Resident Seoul National University College of Medicine and Hospital, Republic of Korea
Objectives: S-001 is a newly developed mRNA-based therapy that binds to the messenger ribonucleic acid of TGF-β in a complementary manner, regulating gene expression and subsequent protein expression. It has been developed as a therapeutic agent for solid tumors that overproduce TGF-β, such as pancreatic cancer. This study aimed to establish a pharmacokinetic (PK)-pharmacodynamic (PD) model to suggest an optimal dosing regimen for a clinical trial by integrating preclinical PK and PD data with human pancreatic cancer data.
Methods: The PK model was established based on plasma S-001 concentrations observed in ICR mice following intraperitoneal administration and in Cynomolgus monkeys following intravenous infusion. PK model parameters from two different species were allometrically scaled to humans. The initial PD model was developed using tumor volume-time profiles obtained from human pancreatic cancer xenograft mice. Considering the difference in tumor growth rate between human and mouse, PD model parameters, including tumor growth rate constant, baseline and maximum tumor volume, were adjusted using previously reported human pancreatic cancer data.[1] The PK-PD model was evaluated by comparing the plausibility of parameter estimates, objective function value analysis, examination of goodness of fit plot, and visual predictive checks. Using the final PK-PD model, various dose regimens and corresponding tumor volume-time profiles in humans were simulated.
Results: A two-compartment model with first-order absorption and first-order elimination best described the pharmacokinetics of S-001. Tumor growth without treatment followed a logistic growth model, and S-001-mediated tumor growth inhibition was modeled using the Norton-Simon killing model with an Imax function.[2] Simulations based on the final PK-PD model indicated that doses exceeding 1 mg/kg once a week resulted in decelerated tumor growth.
Conclusion: The S-001 PK-PD model for human pancreatic cancer was developed to guide the dosing regimen of a clinical trial by combining the data across species.
Citations: [1] Furukawa H, Iwata R, Moriyama N. Growth rate of pancreatic adenocarcinoma: initial clinical experience. Pancreas. 2001;22(4):366-9. doi: 10.1097/00006676-200105000-00005. PMID: 11345136. [2] Álvaro G. López, Kelly C. Iarosz, Antonio M. Batista, Jesús M. Seoane, Ricardo L. Viana, Miguel A.F. Sanjuán, Nonlinear cancer chemotherapy: Modelling the Norton-Simon hypothesis, Communications in Nonlinear Science and Numerical Simulation, 2019, https://doi.org/10.1016/j.cnsns.2018.11.006.
