Abstract
BACKGROUND: ASC10, an oral double prodrug of the antiviral ribonucleoside analog ASC10-A (also referred to as NHC), is currently in clinical trials for the treatment of COVID-19. Upon administration, ASC10 undergoes rapid biotransformation into the monoprodrug molnupiravir, which then swiftly converts to the active metabolite ASC10-A. Alternatively, ASC10 can directly transform into ASC10-A without forming molnupiravir as an intermediate. This study aimed to describe the population pharmacokinetics (popPK) of ASC10-A in healthy Chinese subjects and to inform clinical drug development. METHODS: We performed popPK modeling for ASC10-A using data from a Phase I clinical trial involving 57 healthy subjects and 1634 observations. The M3 method was employed to handle data below the quantification limit (BQL), while the Laplacian algorithm was implemented for popPK modeling. The final model was evaluated through goodness-of-fit (GOF) plots, non-parametric bootstrap method, and visual predictive check (VPC). The model-based simulations were performed to generate concentration-time profiles for ASC-10 or NHC across different studies, evaluate the exposure levels of ASC10-A under an 800 mg twice-daily dosing regimen (consistent with the recommended dose of molnupiravir), and quantify the covariate effects on the pharmacokinetic parameters of ASC10-A. RESULTS: The ASC10-A pharmacokinetics was described using a two-compartment model with first-order elimination and transit compartment absorption. Food intake and body weight were identified as influential variables on ASC10-A pharmacokinetics. The simulation results revealed that the ASC10-A exposure decreased with increasing body weight, and participants fasting could result in a higher peak concentration while retaining a similar exposure to those fed. The ASC10 dosing regimen of 800 mg every 12 hours could provide desirable exposure associated with clinical response. CONCLUSION: This study provides a comprehensive population pharmacokinetic profile of ASC10-A in healthy Chinese volunteers. These findings support the clinical development and identification of effective regimens for ASC10.