Effective, but Safe? Physiologically Based Pharmacokinetic (PBPK)-Modeling-Based Dosing Study of Molnupiravir for Risk Assessment in Pediatric Subpopulations

Figure 1. Schematic conversion of molnupiravir toward NHC-TP. Conversion of molnupiravir into its active form (NHC-TP) via NHC. Molnupiravir is rapidly hydrolyzed in plasma to NHC, which is taken up by host cells and further metabolized to the triphosphate form.

Figure 2. Schematic representation for assessment of a safe but effective dose from adults to children. A safe, but effective dose was modeled using the information from PK data to estimate a safe dose in pediatric populations bearing in mind the risk for bone and cartilage toxicity. The graphic was created with https://www.biorender.com.

Figure 3. Molnupiravir-NHC PBPK human models for ascending single doses. The continuous line represents the mean simulated plasma concentration of NHC. The dashed lines represent the 5–95% CI. The blue dots with error bars indicate the observed plasma concentrations. All of the observed data are within the CI of the simulated curves. Plasma concentrations of NHC were simulated for oral solutions (a–e) of 50 mg (a), 100 mg (b), 200 mg (c), 400 mg (d), and 600 mg (e) as well as for formulation as a capsule (f–h) for 800 mg (f), 1200 mg (g), and 1600 mg (h).

Figure 4. Concentration–time profiles for neonates at 75 mg/kg BID compared to adults at 1200 mg BID. NHC plasma concentration–time profiles for 75 mg/kg of BID (black) in neonates and 1200 mg of BID (blue) in adults over 5.5 days. Mean observed data as well as error bars for adults are shown in green. The continuous lines represent the predicted mean plasma concentrations, whereas the lower and upper dashed lines depict the 95% CI. The EC50 for the omicron (black) variant and the wildtype (red) are shown as dashed lines.

Figure 5. Concentration–time profiles for infants at 75 mg/kg BID compared to adults at 1200 mg BID. NHC plasma concentration–time profiles for 75 mg/kg of BID (black) in infants and 1200 mg of BID (blue) in adults over 5.5 days. Mean observed data as well as error bars for adults are shown in green. The continuous lines represent the predicted mean plasma concentrations, whereas the lower and upper dashed line depict 95% CI. The EC50 for the omicron (black) variant and the wildtype (red) are shown as dashed lines.

Figure 6. Concentration–time profiles for children in early childhood at 75 mg/kg BID compared to adults at 1200 mg BID. NHC plasma concentration–time profiles for 75 mg/kg of BID (black) in children in early childhood and 1200 mg of BID (blue) in adults over 5.5 days. Mean observed data as well as error bars for adults are shown in green. The continuous lines represent the predicted mean plasma concentrations, whereas the lower and upper dashed line depict 95% CI. The EC50 for the omicron (black) variant and the wildtype (red) are shown as dashed lines.