Britta Steffens (1), Dominic Bräm (1), Daniela Hofmann (2), Jennifer Keiser (2,3), Marc Pfister (1,3)
(1) Pediatric Pharmacology and Pharmacometrics, University of Basel Children‘s Hospital UKBB, Basel, Switzerland, (2) Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland, (3) Department of Clinical Research, University of Basel and University Hospital Basel, Basel, Switzerland
Introduction: Moxidectin is a promising drug candidate that has the potential to complement the depleted drug arsenal against infections with soil-transmitted helminths (STH), including Strongyloides stercoralis and Trichuris trichiura. Several studies reported moxidectin to be a safe and efficacious alternative to ivermectin both against S. stercoralis and in combination with albendazole against T. trichiura ([1], [2]), Recent works characterize population pharmacokinetics (PK) of moxidectin in S. stercoralis-infected adults. The overall aim in this study was to extend recently developed pharmacometric (PMX) model [3] to adolescents to investigate moxidectin PK with and without albendazole and, based on this, to perform exploratory efficacy analyses.
Methods: PK Samples of 25 T. trichiura-infected adolescents (median age 16 years, median weight 46.6 kg) from Tanzania, Pemba Island, were collected at four time points: 6h, 21h, 27h and 48h post treatment. 10 Adolescents were treated with a single 8 mg moxidectin dose, and 15 adolescents were treated with a combination of 8 mg moxidectin and 400 mg albendazole. In addition, PK samples of 96 S. stercoralis-infected adults (median age 46 years, median weight 56.2 kg) from Laos, 6 sample time points (2, 4, 6, 7, 24, 80 h) post treatment, treated with single moxidectin dose were included. PK model of moxidectin on samples of both, adolescents and adults, was developed in the the non-linear mixed effects framework and compared to already existing PK model [3]. Drug-drug interaction (DDI) effect was tested on adolescent data only. For exposure-response analyses, PK exposure measures such as Cmax and AUC of both, moxidectin and the active metabolite of albendazole, albendazole sulfoxide (based on results from [4]), were explored to explain differences in egg reduction.
Results: A two-compartment model, first-order absorption, no delay in absorption, with a proportional residual error and allometric scaling on volume and clearance parameters best described adolescent PK data. Age and sex on volume parameters were further statistically significant covariates. However, as they did not significantly improve model fit and BIC, they were not included in final model. When testing final model on adolescent data only, population parameters were similar to those from developed PK model [3] except for the transit compartment. Excluding sampling points beyond 50 h, these differences were reduced. For adolescent data, no albendazole DDI effect on moxidectin PK was found. As already claimed in recent studies for T. trichuria [1] and S. stercoralis [2], adolescents with combination therapy showed high relative egg reduction (EPG) with median EPG 97% vs. 85% for monotherapy. However, only 10% adolescent with moxidectin monotherapy and 33% with combination therapy were completely cured. This higher efficacy could not be explained by differences in covariates and no significant relationship between EPG and tested PK exposure measures could be identified.
Conclusions: A recently developed PMX model for S. stercoralis-infected adults without delayed absorption well fitted T. trichiura-infected adolescents. Similar effects of weight, sex, and age were found. Co-administered albendazole increased efficacy without influencing PK of moxidectin.
References:
[1] Welsche et al. (2022), Efficacy and safety of moxidectin and albendazole compared with ivermectin and albendazole coadministration in adolescents infected with Trichuris trichiura in Tanzania: an open-label, non-inferiority, randomised, controlled, phase 2b/3 trial
[2] Sprecher et al. (2023), Efficacy and safety of moxidectin compared with ivermectin against Strongyloides stercoralis infection in adults in Laos and Cambodia: a randomised, double-blind, non-inferiority, phase 2b/3 trial
[3] Smit et al. (2022), Characterization of the Population Pharmacokinetics of Moxidectin in Adults Infected with Strongyloides Stercoralis: Support for a Fixed‑Dose Treatment Regimen
[4] Nwogu-Attah et al. (2024), Understanding drug exposure and Trichuris trichiura cure rates: a pharmacometric approach for albendazole-ivermectin co-medication in Tanzania and Côte d’Ivoire (in submission)
Reference: PAGE 32 (2024) Abstr 11231 [www.page-meeting.org/?abstract=11231]
Poster: Drug/Disease Modelling - Infection