Significant progress has been made in the development of lipid nanoparticle (LNP)-encapsulated messenger RNA (mRNA)-based modalities with numerous candidates entering clinical trials. These novel modalities require the application of innovative quantitative models to inform the development of mRNA-LNP-based candidates. To this end, we conducted a comprehensive search of registered clinical trials related to mRNA-based modalities on ClinicalTrials.gov, summarizing the current advancements of mRNA-LNP-based modalities and their expanding therapeutic applications. Also, we performed a thorough review of quantitative models related to mRNA-LNP-based modalities from PubMed, Google Scholar, and Embase databases, exploring the model structures employed to capture the in vivo processes of mRNA-LNP, along with their current applications. Between 2002 and October 28, 2024, around 189 clinical trials were registered on ClinicalTrials.gov, encompassing approximately 132 unique mRNA-based modalities targeting 18 disease areas. There are 15 studies that have published quantitative models supporting both the preclinical and clinical development of mRNA-LNP-based therapeutics. Detail regarding quantitative modeling of mRNA-LNP, especially absorption, distribution, metabolism, and excretion, as well as the activation processes of immune responses induced by mRNA-LNP-based vaccines are reviewed. Furthermore, we offer insights for future research related to mRNA-LNP-related models, aimed at enhancing predictive performance and facilitating the expedited advancement of mRNA-LNP-related clinical development.

Background/Objectives: Physiologically based pharmacokinetic (PBPK) absorption models are instrumental for assessing drug absorption prior to clinical food effect studies, though discrepancies in predictive and actual outcomes are observed. This study focused on immediate release formulations of weakly basic water-insoluble compounds, namely rivaroxaban, ticagrelor, and PB-201, to investigate factors that could improve the predictive accuracy of PBPK models regarding food effects. Methods: Comprehensive in vitro experimental results provided the basis for the development of mechanistic absorption models, which were then combined with mechanistic disposition models to predict the systemic exposure of the model drugs in both fasted and fed states. Results: The developed PBPK models showed moderate to high predictive accuracy for food effects in Caucasian populations. For the Chinese population, the ticagrelor model’s initial overestimation of fed-state absorption was addressed by updating the permeability parameters from Caco-2 cell assays to those derived from parallel artificial membrane permeability assays in FaSSIF and FeSSIF media. This refinement was also applied to the rivaroxaban and ticagrelor models, leading to a more accurate representation of absorption in Caucasians. Conclusions: This study highlights the importance of apparent permeability in enhancing the predictive accuracy of PBPK absorption models for weakly basic water-insoluble compounds. Furthermore, the precipitation of PB-201 in the two-stage transfer experiments suggests that precipitation may not be a universal phenomenon for such compounds in vivo. Consequently, the precipitation rate constant, a theoretically essential parameter, should be determined based on experimental evidence to avoid overparameterization and ensure robust predictive accuracy of PBPK models.

HKS21542, a highly selective activator of peripheral kappa opioid receptor agonists, plays a critical role in antinociception and itch inhibition during clinical development. Due to its indication population and elimination characteristics, it is imperative to evaluate the potential HSK21542 systemic exposure in individuals with renal impairment, hepatic impairment, the elderly, and the geriatric population. Here, a physiologically-based pharmacokinetic (PBPK) model for HSK21542 was developed based on in vitro metabolism and transport characteristics and in vivo elimination mechanism. Meanwhile, the potential systemic exposure of HSK21542 in specific populations was evaluated. The predicted results indicated increased systemic exposure in patients with renal impairment, hepatic impairment and in the elderly. Compared to the healthy volunteers aged 20-60 years, the AUC_0-24h increased by 52 %-71 % in population with moderate to severe renal impairment, by 46 %-77 % in those with mild to severe hepatic impairment, and by 45 %-85 % in the elderly population aged 65-95-years. Conversely, the pediatric population demonstrated a potential decrease in systemic exposure, ranging from 20 % to 37 % in patients aged 0-17 years due to the physiological characteristics. Combined with the predicted results and the exposure-response relationship observed for HSK21542 and its analog (CR845), dosage regimens were designed for the target population with renal and hepatic impairment, supporting the successfully conducted trials (CTR20201702 and CTR20211940). Moreover, the observed exposure of HSK21542 in the elderly closely matched the predicted results within the same age group. Additionally, based on the predicted results, potential reductions in systemic exposure in pediatric patients should be carefully considered to avoid potential treatment failure in future clinical trials.