Viral Dynamic Model‐Informed Dose Selection of Mosnodenvir Prophylaxis against DENV ‐3 in a Controlled Human Infection Model

Résumé fourni par la source

Dengue virus (DENV) infection is a significant global health threat. Mosnodenvir (JNJ‐64281802) is a pan‐serotype small molecule antiviral blocking DENV replication. A Phase IIa study (NCT05048875) evaluated the antiviral activity, safety, and pharmacokinetics of mosnodenvir as prophylaxis against DENV‐3 in a controlled human infection model (CHIM). A combined population pharmacokinetic (PopPK) and viral dynamic model (VDM) was developed to estimate the prophylactic effect of mosnodenvir and to inform dose selection. The PopPK model is a two‐compartment model based on plasma pharmacokinetic data from three Phase I studies and Cohort 1 of the Phase IIa study. Mosnodenvir exposure metrics were estimated for participants receiving high, medium, or low doses. A VDM with an immune response compartment adequately described DENV‐3 RNA profiles for placebo participants and was subsequently extended by including a sigmoid E max relationship with average mosnodenvir concentration at steady state ( C avg,ss ) to capture the antiviral effect on virion production rate. Simulations supported daily and weekly mosnodenvir dosing regimens to further characterize the pharmacokinetic/pharmacodynamic relationship in Cohort 2. Based on the complete Phase IIa study data, the basic reproductive number for DENV‐3 in this CHIM was estimated at 21.7, and the typical C avg,ss required to achieve complete virus eradication was estimated to be 1,410 ng/mL. In conclusion, the combined PopPK and VDM approach effectively informed dose selection and characterized the pharmacokinetic‐antiviral activity relationship, supporting the development of mosnodenvir as a prophylactic treatment for dengue infection.

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