Optimizing moxidectin dosing for <i>Strongyloides stercoralis</i> infections: Insights from pharmacometric modeling
Daniela Hofmann, Cornelis Smit, Somphou Sayasone, Marc Pfister, Jennifer Keiser
Abstract
Abstract Moxidectin is a frontrunner drug candidate in the treatment of strongyloidiasis. A dose of 8 mg is recommended to treat this indication, which shows a reasonably good efficacy and tolerability profile. Yet, owing to the unique life cycle of Strongyloides stercoralis ( S. stercoralis ) that entails internal autoinfection, a curative treatment would be desirable. Population‐based pharmacometric modeling that would help to identify an ideal dosing strategy are yet lacking. The aims of this study were to (i) explore the exposure‐efficacy response relationship of moxidectin in treating S . stercoralis and (ii) evaluate whether moxidectin treatment outcomes in terms of cure rates at baseline as compared to post‐treatment could be optimized. Our pharmacodynamic model suggests high predictive power (area under the concentration time curve‐receiver operating characteristic [AUC‐ROC] 0.817) in the probability of being cured by linking an exposure metric (i.e., AUC 0‐24 or maximum concentration [C max ]) to baseline infection intensity. Pharmacometric simulations indicate that with a minimum dose of 4 mg a maximum cure rate of ~ 95% is established in the low infection intensity group (larvae per gram [LPG] ≥0.4–1), whereas in the moderate‐to‐high intensity group (LPG >1) the cure rate plateaus at ~ 87%, following an 8 mg dose. To enhance efficacy further, studies using repeated dosing based on the duration of the autoinfection cycle, for example a two‐dose regimen 3 weeks apart should be considered. Simulations revealed similar C max in both treatment courses of a two‐dose regimen; hence safety should not be a concern. Collectively, our results provide evidence‐based guidance for enhanced dosing strategies and should be considered when designing future treatment strategies.