Pharmacokinetics, safety, and tolerability of oxfendazole in healthy volunteers: A randomized, placebo-controlled first-inhuman single-dose escalation study
| Autor: | Thomas Conrad, Thanh Bach, Jessie K. Kennedy, Armando E. Gonzalez, Larissa V. Stebounova, Hector H. Garcia, Kiran Gajurel, Daryl J. Murry, Greg Deye, Patricia L. Winokur, Walt Jones, Denice M. Hodgson-Zingman, John R. Horton, Ellen E. Codd, Effie Y.H. Nomicos, Guohua An, Robert H. Gilman, Dilek Ince |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
double blind procedure ultra performance liquid chromatography limit of quantitation Clinical pharmacokinetics diarrhea volume of distribution Pharmacology 0302 clinical medicine Elimination rate constant aspartate aminotransferase Pharmacology (medical) Volume of distribution 0303 health sciences drug dose regimen adult Healthy Volunteers medicine.drug_formulation_ingredient priority journal oxfendazole glucuronide First-in-human study drug exposure Biological Availability bicarbonate urinary excretion Clinical Therapeutics purl.org/pe-repo/ocde/ford#3.03.08 [https] Article 03 medical and health sciences Pharmacokinetics Taenia solium activated partial thromboplastin time Humans neutropenia no-observed-adverse-effect level purl.org/pe-repo/ocde/ford#3.01.05 [https] human normal human arthralgia liquid chromatography-mass spectrometry elimination half-life Dose-Response Relationship Drug 030306 microbiology maximum plasma concentration leukopenia drug bioavailability major clinical study drug metabolism flatulence plasma half life time to maximum plasma concentration randomized controlled trial drug solubility Benzimidazoles drug metabolite drug tolerability drug safety phase 1 clinical trial Administration Oral Anthelmintic agent Area under the curve single drug dose Middle Aged sore throat unclassified drug Infectious Diseases female Tolerability leukocytosis Female eosinophilia medicine.drug Half-Life bicarbonate blood level Adult oxfendazole Oxfendazole pharmacokinetic parameters Adolescent side effect area under the curve 030231 tropical medicine oxfendazole sulfate Young Adult Double-Blind Method male first in human study medicine controlled study fenbendazole viral gastroenteritis business.industry Cysticercosis oxfendazole sulfone renal clearance intestine absorption elimination rate constant Fenbendazole PR interval business drug dose escalation plasma concentration-time curve |
| Popis: | 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.). |
| Databáze: | OpenAIRE |
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