Abstract
Abstract
Small-interfering RNA (siRNA) therapies can produce antiviral effects that persist beyond the dosing interval, but the quantitative relationship among administered dose, tissue exposure, endpoint-specific potency, and response duration is difficult to determine directly in 4 vivo. Here, we developed a mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model 5 for the HBV-targeting siRNA KC13-M2G2 using published longitudinal mouse data obtained 6 after three weekly subcutaneous doses of 0.3, 1, and 3 mg/kg. The model links subcutaneous 7 absorption and systemic distribution to hepatic uptake, liver exposure, and three endpoint-8 specific inhibitory functions describing suppression of HBsAg, HBeAg, and HBV DNA 9 production. By combining longitudinal in vivo biomarker trajectories with mechanistic 10 PK/PD modeling, we reconstructed quantitative dose–exposure–effect relationships within 11 the experimentally studied dose range, thereby extending the dose-response concept beyond 12 concentration-controlled in vitro assays. The fitted model reproduced the principal dose-13 dependent patterns of all three virological markers. HBsAg and HBV DNA inhibition were 14 predicted to reach high effect levels at substantially lower hepatic exposure than HBeAg 15 inhibition, consistent with marked endpoint-specific differences in the estimated EC 50 values.