What Can We Learn from the PK Profiles of FDA Approved mRNA Vaccines

BioNTech/Pfizer’s BNT162b2 (COMIRNATY^®) and Moderna’s mRNA-1273 (SPIKEVAX^®) mRNA vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were fast-tracked for approval by the Food and Drug Administration (FDA) in December 2020. With the approval of these two mRNA vaccines, more and more pipelines of mRNA as preventive and therapeutic treatment have been developed quickly. However, the accelerated development of mRNA vaccines faces many challenges, including whether it is necessary to conduct preclinical studies on the PK properties of mRNA vaccines, how to proceed with the research, and what PK (Pharmacokinetic) profiles the mRNA vaccines have. This blog provides insights into the preclinical data of the two approved vaccines, offering a valuable reference for mRNA vaccine development.

The summary of the PK profile of mRNA vaccines based on the FDA approved BNT162b2 and mRNA-1273

The preclinical PK studies of BNT162b2 and mRNA-1273 can be divided into two categories: (1) research on the biodistribution of the mRNA and (2) studies on the in vivo PK, tissue distribution, excretion, and metabolism of the novel lipid components used in the vaccine. Based on the interpretation of preclinical PK data of BNT162b2 and mRNA-1273, this blog summarizes the PK profile of LNP-delivered mRNA vaccines:

• The biodistribution of mRNA will be dependent on the LNP delivery system used. Based on the application materials for approved vaccines, it could be accepted for the FDA to use surrogate mRNA formulated in the same LNP as the test article for the tissue distribution evaluation. After intramuscular injection of an mRNA vaccine, mRNA will have higher exposure in tissues compared to plasma, with prolonged and continuous distribution at the injection site. Meanwhile, mRNA will more tends to be distributed in the liver due to the liver-targeting property of LNP, and showed certain exposure in the lymph nodes and spleen (immune system organs) which should be paid attention to. Overall, mRNA undergoes rapid distribution and elimination in most tissues with T_max within 24 hours and T_last within 72 hours post-dose. Notably, mRNA may have a persistent distribution at the injection site, lymph nodes, and spleen for 2–3 weeks, with a slow elimination rate.

  
  

• Among the components of the LNP delivery system, phospholipids, and cholesterol are natural endogenous lipids, for which the PK profile does not need to be evaluated. However, ionizable cationic lipids and PEG lipids, as exogenous components, need to be assessed for their absorption, distribution, metabolism, and excretion processes, considering the unknown in vivo disposition, toxicity, and immunogenicity of these components.

  
  

• Based on the structural features and study results of several lipid molecules in the BNT162b2 and mRNA-1273 delivery systems, it has been observed that both lipid molecules undergo different degrees of hydrolytic metabolism in vivo that are related to their structures. Excretion study revealed that the recovery rate of the original lipid molecules is generally inadequate in the urine, feces, and bile. The tissue distribution of lipids is relatively consistent with that of mRNA, exhibiting the most abundant and longest distribution at the injection site, followed by the liver (LNP target tissue) and immune tissues, such as the spleen and lymph nodes.

How WuXi AppTec DMPK can assist you in developing mRNA vaccines

WuXi AppTec DMPK has established an integrated bioanalytical platform, which incorporates various assays such as quantitative polymerase chain reaction (qPCR) and branched DNA assay for mRNA plasma and tissue detection; and mass spectrometry method for delivery vectors evaluation. With our extensive experience in PK research and development, we look forward to assisting clients in accelerating the progress of mRNA vaccines and drug projects.

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

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