Predicting the systemic exposure and lung concentration of nafamostat using physiologically-based pharmacokinetic modeling

Abstract

Nafamostat has been actively studied for its neuroprotective activity and effect on various indications, such as coronavirus disease 2019 (COVID-19). Nafamostat has low water solubility at a specific pH and is rapidly metabolized in the blood. Therefore, it is administered only intravenously, and its distribution is not well known. The main purposes of this study are to predict and evaluate the pharmacokinetic (PK) profiles of nafamostat in a virtual healthy population under various dosing regimens. The most important parameters were assessed using a physiologically based pharmacokinetic (PBPK) approach and global sensitivity analysis with the Sobol sensitivity analysis. A PBPK model was constructed using the SimCYP ® simulator. Data regarding the in vitro metabolism and clinical studies were extracted from the literature to assess the predicted results. The model was verified using the arithmetic mean maximum concentration (C max ), the area under the curve from 0 to the last time point (AUC 0-t ), and AUC from 0 to infinity (AUC 0-∞ ) ratio (predicted/observed), which were included in the 2-fold range. The simulation results suggested that the 2 dosing regimens for the treatment of COVID-19 used in the case reports could maintain the proposed effective concentration for inhibiting severe acute respiratory syndrome coronavirus 2 entry into the plasma and lung tissue. Global sensitivity analysis indicated that hematocrit, plasma half-life, and microsomal protein levels significantly influenced the systematic exposure prediction of nafamostat. Therefore, the PBPK modeling approach is valuable in predicting the PK profile and designing an appropriate dosage regimen.

PBPK‐led assessment of antimalarial drugs as candidates for Covid‐19: Simulating concentrations at the site of action to inform repurposing strategies

“…This paper presents how this approach was used to identify potential new therapeutic agents for an emerging infectious disease during a public health emergency when access to clinical populations was limited and urgent solutions were required. During the COVID‐19 pandemic, PBPK modeling was applied to evaluate potential drug repurposing candidates, including the accumulation of drug into ELF and lung mass, similar to the current evaluation 38,42,43,46–50 . Notably, PBPK modeling findings were informative in the clinical development of remdesivir 42,50 …”

“…During the COVID‐19 pandemic, PBPK modeling was applied to evaluate potential drug repurposing candidates, including the accumulation of drug into ELF and lung mass, similar to the current evaluation. 38 , 42 , 43 , 46 , 47 , 48 , 49 , 50 Notably, PBPK modeling findings were informative in the clinical development of remdesivir. 42 , 50 …”

“…During the COVID-19 pandemic, PBPK modeling was applied to evaluate potential drug repurposing candidates, including the accumulation of drug into ELF and lung mass, similar to the current evaluation. 38,42,43,[46][47][48][49][50] Notably, PBPK modeling findings were informative in the clinical development of remdesivir. 42,50 A key advantage of PBPK modeling is that it enables early simulation and prediction of drug behavior based on known physiological and biochemical parameters before clinical data become available.…”

Antiandrogens as Therapies for COVID-19: A Systematic Review

“…Nevertheless, other TMPRSS2-targeted therapies have been tested, such as nafamostat mesylate and bromhexine. In vitro, Nafamostat resulted effective in preventing viral entrance [9,[29][30][31]. Despite the efficacy achieved in a preclinical setting [30], animal and clinical studies are limited and some other works disconfirmed its efficacy [32,33].…”

The Application of a Physiologically Based Toxicokinetic Model in Health Risk Assessment

“…The parameters with high sensitivity are considered the key factors that should be accurately controlled to improve the prediction accuracy of the models. Jeong et al [103] used a PBTK approach, coupled with global sensitivity analysis, to predict and evaluate the pharmacokinetic profiles of nafamostat in a virtual healthy population under various dosing regimens, and the results suggested that the hepatic distribution and metabolism had a significant impact on systemic exposure and clearance of nafamostat.…”