Journal article
Population Pharmacokinetic Model of Oxfendazole and Metabolites in Healthy Adults following Single Ascending Doses
Antimicrobial agents and chemotherapy, Vol.65(4), e02129-20
04/01/2021
DOI: 10.1128/AAC.02129-20
PMCID: PMC8097468
PMID: 33526484
Abstract
Oxfendazole is a potent veterinary benzimidazole anthelmintic under transition to humans for the treatment of multiple parasitic infectious diseases. The first-inhuman study evaluating the disposition of oxfendazole and its metabolites in healthy adults following single ascending oral doses from 0.5 to 60 mg/kg of body weight shows that oxfendazole pharmacokinetics is substantially nonlinear, which complicates correlating oxfendazole dose to exposure. To quantitatively capture the relation between oxfendazole dose and exposure, a population pharmacokinetic model for oxfendazole and its metabolites, oxfendazole sulfone and fenbendazole, in humans was developed using a nonlinear mixed-effect modeling approach. Our final model incorporated mechanistic characterization of dose-limited bioavailability as well as different oxfendazole metabolic processes and provided insight into the significance of presystemic metabolism in oxfendazole and metabolite disposition. Oxfendazole clinical pharmacokinetics was best described by a one-compartment model with nonlinear absorption and linear elimination. Oxfendazole apparent clearance and apparent volume of distribution were estimated to be 2.57 liters/h and 352 liters, respectively, at the lowest dose (0.5 mg/kg), indicating that oxfendazole is a low extraction drug with moderate distribution. The disposition of both metabolites was adequately characterized by a one-compartment model with formation rate-limited elimination. Fenbendazole formation from oxfendazole was primarily through systemic metabolism, while both presystemic and systemic metabolism were critical to the formation of oxfendazole sulfone. Our model adequately captured the concentration-time profiles of both oxfendazole and its two metabolites in healthy adults over a wide dose range. The model can be used to predict oxfendazole disposition under new dosing regimens to support dose optimization in humans.
Details
- Title: Subtitle
- Population Pharmacokinetic Model of Oxfendazole and Metabolites in Healthy Adults following Single Ascending Doses
- Creators
- Thanh Bach - University of IowaDaryl J. Murry - University of Nebraska Medical CenterLarissa Stebounova - University of IowaGregory Deye - National Institute of Allergy and Infectious DiseasesPatricia Winokur - Roy J. and Lucille A. Carver College of MedicineGuohua An - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Antimicrobial agents and chemotherapy, Vol.65(4), e02129-20
- Publisher
- Amer Soc Microbiology
- DOI
- 10.1128/AAC.02129-20
- PMID
- 33526484
- PMCID
- PMC8097468
- ISSN
- 0066-4804
- eISSN
- 1098-6596
- Number of pages
- 14
- Grant note
- HHSN272200800008C; HHSN24220130020I / Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, through the Vaccine and Treatment Evaluation Unit 5U54TR001356 / National Center for Advancing Translational Sciences; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS)
- Language
- English
- Date published
- 04/01/2021
- Academic Unit
- Infectious Diseases; Pharmaceutical Sciences and Experimental Therapeutics; Medicine Administration; Holden Comprehensive Cancer Center; Internal Medicine
- Record Identifier
- 9984359768302771
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