MTS and RealTime-Glo assays. Analysis of the drug combination matrix was performed using Synergy and Synergyfinder packages. Calculated drug interaction metrics showed high synergy between Siremadlin and Trametinib: 23.12%, or a 7.48% increase of combined drug efficacy (concentration-independent parameter β from Synergy package analysis and concentration-dependent δ parameter from Synergyfinder analysis, respectively). In order to select the optimal PD interaction parameter which may translate observed in vitro synergy metrics into the in vivo setting, further PK/PD studies on cancer xenograft animal models coupled with PBPK/PD modelling are needed.
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content type line 23
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms232112984