Pharmacokinetics, Safety, and Tolerability of Oxfendazole in Healthy Adults in an Open-Label Phase 1 Multiple Ascending Dose and Food Effect Study

Abstract

Neurocysticercosis and trichuriasis are difficult-to-treat parasitic infections that affect more than 1.5 billion people worldwide. Oxfendazole, a potent broad-spectrum benzimidazole anthelmintic approved for use in veterinary medicine, has shown substantial antiparasitic activity against neurocysticercosis and intestinal helminths in preclinical studies. As part of a program to transition oxfendazole from veterinary medicine to human use, phase I multiple ascending dose and food effect studies were conducted. Thirty-six healthy adults were enrolled in an open-label study which evaluated (i) the pharmacokinetics and safety of oxfendazole following multiple ascending doses of oxfendazole oral suspension at 3, 7.5, and 15 mg/kg once daily for 5 days and (ii) the effect of food on oxfendazole pharmacokinetics and safety after a single 3-mg/kg dose administered following an overnight fast or the consumption of a fatty breakfast. Following multiple oral dose administration, the intestinal absorption of oxfendazole was rapid, with the time to maximum concentration of drug in serum (Tmax) ranging from 1.92 to 2.56 h. A similar half-life of oxfendazole (9.21 to 11.8 h) was observed across all dose groups evaluated, and oxfendazole exhibited significantly less than a dose-proportional increase in exposure. Oxfendazole plasma exposures were higher in female subjects than in male subjects. Following daily administration, oxfendazole reached a steady state in plasma on study day 3, with minimal accumulation. Food delayed the oxfendazole Tmax by a median of 6.88 h and resulted in a 49.2% increase in the maximum observed drug concentration in plasma (Cmax) and an 86.4% increase in the area under the concentration-time curve (AUC). Oxfendazole was well tolerated in all study groups, and there were no major safety signals identified in this study. (This study has been registered at ClinicalTrials.gov under identifier NCT03035760.).

Keywords: clinical pharmacokinetics; food effect; oxfendazole; soil-transmitted helminthiasis.

Copyright © 2020 American Society for Microbiology.

Figures

FIG 1

Concentration-time profiles of oxfendazole in healthy adults following multiple ascending doses at 3, 7.5, and 15 mg/kg once daily for 5 days. Each dose group consisted of 8 subjects. Data are presented as means ± SD.

FIG 2

Effect of sex on oxfendazole exposure (AUCτ), peak concentration (Cmax), and trough concentration (Ctrough) following the first and fifth doses in 7.5-mg/kg and 15-mg/kg dose groups. The dots represent individual observed data. The middle lines represent the medians. The lower and upper hinges correspond to 25th and 75th percentiles. The upper and lower notches extend to the largest and smallest values, respectively, that are no more than 1.58 times the interquartile range (i.e., the distance between 25th and 75th percentiles).

FIG 3

Concentration-time profiles of a single dose of oxfendazole at 3 mg/kg under the fasted state and the fed state. Food effect on the pharmacokinetics of oxfendazole was evaluated using a randomized two-period crossover study design with 12 subjects in which each subject received a single dose of oxfendazole under the fasted state and fed state, but with different sequences. Data are presented as means ± SD.

FIG 4

Time courses of hemoglobin concentrations in male subjects (top panels) and female subjects (bottom panels) in the multiple ascending dose study (group 1, 7 males/1 female; group 2, 5 males/3 females; group 3, 4 males/4 females) and the food effect study (group 4, 9 males/3 females). The green rectangles represent the normal range of hemoglobin concentrations for each gender. The yellow, orange, and red rectangles represent grade 1 (mild), grade 2 (moderate), and grade 3 (severe) toxicity levels, respectively.

FIG 5

(A) Schematic diagram of the multiple ascending dose study and the food effect study. (B and C) Schedules of blood sample collection for pharmacokinetics assessment and adverse event assessment for subjects participating in the multiple ascending dose evaluation (B) and the food effect evaluation (C).