Abstract
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 CYP-interaction 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-N4-hydroxycytidine (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.