Effective, but Safe? Physiologically Based Pharmacokinetic (PBPK)-Modeling-Based Dosing Study of Molnupiravir for Risk Assessment in Pediatric Subpopulations
Sarang Mishra, Katharina Rox
ACS Pharmacology & Translational Science, doi:10.1021/acsptsci.4c00535
Despite the end of COVID-19 pandemic, only intravenous remdesivir was approved for treatment of vulnerable pediatric populations. Molnupiravir is effective against viruses beyond SARS-CoV-2 and is orally administrable without CYPinteraction liabilities but has a burden of potential bone or cartilage toxicity, observed at doses exceeding 500 mg/kg/day in rats. Especially, activity of molnupiravir against viruses, such as Ebola, with high fatality rates and no treatment option warrants the exploration of potentially effective but safe doses for pediatric populations, i.e., neonates (0-27 days), infants (1-12 months), and children in early childhood (1-12 years). The bone and cartilage toxicity risk for these populations based on the preclinical results has not been systematically investigated yet. Using physiologically based pharmacokinetic (PBPK) modeling, we developed adult PBPK models for doses ranging from 50 to 1200 mg with minimal parameter optimization because of incorporation of CES1, a carboxylesterase. Therein, CES1 served as the main driver for conversion of molnupiravir to its active metabolite β-d-N4hydroxycytidine (NHC). By incorporation of the ontogeny of CES1 for pediatric populations, we successfully developed PBPK models for different doses ranging from 10 to 75 mg/kg. For molnupiravir, efficacy is driven by the area under the curve (AUC). To achieve a similar AUC to that seen in adults, a dose of around 28 mg/kg BID was necessary in all three investigated pediatric subpopulations. This dose exceeded the safe dose observed in dogs and was slightly below the toxicity-associated human equivalent dose in rats. In summary, the pediatric PBPK models suggested that an efficacious dose posed a toxicity risk. These data confirmed the contraindication for children <18 years.
■ ASSOCIATED CONTENT
* sı Supporting Information The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsptsci.4c00535 . Mass spectrometric conditions for molnupiravir and NHC; demographic and ontogenic parameters for subpopulations of the study; EC 50 values of NHC against different SARS-CoV-2 VOC; time over EC 50 for adult and pediatric models at selected doses; dose linearity comparison for dose correlated with AUC and C max ; simulated and observed concentration-time profiles for NHC after administration of multiple doses; NHC plasma concentration-time profile for neonates at different doses; NHC plasma concentration-time profile for infants at different doses; and NHC plasma concentration-time profile at different doses for children in early childhood (PDF) ■ AUTHOR INFORMATION Author Contributions S.M. built the PBPK models, contributed ADME data, analyzed the data, and wrote the original draft of the manuscript. K.R. conceived the study, reviewed PBPK models, contributed ADME data, analyzed the data, contributed to writing of the original draft, reviewed and edited the manuscript, supervised the study, and acquired funding.
Notes The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 101005077. The JU receives support from the European Union's Horizon 2020 research and innovation..
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