Sustained Drug Exposure Drives Efficacy in Mice: PK/PD Analysis of Corallopyronin A against Wolbachia using...

Corallopyronin A (CorA) depletes essential Wolbachia endosymbionts of filarial nematodes and is therefore a promising candidate for treating the neglected tropical diseases lymphatic filariasis and onchocerciasis. To optimize anti-Wolbachia therapy, the pharmacokinetic/pharmacodynamic (PK/PD) relationship was investigated. Due to the intra-nematode and -cellular target, conventional minimal inhibitory concentration could not be determined. Instead, an iterative approach was used to define PD efficacy thresholds and compare them with IC₅₀/IC₉₀ values from infected cells. A physiologically based biopharmaceutics model (PBBM) was developed in GastroPlus®, incorporating physicochemical in vitro and in vivo parameters to predict PK in mice. A mechanistic dissolution model for a CorA-povidone suspension was implemented and verified with in vivo single dose PK data. Simulations provided trough and peak concentrations (C_max), AUC and time above threshold for multiple dosing regimens. In vivo efficacy was assessed in a Litomosoides sigmodontis mouse infection model by quantifying Wolbachia burden. CorA showed potent in vitro activity (IC₅₀/ IC₉₀: 0.007/0.030 µg/mL). In vivo, fractionated dosing improved efficacy. C_max poorly predicted treatment outcome, while trough concentration and AUC over iterative model dependent efficacy threshold correlated strongly with the Wolbachia reduction (R²: 0.89 and 0.81). These thresholds show strong concordance with the experimentally determined IC₅₀/IC₉₀ values. The duration of drug exposure above 2.25 µg/mL was the most accurate predictor of efficacy (R²: 0.93). Based on the PK/PD modeling, an effective mouse dose of 16 mg/kg BID was identified. These findings highlight the importance of sustained drug exposure for optimizing CorA regimens and will guide clinical development.