Characterization of the Population Pharmacokinetics of Moxidectin in Adults Infected with Strongyloides Stercoralis: Support for a Fixed-Dose Treatment Regimen

Abstract

Background: Moxidectin has recently attracted attention as a novel candidate for the treatment of helminth infections, including Strongyloides stercoralis. This study aims to characterize the population pharmacokinetics (PPK) of moxidectin in S. stercoralis-infected adults using a pharmacometric approach, and to perform model-based simulations to explore different drug dosing strategies.

Methods: A PPK study embedded in a dose-escalation phase IIa trial was conducted in NamBak, Laos. Eight micro blood samples were collected from each of 96 S. stercoralis-infected adults following a moxidectin dose-ranging study, from 2 to 12 mg. A PPK model was developed using nonlinear mixed-effects modeling, and dosing strategies were explored using simulations in S. stercoralis-infected subjects with varying age and body weight (n = 5000 per dosing strategy).

Results: A two-compartment model including delayed absorption with lag-time best described the available PK data. Allometric scaling was applied to account for the influence of body weight. High clearance was found in the infected adults (4.47 L/h [95% confidence interval 3.63-5.39] for a 70 kg individual) compared with that previously reported for healthy adults. Model-based simulations indicated similar variability in mean ± standard deviation area under the curve from time zero to infinity of 1907 ± 1552 and 2175 ± 1670 ng × h/mL in the 60-70 kg weight group, after 8 mg fixed- or weight-based dosing, respectively.

Conclusion: We describe the first PPK model for moxidectin in adults with S. stercoralis infection. Equivalent exposures after fixed-dose and weight-dependent dosing strategies support the use of a simple fixed-dose approach, particularly in large-scale treatment programs.

Trial registration: Registered at ClinicalTrials.gov (NCT04056325).

Conflict of interest statement

Marc Pfister has part‐time employment with the consulting company Certara LP (USA). Cornelis Smit, Daniela Hofmann, Somphou Sayasone, and Jennifer Keiser declare no competing interests for this work.

© 2021. The Author(s).

Figures

Fig. 1

Prediction-corrected visual predictive check for the final pharmacokinetic model, split by dose group. Upper panels: lines represent the 5th (dashed), 50th (solid), and 95th (dashed) percentiles of the prediction-corrected observed data. The shaded areas indicate the 90% confidence intervals of the 5th, 50th, and 95th percentiles of the simulated data (n = 500 datasets). The black and grey circles correspond to the prediction-corrected observed values and simulated values for observations below the LLOQ, respectively. Lower panels: the solid line represents the fraction of observations below the LLOQ, with the area indicating the 95% prediction interval of the fraction below the LLOQ based on the simulations (n = 500). LLOQ lower limit of quantification, LOQ limit of quantification

Fig. 2

AUC∞ values obtained following simulations with either a fixed-dose (black boxplots) or weight-based (grey boxplots) dosing strategy, based on the pharmacokinetic model in individuals with varying age and body weight (n = 5000 per dosing strategy). Each boxplot represents the median and interquartile range for each weight group. AUC∞ area under the curve from time zero to infinity