The development of in vitro/in vivo translational methods and a clinical trial framework for synergistically acting drug combinations are needed to identify optimal therapeutic conditions with the most effective therapeutic strategies. We performed physiologically based pharmacokinetic-pharmacodynamic (PBPK/PD) modelling and virtual clinical trial simulations for siremadlin, trametinib, and their combination in a virtual representation of melanoma patients. In this study, we built PBPK/PD models based on data from in vitro absorption, distribution, metabolism, and excretion (ADME), and in vivo animals' pharmacokinetic-pharmacodynamic (PK/PD) and clinical data determined from the literature or estimated by the Simcyp simulator (version V21). The developed PBPK/PD models account for interactions between siremadlin and trametinib at the PK and PD levels. Interaction at the PK level was predicted at the absorption level based on findings from animal studies, whereas PD interaction was based on the in vitro cytotoxicity results. This approach, combined with virtual clinical trials, allowed for the estimation of PK/PD profiles, as well as melanoma patient characteristics in which this therapy may be noninferior to the dabrafenib and trametinib drug combination. PBPK/PD modelling, combined with virtual clinical trial simulation, can be a powerful tool that allows for proper estimation of the clinical effect of the above-mentioned anticancer drug combination based on the results of in vitro studies. This approach based on in vitro/in vivo extrapolation may help in the design of potential clinical trials using siremadlin and trametinib and provide a rationale for their use in patients with melanoma.