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Antimicrob Agents Chemother. 2019 Mar 27;63(4). pii: e02255-18. doi: 10.1128/AAC.02255-18. Print 2019 Apr.

Pharmacokinetics, Safety, and Tolerability of Oxfendazole in Healthy Volunteers: a Randomized, Placebo-Controlled First-in-Human Single-Dose Escalation Study.

Author information

1
Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa, USA guohua-an@uiowa.edu patricia-winokur@uiowa.edu.
2
Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa, USA.
3
Division of Infectious Diseases, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
4
Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
5
Codd Consulting, LLC, Blue Bell, Pennsylvania, USA.
6
Oxfendazole Development Group, Blue Bell, Pennsylvania, USA.
7
Tropical Projects, Hitchin, United Kingdom.
8
School of Veterinary Medicine, Universidual Nacional Mayor de San Marcos, Lima, Peru.
9
Center for Global Health, Universidad Peruana Cayetano Heredia, Lima, Peru.
10
Division of Cardiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
11
The Emmes Corporation, Rockville, Maryland, USA.
12
Johns Hopkins School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
13
Division of Infectious Diseases, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA guohua-an@uiowa.edu patricia-winokur@uiowa.edu.
#
Contributed equally

Abstract

Cysticercosis is a parasitic disease that frequently involves the human central nervous system (CNS), and current treatment options are limited. Oxfendazole, a veterinary medicine belonging to the benzimidazole family of anthelmintic drugs, has demonstrated substantial activity against the tissue stages of Taenia solium and has potential to be developed as an effective therapy for neurocysticercosis. To accelerate the transition of oxfendazole from veterinary to human use, the pharmacokinetics, safety, and tolerability of oxfendazole were evaluated in healthy volunteers in this phase 1 first-in-human (FIH) study. Seventy subjects were randomly assigned to receive a single oral dose of oxfendazole (0.5, 1, 3, 7.5, 15, 30, or 60 mg oxfendazole/kg body weight) or placebo and were followed for 14 days. Blood and urine samples were collected, and the concentrations of oxfendazole were measured using a validated ultraperformance liquid chromatography mass spectrometry method. The pharmacokinetic parameters of oxfendazole were estimated using noncompartmental analysis. Oxfendazole was rapidly absorbed with a mean plasma half-life ranging from 8.5 to 11 h. The renal excretion of oxfendazole was minimal. Oxfendazole exhibited significant nonlinear pharmacokinetics with less than dose-proportional increases in exposure after single oral doses of 0.5 mg/kg to 60 mg/kg. This nonlinearity of oxfendazole is likely due to the dose-dependent decrease in bioavailability that is caused by its low solubility. Oxfendazole was found to be well tolerated in this study at different escalating doses without any serious adverse events (AEs) or deaths. There were no significant differences in the distributions of hematology, biochemistry, or urine parameters between oxfendazole and placebo recipients. (This study has been registered at ClinicalTrials.gov under identifier NCT02234570.).

KEYWORDS:

anthelmintic agent; clinical pharmacokinetics; cysticercosis; first-in-human study; oxfendazole

PMID:
30745383
PMCID:
PMC6437481
[Available on 2019-09-27]
DOI:
10.1128/AAC.02255-18

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