PI-103 - UTILISING PHYSIOLOGICAL LYMPH FLOWS TO ENHANCE A MINIMAL PHYSIOLOGICALLY BASED PHARMACOKINETIC AND QUANTITATIVE SYSTEMS PHARMACOLOGY MODEL FOR BIODISTRIBUTION OF MRNA ENCAPSULATED IN LIPID NANOPARTICLES WITH LIPID 5 IN RATS

J. Tait¹, K. Miyazawa², N. Trevaskis¹, H. Bazzazi², L. Van³, R. Marriott¹, C. Kirkpatrick¹, C. Landersdorfer¹, N. Nebot¹; ¹Monash University, Melbourne, Victoria, Australia, ²Moderna, Cambridge, MA, USA, ³Moderna, Inc., Cambridge, MA, USA.

Background: Minimal physiologically based pharmacokinetic and quantitative systems pharmacology (mPBPK-QSP) models are well-suited to characterize the biodistribution of therapeutic messenger RNA encapsulated in lipid nanoparticles (LNP-mRNA) and inform drug development. Despite playing an important role in the redistribution of macromolecules, the lymphatic system is rarely considered in mPBPK models for nanoparticles. Indeed, few mPBPK models in rodents incorporate lymph flow, often assumed to be 0.2% of blood flow. The objective of this study was to incorporate physiologically determined lymph flow values to an mPBPK-QSP model and describe the biodistribution of LNP-mRNA (containing Lipid 5) in rats.

Methods: A published mPBPK-QSP platform model was used as the base model (Miyazawa et al, Front. Nanotechnol. 2024; 6:1330406). Public domain data was sourced from Ci et al (PMID: 37208184) which reported a single dose of LNP-mRNA (containing ionizable lipid, Lipid 5, and 2 mg/kg mRNA), and plasma and liver mRNA concentrations over time. The mPBPK-QSP platform model was enhanced to include lymph flow based on physiologically measured values in rats (Yadav et al. PMID: 29305921; Trevaskis et al. PMID: 32670074; Humphreys et al. PMID: 16992278). This enhanced model was then utilized to explore non-linear transport mechanisms to describe the pharmacokinetic profiles. All model building and calibration was undertaken with MATLAB SimBiology (R2023b).

Results: The addition of physiologically determined lymph flow to the mPBPK-QSP platform model improved the ability to describe mRNA pharmacokinetics following dosing of the LNP-mRNA in rats. Including non-linear transport of mRNA from plasma to the interstitial space improved the maximal concentration (Cmax) fit in plasma and liver tissue (Table). Adapting cellular uptake to include capacity-limited phagocytosis for macrophages and Kupffer cells improved the shape of the terminal slopes of mRNA concentrations in plasma and liver tissue.

Conclusion: The physiologically correct parameterization in our mPBPK-QSP model provides greater understanding of plasma and liver pharmacokinetics of LNP-mRNA. This enhanced model could quantify the impact of food or disease on lymphatic flow to inform and optimize the drug development of LNP-mRNA therapeutics.