Understanding Drug Exposure and Trichuris trichiura Cure Rates: A Pharmacometric Approach for Albendazole-Ivermectin Co-medication in Tanzania and Côte d'Ivoire.

BACKGROUND AND OBJECTIVE: Trichuriasis caused by the human whipworm Trichuris trichiura poses a significant public health concern. Albendazole-ivermectin co-medication is currently the most effective treatment. Studies conducted in Tanzania and Côte d'Ivoire unveiled differences in efficacy for albendazole-ivermectin combination therapy in both countries. A pharmacometrics approach was used to assess co-medication and study population effects on the pharmacokinetics of the two main metabolites of albendazole. An exploratory exposure-efficacy analysis was also carried out to investigate relationships between exposure measures and the egg reduction rate. METHODS: Pharmacokinetic data from studies in Tanzania and Côte d'Ivoire in adolescents (aged 12-19 years) were included in the pharmacometric analysis. Participants received a single dose of either albendazole 400 mg alone or in combination with ivermectin 200 µg/kg. A pharmacometric analysis was performed to investigate the potential effects of the study population and co-administered ivermectin on the apparent clearance of the metabolites of albendazole. Non-linear mixed-effects modeling was conducted with MonolixSuite 2023R1. The pharmacokinetic exposure measures derived from simulations with individual model parameters were used in the exploratory-exposure response analysis. RESULTS: Pharmacokinetic profiles were best described by a two-compartment model for albendazole sulfoxide and a one-compartment model for albendazole sulfone, with a transit compartment and linear elimination. While no co-medication effect was found, apparent clearance of albendazole sulfoxide (albendazole sulfone) in the Tanzanian study population was 75% (46%) higher than that in the Côte d'Ivoire study population. Exposure-efficacy response analyses indicated that peak concentration and the time-above-exposure threshold were associated with the egg reduction rate. CONCLUSIONS: Study population but not co-administered ivermectin showed an effect on apparent clearance of albendazole sulfoxide and albendazole sulfone. Polymorphisms in drug-metabolizing enzymes and host-parasite interaction may explain this result. Difference in drug exposure did not explain the disparate efficacy responses in Tanzania and Côte d'Ivoire. Peak concentration and time-above-threshold were exposure measures associated with the egg reduction rate. Further studies evaluating genetic and resistance patterns in various regions in Africa are warranted.

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.

BACKGROUND: Infection with the soil-transmitted helminth Strongyloides stercoralis affects up to 600 million people globally, most of whom live in rural areas with poor sanitation. If untreated, infection leads to long-lasting morbidity and might even be life-threatening. Moxidectin might be a promising alternative to ivermectin, the only currently recommended single-dose treatment. We aimed to assess whether moxidectin is non-inferior in terms of efficacy and safety compared with ivermectin. METHODS: In this randomised, double-blind, parallel-group, non-inferiority, phase 2b/3 trial in communities in Laos and Cambodia, adults aged 18-65 years were screened for the presence of S stercoralis larvae in their stool via sextuplicate quantitative Baermann assays. Using computer-generated group allocation (block randomisation stratified by infection intensity), parasitologically (two or more positive Baermann assays) and clinically eligible participants were randomly assigned (1:1) to receive single oral doses of either moxidectin (8 mg) and ivermectin-matched placebo, or ivermectin (200 µg/kg bodyweight) and moxidectin-matched placebo. The primary endpoint was cure rate assessed at 14-21 days after treatment, using the available-case population analysed according to intention-to-treat principles. Moxidectin was considered non-inferior to ivermectin if the lower limit of the two-sided 95% CI of the difference was greater than the non-inferiority margin of -10 percentage points. Safety endpoints were assessed before treatment, and at 2-3 h, 24 h, and 14-21 days after treatment. This trial is registered at ClinicalTrials.gov, NCT04056325 and NCT04848688. FINDINGS: Between Dec 6, 2020, and May 21, 2022, 4291 participants were screened, 726 of whom were enrolled and randomly assigned to moxidectin (n=363) or ivermectin (n=363). For the participants with primary outcome data, we observed a cure rate of 93·6% (95% CI 90·5 to 96·0; 324 of 346 participants) in the moxidectin group and 95·7% (93·0 to 97·6; 335 of 350 participants) in the ivermectin group, resulting in a between-group difference of -2·1 percentage points (95% CI -5·5 to 1·3). The most common adverse events were abdominal pain (32 [9%] of 363 with moxidectin vs 34 [9%] of 363 with ivermectin) and headache (25 [7%] vs 30 [8%]), which were predominantly mild and transient. INTERPRETATION: Moxidectin was non-inferior to ivermectin in terms of efficacy in the treatment of strongyloidiasis. Additionally, both drugs had a similar safety profile. The fixed dose and lower cost of moxidectin compared with ivermectin make it a valuable alternative for people with strongyloidiasis. FUNDING: Swiss National Science Foundation.

Efficacy and Safety of Moxidectin-Albendazole and Ivermectin-Albendazole Combination Therapy Compared to Albendazole Monotherapy in Adolescents and Adults Infected with Trichuris trichiura: A Randomized, Controlled Superiority Trial.

BACKGROUND: The currently recommended benzimidazole monotherapy is insufficiently effective to control infection with the soil-transmitted helminth Trichuris trichiura. Ivermectin-albendazole combination has shown promising, but setting-dependent efficacy, with therapeutic underperformance in Côte d'Ivoire. We evaluated whether moxidectin-albendazole could serve as an alternative to albendazole monotherapy in Côte d'Ivoire. METHODS: In this community-based, randomized, placebo-controlled, parallel-group superiority trial, individuals aged 12-60 years were screened for T. trichiura eggs in their stool using quadruplicate Kato-Katz thick smears. Diagnostically and clinically eligible participants were randomly assigned (1:1:1) to receive single oral doses of moxidectin (8 mg) and albendazole (400 mg), ivermectin (200 µg/kg) and albendazole (400 mg), or albendazole (400 mg) and placebo. The primary outcome was proportion cured, ie, cure rate (CR), assessed at 2-3 weeks post-treatment. Safety endpoints were assessed pre-treatment and at 3 and 24 hours post-treatment. RESULTS: For the 210 participants with primary outcome data, we observed CRs of 15.3% in the moxidectin-albendazole arm and 22.5% in the ivermectin-albendazole arm, which did not differ significantly from the CR of 13.4% in the albendazole arm (differences: 1.8%-points [95% confidence interval: -10.1 to 13.6] and 9.1%-points [-3.9 to 21.8], respectively). Most common adverse events were abdominal pain (range across arms: 11.9%-20.9%), headache (4.7%-14.3%), and itching (5.8%-13.1%), which were predominantly mild and transient. CONCLUSIONS: All therapies showed similar low efficacy in treating trichuriasis in Côte d'Ivoire. Alternative treatment options need to be evaluated, and further analyses should be conducted to understand the lack of enhanced activity of the combination therapies in Côte d'Ivoire. CLINICAL TRIALS REGISTRATION: NCT04726969.

Evaluation of code-based algorithms to identify pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension patients in large administrative databases.

Large administrative healthcare (including insurance claims) databases are used for various retrospective real-world evidence studies. However, in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension, identifying patients retrospectively based on administrative codes remains challenging, as it relies on code combinations (algorithms) and the accuracy for patient identification of most of them is unknown. This study aimed to assess the performance of various algorithms in correctly identifying patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension in administrative databases. A systematic literature review was performed to find publications detailing code-based algorithms used to identify pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension patients. PheValuator, a diagnostic predictive modelling tool, was applied to three US claims databases, yielding models that estimated the probability of a patient having the disease. These models were used to evaluate the performance characteristics of selected pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension algorithms. With increasing algorithm complexity, average positive predictive value increased (pulmonary arterial hypertension: 13.4-66.0%; chronic thromboembolic pulmonary hypertension: 10.3-75.1%) and average sensitivity decreased (pulmonary arterial hypertension: 61.5-2.7%; chronic thromboembolic pulmonary hypertension: 20.7-0.2%). Specificities and negative predictive values were high (≥97.5%) for all algorithms. Several of the algorithms performed well overall when considering all of these four performance parameters, and all algorithms performed with similar accuracy across the three claims databases studied, even though most were designed for patient identification in a specific database. Therefore, it is the objective of a study that will determine which algorithm may be most suitable; one- or two-component algorithms are most inclusive and three- or four-component algorithms identify most precise pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension populations, respectively.