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

by Selleckchem | Aug 14 2023

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.

Comments:

The passage you provided describes a study that utilized physiologically based pharmacokinetic-pharmacodynamic (PBPK/PD) modeling and virtual clinical trial simulations to evaluate the efficacy and optimal conditions for using a combination of siremadlin and trametinib as a potential therapy for melanoma.

The researchers developed PBPK/PD models using data from in vitro absorption, distribution, metabolism, and excretion (ADME) studies, as well as in vivo animal pharmacokinetic-pharmacodynamic (PK/PD) data and clinical data obtained from literature sources or estimated using the Simcyp simulator. These models were designed to capture the interactions between siremadlin and trametinib at both the PK and PD levels.

Interactions at the PK level, specifically absorption, were predicted based on findings from animal studies. On the other hand, PD interactions were based on in vitro cytotoxicity results. By combining these PBPK/PD models with virtual clinical trial simulations, the researchers were able to estimate the pharmacokinetic and pharmacodynamic profiles of the drug combination and identify patient characteristics in which this therapy could be comparable to the standard dabrafenib and trametinib drug combination.

The use of PBPK/PD modeling and virtual clinical trials allowed the researchers to extrapolate from in vitro studies to estimate the clinical effects of the siremadlin and trametinib combination. This approach can be valuable in the design of potential clinical trials involving these drugs and provide a scientific basis for their use in melanoma patients.

In summary, the study utilized PBPK/PD modeling and virtual clinical trial simulations to investigate the effectiveness and optimal conditions for combining siremadlin and trametinib as a potential therapy for melanoma. The approach employed in vitro/in vivo extrapolation to inform the design of clinical trials and provide a rationale for the use of these drugs in patients with melanoma.