Clinical and Quantitative Pharmacology Considerations of mRNA Therapeutics and Vaccine Development: Bridging Translational and Platform Gaps for Enhanced Decision Making.

Messenger RNA (mRNA) technology has emerged as a transformative modality in modern therapeutics and vaccine development, offering a versatile platform for targeted protein expression. This manuscript proposes a clinical and quantitative pharmacology framework to facilitate the development of mRNA therapies from preclinical research to clinical development. We discuss the unique pharmacological and ADME properties of mRNA and its lipid nanoparticle (LNP) delivery system, along with key bioanalytical and regulatory considerations. Specific clinical pharmacology strategies and quantitative approaches are illustrated through real-world examples in oncology, rare metabolic diseases, and vaccines. Finally, we propose a forward-looking clinical and quantitative pharmacology framework that integrates translational modeling, population modeling, physiological-based pharmacokinetic (PBPK), quantitative systems pharmacology (QSP), and Artificial Intelligence (AI)/Machine Learning (ML)-assisted predictive modeling. This integrated approach aims to build platform knowledge of mRNA-based therapies and inform decision making across the drug discovery and development lifecycle in an evolving regulatory landscape.