Pharmacokinetics, safety, and tolerability of oxfendazole in healthy volunteers: A randomized, placebo-controlled first-inhuman single-dose escalation study

Guohua An, Daryl J. Murry, Kiran Gajurel, Thanh Bach, Greg Deye, Larissa V. Stebounova, Ellen E. Codd, John Horton, Armando E. Gonzalez, Hector H. Garcia, Dilek Ince, Denice Hodgson-Zingman, Effie Y.H. Nomicos, Thomas Conrad, Jessie Kennedy, Walt Jones, Robert H. Gilman, Patricia Winokur

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere02255-18
JournalAntimicrobial Agents and Chemotherapy
Volume63
Issue number4
DOIs
StatePublished - Apr 2019

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Healthy Volunteers
Pharmacokinetics
Placebos
Safety
oxfendazole
Urine
Taenia solium
Neurocysticercosis
Cysticercosis
Parasitic Diseases
Anthelmintics
Veterinary Medicine
Hematology
Liquid Chromatography
Biochemistry
Solubility
Biological Availability
Half-Life
Mass Spectrometry
Central Nervous System

Keywords

  • Anthelmintic agent
  • Clinical pharmacokinetics
  • Cysticercosis
  • First-in-human study
  • Oxfendazole

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Pharmacokinetics, safety, and tolerability of oxfendazole in healthy volunteers : A randomized, placebo-controlled first-inhuman single-dose escalation study. / An, Guohua; Murry, Daryl J.; Gajurel, Kiran; Bach, Thanh; Deye, Greg; Stebounova, Larissa V.; Codd, Ellen E.; Horton, John; Gonzalez, Armando E.; Garcia, Hector H.; Ince, Dilek; Hodgson-Zingman, Denice; Nomicos, Effie Y.H.; Conrad, Thomas; Kennedy, Jessie; Jones, Walt; Gilman, Robert H.; Winokur, Patricia.

In: Antimicrobial Agents and Chemotherapy, Vol. 63, No. 4, e02255-18, 04.2019.

Research output: Contribution to journalArticle

An, G, Murry, DJ, Gajurel, K, Bach, T, Deye, G, Stebounova, LV, Codd, EE, Horton, J, Gonzalez, AE, Garcia, HH, Ince, D, Hodgson-Zingman, D, Nomicos, EYH, Conrad, T, Kennedy, J, Jones, W, Gilman, RH & Winokur, P 2019, 'Pharmacokinetics, safety, and tolerability of oxfendazole in healthy volunteers: A randomized, placebo-controlled first-inhuman single-dose escalation study', Antimicrobial Agents and Chemotherapy, vol. 63, no. 4, e02255-18. https://doi.org/10.1128/AAC.02255-18
An, Guohua ; Murry, Daryl J. ; Gajurel, Kiran ; Bach, Thanh ; Deye, Greg ; Stebounova, Larissa V. ; Codd, Ellen E. ; Horton, John ; Gonzalez, Armando E. ; Garcia, Hector H. ; Ince, Dilek ; Hodgson-Zingman, Denice ; Nomicos, Effie Y.H. ; Conrad, Thomas ; Kennedy, Jessie ; Jones, Walt ; Gilman, Robert H. ; Winokur, Patricia. / Pharmacokinetics, safety, and tolerability of oxfendazole in healthy volunteers : A randomized, placebo-controlled first-inhuman single-dose escalation study. In: Antimicrobial Agents and Chemotherapy. 2019 ; Vol. 63, No. 4.
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