How to Conduct Preclinical Pharmacokinetic Evaluation of mRNA-Based Therapeutics?

With the extraordinary clinical success of two mRNA vaccines, mRNA-based therapeutics are experiencing a global development boom. mRNA-based therapeutics can be classified into two categories based on the encoded protein type: mRNA vaccines and mRNA therapeutic drugs. mRNA vaccine development technology is well established, whereas the development of mRNA therapeutic drugs has faced several challenges, including improving protein expression levels, reducing immunogenicity, improving tissue targeting, exerting long-term effects, and long-term safety for repeated use. As mRNA-based therapeutics are promising, this blog discusses the PK assessment to assist in developing mRNA vaccines and mRNA therapeutic drugs.

The key points of PK studies of mRNA-based therapeutics: mRNA vaccines, mRNA therapeutic drugs, and novel excipients

• For mRNA vaccines, PK studies are not required, while only biodistribution studies typically need to be conducted.

• PK studies of mRNA therapeutic drugs are conducive to understanding the dose-response relationship of the drugs, and the studies of absorption and distribution are necessary for mRNA therapeutic drugs.

• For novel pharmaceutical excipients, a complete absorption, distribution, metabolism, and excretion (ADME) study is essential.

• The structure of mRNA-based therapeutics also affects PK studies. The potential drug interaction risk of pharmaceutical excipients needs to be assessed on a case-by-case basis.

• Development of mRNA delivery systems is also one of the hotspots in research and development. PK studies have primarily focused on the LNP delivery system because one of its principal constituents, ionizable cationic lipids, predominantly contribute to cytotoxic effects, whereas PEGylated lipids tend to cause immunogenicity.

The strategies for preclinical PK assessment of mRNA-based therapeutics

Preclinical PK studies of mRNA-based therapeutics can be divided into three types, focusing on mRNA vaccines, mRNA therapeutic drugs, and novel excipients.

1. It is necessary for mRNA vaccines to conduct biodistribution studies using the traditional tissue harvesting method, in vivo imaging method, or LNP-encapsulated alternative mRNAs.

2. PK and biodistribution studies are necessary for mRNA therapeutic drugs. Plasma PK studies need to be analyzed according to the mechanism of drug action, the purpose of the assay, and the difficulty of detection. For biodistribution studies, the researchers can first examine mRNA distribution, and then investigate the concentrations of the encoded proteins or biomarkers in key tissues based on the mRNA distribution results.

3. Studies of novel excipients include in vitro, in vivo, and drug interaction studies. In vitro studies include metabolic stability studies and metabolite identification in various systems. In vivo studies include absorption, distribution, metabolism, and excretion studies in animals to characterize the in vivo processes. Drug interactions of novel excipients are examined depending on the degree of risk.

How can WuXi AppTec DMPK help you?

Currently, there are no regulations specifically for qPCR analysis of mRNA. To evaluate the PK profiles of mRNA-based therapeutics, WuXi AppTec DMPK has established integrated bioanalytical platforms and an internal standard by referring to the consensus on qPCR method validation provided by the Global CRO Council in Bioanalysis (GCC). Based on the establishment of an integrated analytical platform and our extensive experience in PK studies of mRNA, we are capable of assisting our clients in shortening the development cycle of mRNA-based therapeutics.

If you want to learn more details about the development of mRNA-based therapeutics, please read the article now.

Committed to accelerating drug discovery and development, we offer a full range of discovery screening, preclinical development, clinical drug metabolism, and pharmacokinetic (DMPK) platforms and services. With research facilities in the United States (New Jersey) and China (Shanghai, Suzhou, Nanjing, and Nantong), 1,000+ scientists, and over fifteen years of experience in Investigational New Drug (IND) application, our DMPK team at WuXi AppTec are serving 1,500+ global clients, and have successfully supported 1,200+ IND applications.  

Talk to a WuXi AppTec expert today to get the support you need to achieve your drug development goals.

Committed to accelerating drug discovery and development, we offer a full range of discovery screening, preclinical development, clinical drug metabolism, and pharmacokinetic (DMPK) platforms and services. With research facilities in the United States (New Jersey) and China (Shanghai, Suzhou, Nanjing and Nantong), 1,000+ scientists and over fifteen years of experience in Investigational New Drug (IND) application, our DMPK team at WuXi AppTec are serving 1,500+ global clients, and have successfully supported 1,200+ IND applications.  Talk to a WuXi AppTec expert today to get the support you need to achieve your drug development goals.