Repurposing Oxfendazole for Onchocerciasis: Population Pharmacokinetics of a Tablet Formulation in Healthy African Adults

TL;DR

This study examines how a new tablet form of oxfendazole behaves in the body of healthy African adults, aiming to find the best dose for treating onchocerciasis.

Contribution

The first population pharmacokinetic analysis of oxfendazole tablet in African adults, supporting dosing for future trials.

Findings

Oxfendazole absorption follows first-order kinetics with first-pass metabolism.

A 400 mg once-daily or 50 mg twice-daily dose for 5 days achieves target exposure with low safety risk.

Population pharmacokinetic model supports future clinical trial dose selection.

Abstract

Global efforts to eliminate onchocerciasis are hampered by the lack of a macrofilaricidal drug capable of killing adult parasites. Oxfendazole, a veterinary anthelminthic, exhibits macrofilaricidal activity and holds promise to shorten treatment durations. Phase 1 studies in healthy Caucasian adults demonstrated favorable pharmacokinetics and safety using a veterinary oral liquid formulation. More recently, a Phase 1 bioavailability trial (NCT04920292) evaluated a field‐applicable tablet formulation in healthy African adults. This study presents a secondary analysis to (i) characterize the population pharmacokinetics of oxfendazole and its major metabolites in healthy African adults receiving the tablet formulation and (ii) propose a dosing regimen for Phase 2 evaluation in patients with onchocerciasis. Thirty healthy African adults were enrolled, and plasma concentration–time profiles of oxfendazole, fenbendazole, and oxfendazole sulfone were obtained from 24 participants who received oxfendazole (8 per dose group: 100 mg single dose, 400 mg single dose, 400 mg once daily for 5 days). All cohorts were pooled and analyzed using nonlinear mixed effects modeling. Oxfendazole absorption was best described by first‐order kinetics with first‐pass metabolism. Dose‐limited bioavailability was evident. Disposition was best described by one‐compartment models with linear elimination. Simulations suggested that 400 mg once daily (or 50 mg twice daily) for 5 days is required to achieve putative exposure targets (> 200 ng/mL for 5 days), with low risk of safety concerns. The population pharmacokinetic model adequately described oxfendazole pharmacokinetics in healthy African adults and supports dosing selection for future clinical trials.

Trial Registration:
ClinicalTrials.gov Identifier: NCT04920292

What is the current knowledge on the topic?
○Oxfendazole is a veterinary anthelminthic with macrofilaricidal activity against a broad range of parasitic worms. Following a repurposing strategy, it is currently under clinical development for the treatment of human helminth infections, including onchocerciasis. Earlier Phase 1 studies in healthy Caucasian volunteers receiving a liquid formulation showed favorable pharmacokinetics and safety. To support broader use in endemic settings, a field‐adapted tablet formulation was developed.
What question did this study address?
○This study characterized the population pharmacokinetic properties of the oxfendazole tablet in healthy African adults and identified suitable dosing regimens for Phase 2 trials in onchocerciasis patients.
What does this study add to our knowledge?
○This is the first population pharmacokinetic analysis of oxfendazole in African adults using the tablet formulation. The model incorporated first‐pass metabolism and dose‐limited bioavailability and revealed substantial variability in drug exposure. Simulations suggested that a 400 mg once‐daily or 50 mg twice daily dose of oxfendazole over 5 days is likely to achieve proposed target exposures, with low risk of safety concerns.
How might this change drug discovery, development, and/or therapeutics?
○The developed model provides a quantitative basis to guide dose selection of oxfendazole in future clinical trials. Despite variability in exposure and the need for formulation optimization, the findings support continued development of oxfendazole as a macrofilaricidal drug for onchocerciasis.

What is the current knowledge on the topic?
○Oxfendazole is a veterinary anthelminthic with macrofilaricidal activity against a broad range of parasitic worms. Following a repurposing strategy, it is currently under clinical development for the treatment of human helminth infections, including onchocerciasis. Earlier Phase 1 studies in healthy Caucasian volunteers receiving a liquid formulation showed favorable pharmacokinetics and safety. To support broader use in endemic settings, a field‐adapted tablet formulation was developed.

Oxfendazole is a veterinary anthelminthic with macrofilaricidal activity against a broad range of parasitic worms. Following a repurposing strategy, it is currently under clinical development for the treatment of human helminth infections, including onchocerciasis. Earlier Phase 1 studies in healthy Caucasian volunteers receiving a liquid formulation showed favorable pharmacokinetics and safety. To support broader use in endemic settings, a field‐adapted tablet formulation was developed.

What question did this study address?
○This study characterized the population pharmacokinetic properties of the oxfendazole tablet in healthy African adults and identified suitable dosing regimens for Phase 2 trials in onchocerciasis patients.

This study characterized the population pharmacokinetic properties of the oxfendazole tablet in healthy African adults and identified suitable dosing regimens for Phase 2 trials in onchocerciasis patients.

What does this study add to our knowledge?
○This is the first population pharmacokinetic analysis of oxfendazole in African adults using the tablet formulation. The model incorporated first‐pass metabolism and dose‐limited bioavailability and revealed substantial variability in drug exposure. Simulations suggested that a 400 mg once‐daily or 50 mg twice daily dose of oxfendazole over 5 days is likely to achieve proposed target exposures, with low risk of safety concerns.

This is the first population pharmacokinetic analysis of oxfendazole in African adults using the tablet formulation. The model incorporated first‐pass metabolism and dose‐limited bioavailability and revealed substantial variability in drug exposure. Simulations suggested that a 400 mg once‐daily or 50 mg twice daily dose of oxfendazole over 5 days is likely to achieve proposed target exposures, with low risk of safety concerns.

How might this change drug discovery, development, and/or therapeutics?
○The developed model provides a quantitative basis to guide dose selection of oxfendazole in future clinical trials. Despite variability in exposure and the need for formulation optimization, the findings support continued development of oxfendazole as a macrofilaricidal drug for onchocerciasis.

The developed model provides a quantitative basis to guide dose selection of oxfendazole in future clinical trials. Despite variability in exposure and the need for formulation optimization, the findings support continued development of oxfendazole as a macrofilaricidal drug for onchocerciasis.

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