Effective, but\nSafe? Physiologically Based Pharmacokinetic\n(PBPK)-Modeling-Based Dosing Study of Molnupiravir for Risk Assessment\nin Pediatric Subpopulations

Despite the end of COVID-19 pandemic, only intravenous\nremdesivir\nwas approved for treatment of vulnerable pediatric populations. Molnupiravir\nis effective against viruses beyond SARS-CoV-2 and is orally administrable\nwithout CYP-interaction liabilities but has a burden of potential\nbone or cartilage toxicity, observed at doses exceeding 500 mg/kg/day\nin rats. Especially, activity of molnupiravir against viruses, such\nas Ebola, with high fatality rates and no treatment option warrants\nthe exploration of potentially effective but safe doses for pediatric\npopulations, i.e., neonates (0–27 days), infants (1–12\nmonths), and children in early childhood (1–12 years). The\nbone and cartilage toxicity risk for these populations based on the\npreclinical results has not been systematically investigated yet.\nUsing physiologically based pharmacokinetic (PBPK) modeling, we developed\nadult PBPK models for doses ranging from 50 to 1200 mg with minimal\nparameter optimization because of incorporation of CES1, a carboxylesterase.\nTherein, CES1 served as the main driver for conversion of molnupiravir\nto its active metabolite <i>β-d-N4</i>-hydroxycytidine\n(NHC). By incorporation of the ontogeny of CES1 for pediatric populations,\nwe successfully developed PBPK models for different doses ranging\nfrom 10 to 75 mg/kg. For molnupiravir, efficacy is driven by the area\nunder the curve (AUC). To achieve a similar AUC to that seen in adults,\na dose of around 28 mg/kg BID was necessary in all three investigated\npediatric subpopulations. This dose exceeded the safe dose observed\nin dogs and was slightly below the toxicity-associated human equivalent\ndose in rats. In summary, the pediatric PBPK models suggested that\nan efficacious dose posed a toxicity risk. These data confirmed the\ncontraindication for children <18 years.