The Experts below are selected from a list of 249 Experts worldwide ranked by ideXlab platform
Armando E. Gonzalez - One of the best experts on this subject based on the ideXlab platform.
-
Pharmacokinetics, Safety, and Tolerability of Oxfendazole in Healthy Adults in an Open-Label Phase 1 Multiple Ascending Dose and Food Effect Study.
Antimicrobial agents and chemotherapy, 2020Co-Authors: Thanh Bach, Gregory A. Deye, Ellen E. Codd, John R. Horton, Hector H. Garcia, Shirley Galbiati, Jessie K Kennedy, Effie Nomicos, Robert H. Gilman, Armando E. GonzalezAbstract: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.).
-
Pharmacokinetics, Safety, and Tolerability of Oxfendazole in Healthy Volunteers: a Randomized, Placebo-Controlled First-in-Human Single-Dose Escalation Study.
Antimicrobial agents and chemotherapy, 2019Co-Authors: Daryl J. Murry, Thanh Bach, Larissa V. Stebounova, Kiran Gajurel, Greg Deye, Ellen E. Codd, John R. Horton, Armando E. Gonzalez, Hector H. GarciaAbstract: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.).
-
Oxfendazole: a promising agent for the treatment and control of helminth infections in humans
Expert review of anti-infective therapy, 2018Co-Authors: Armando E. Gonzalez, Ellen E. Codd, John R. Horton, Hector H. Garcia, Robert H. GilmanAbstract:Introduction: Oxfendazole (methyl [5-(phenylsulphinyl)-1H benzimidazole-2-yl] carbamate) has a particularly long metabolic half-life in ruminants, and its metabolite fenbendazole also has anthelmin...
-
preclinical studies on the pharmacokinetics safety and toxicology of Oxfendazole toward first in human studies
International Journal of Toxicology, 2015Co-Authors: Ellen E. Codd, John R. Horton, Armando E. Gonzalez, Hector H. Garcia, Claire Mcfarlane, Edward S Riccio, Rupa S Doppalapudi, Jon C Mirsalis, Robert H. GilmanAbstract:A 2-week study in rats identified target organs of Oxfendazole toxicity to be bone marrow, epididymis, liver, spleen, testis, and thymus. Female rats had greater Oxfendazole exposure and exhibited toxicities at lower doses than did males. Decreased white blood cell levels, a class effect of benzimidazole anthelmintics, returned to normal during the recovery period. The no observed adverse effect level was determined to be >5 but <25 mg/kg/d and the maximum tolerated dose 100 mg/kg/d. The highest dose, 200 mg/kg/d, resulted in significant toxicity and mortality, leading to euthanization of the main study animals in this group after 7 days. Oxfendazole did not exhibit genetic toxicology signals in standard Ames bacterial, mouse lymphoma, or rat micronucleus assays nor did it provoke safety concerns when evaluated for behavioral effects in rats or cardiovascular safety effects in dogs. These results support the transition of Oxfendazole to First in Human safety studies preliminary to its evaluation in human helminth diseases.
-
Preclinical studies on the pharmacokinetics, safety, and toxicology of Oxfendazole: Toward first in human studies
International journal of toxicology, 2015Co-Authors: Ellen E. Codd, Armando E. Gonzalez, Hector H. Garcia, Claire Mcfarlane, Edward S Riccio, Rupa S Doppalapudi, Jon C Mirsalis, R. John Horton, Robert H. GilmanAbstract:A 2-week study in rats identified target organs of Oxfendazole toxicity to be bone marrow, epididymis, liver, spleen, testis, and thymus. Female rats had greater Oxfendazole exposure and exhibited toxicities at lower doses than did males. Decreased white blood cell levels, a class effect of benzimidazole anthelmintics, returned to normal during the recovery period. The no observed adverse effect level was determined to be >5 but
Hector H. Garcia - One of the best experts on this subject based on the ideXlab platform.
-
Pharmacokinetics, Safety, and Tolerability of Oxfendazole in Healthy Adults in an Open-Label Phase 1 Multiple Ascending Dose and Food Effect Study.
Antimicrobial agents and chemotherapy, 2020Co-Authors: Thanh Bach, Gregory A. Deye, Ellen E. Codd, John R. Horton, Hector H. Garcia, Shirley Galbiati, Jessie K Kennedy, Effie Nomicos, Robert H. Gilman, Armando E. GonzalezAbstract: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.).
-
Pharmacokinetics, Safety, and Tolerability of Oxfendazole in Healthy Volunteers: a Randomized, Placebo-Controlled First-in-Human Single-Dose Escalation Study.
Antimicrobial agents and chemotherapy, 2019Co-Authors: Daryl J. Murry, Thanh Bach, Larissa V. Stebounova, Kiran Gajurel, Greg Deye, Ellen E. Codd, John R. Horton, Armando E. Gonzalez, Hector H. GarciaAbstract: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.).
-
Oxfendazole: a promising agent for the treatment and control of helminth infections in humans
Expert review of anti-infective therapy, 2018Co-Authors: Armando E. Gonzalez, Ellen E. Codd, John R. Horton, Hector H. Garcia, Robert H. GilmanAbstract:Introduction: Oxfendazole (methyl [5-(phenylsulphinyl)-1H benzimidazole-2-yl] carbamate) has a particularly long metabolic half-life in ruminants, and its metabolite fenbendazole also has anthelmin...
-
preclinical studies on the pharmacokinetics safety and toxicology of Oxfendazole toward first in human studies
International Journal of Toxicology, 2015Co-Authors: Ellen E. Codd, John R. Horton, Armando E. Gonzalez, Hector H. Garcia, Claire Mcfarlane, Edward S Riccio, Rupa S Doppalapudi, Jon C Mirsalis, Robert H. GilmanAbstract:A 2-week study in rats identified target organs of Oxfendazole toxicity to be bone marrow, epididymis, liver, spleen, testis, and thymus. Female rats had greater Oxfendazole exposure and exhibited toxicities at lower doses than did males. Decreased white blood cell levels, a class effect of benzimidazole anthelmintics, returned to normal during the recovery period. The no observed adverse effect level was determined to be >5 but <25 mg/kg/d and the maximum tolerated dose 100 mg/kg/d. The highest dose, 200 mg/kg/d, resulted in significant toxicity and mortality, leading to euthanization of the main study animals in this group after 7 days. Oxfendazole did not exhibit genetic toxicology signals in standard Ames bacterial, mouse lymphoma, or rat micronucleus assays nor did it provoke safety concerns when evaluated for behavioral effects in rats or cardiovascular safety effects in dogs. These results support the transition of Oxfendazole to First in Human safety studies preliminary to its evaluation in human helminth diseases.
-
Preclinical studies on the pharmacokinetics, safety, and toxicology of Oxfendazole: Toward first in human studies
International journal of toxicology, 2015Co-Authors: Ellen E. Codd, Armando E. Gonzalez, Hector H. Garcia, Claire Mcfarlane, Edward S Riccio, Rupa S Doppalapudi, Jon C Mirsalis, R. John Horton, Robert H. GilmanAbstract:A 2-week study in rats identified target organs of Oxfendazole toxicity to be bone marrow, epididymis, liver, spleen, testis, and thymus. Female rats had greater Oxfendazole exposure and exhibited toxicities at lower doses than did males. Decreased white blood cell levels, a class effect of benzimidazole anthelmintics, returned to normal during the recovery period. The no observed adverse effect level was determined to be >5 but
Robert H. Gilman - One of the best experts on this subject based on the ideXlab platform.
-
Pharmacokinetics, Safety, and Tolerability of Oxfendazole in Healthy Adults in an Open-Label Phase 1 Multiple Ascending Dose and Food Effect Study.
Antimicrobial agents and chemotherapy, 2020Co-Authors: Thanh Bach, Gregory A. Deye, Ellen E. Codd, John R. Horton, Hector H. Garcia, Shirley Galbiati, Jessie K Kennedy, Effie Nomicos, Robert H. Gilman, Armando E. GonzalezAbstract: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.).
-
Oxfendazole: a promising agent for the treatment and control of helminth infections in humans
Expert review of anti-infective therapy, 2018Co-Authors: Armando E. Gonzalez, Ellen E. Codd, John R. Horton, Hector H. Garcia, Robert H. GilmanAbstract:Introduction: Oxfendazole (methyl [5-(phenylsulphinyl)-1H benzimidazole-2-yl] carbamate) has a particularly long metabolic half-life in ruminants, and its metabolite fenbendazole also has anthelmin...
-
Original Article Preclinical Studies on the Pharmacokinetics, Safety, and Toxicology of Oxfendazole: Toward First in Human Studies
2016Co-Authors: Ellen E. Codd, John R. Horton, Robert H. Gilman, Claire Mcfarlane, Edward S Riccio, Jon C Mirsalis, O E. Gonzalez, Hugo H. Garcia, For CysticercosisAbstract:A 2-week study in rats identified target organs of Oxfendazole toxicity to be bone marrow, epididymis, liver, spleen, testis, and thymus. Female rats had greater Oxfendazole exposure and exhibited toxicities at lower doses than did males. Decreased white blood cell levels, a class effect of benzimidazole anthelmintics, returned to normal during the recovery period. The no observed adverse effect level was determined to be>5 but <25 mg/kg/d and the maximum tolerated dose 100 mg/kg/d. The highest dose, 200 mg/kg/d, resulted in significant toxicity and mortality, leading to euthanization of the main study animals in this group after 7 days. Oxfendazole did not exhibit genetic toxicology signals in standard Ames bacterial, mouse lymphoma, or rat micro-nucleus assays nor did it provoke safety concerns when evaluated for behavioral effects in rats or cardiovascular safety effects in dogs. These results support the transition of Oxfendazole to First in Human safety studies preliminary to its evaluation in human helminth diseases
-
Regular Article Preclinical Studies on the Pharmacokinetics, Safety, and Toxicology of Oxfendazole: Toward First in Human Studies
2016Co-Authors: Ellen E. Codd, John R. Horton, Robert H. Gilman, Claire Mcfarlane, Edward S Riccio, Jon C Mirsalis, O E. Gonzalez, Hugo H. Garcia, For CysticercosisAbstract:A 2-week study in rats identified target organs of Oxfendazole toxicity to be bone marrow, epididymis, liver, spleen, testis, and thymus. Female rats had greater Oxfendazole exposure and exhibited toxicities at lower doses than did males. Decreased white blood cell levels, a class effect of benzimidazole anthelmintics, returned to normal during the recovery period. The no observed adverse effect level was determined to be>5 but <25 mg/kg/d and the maximum tolerated dose 100 mg/kg/d. The highest dose, 200 mg/kg/d, resulted in significant toxicity and mortality, leading to euthanization of the main study animals in this group after 7 days. Oxfendazole did not exhibit genetic toxicology signals in standard Ames bacterial, mouse lymphoma, or rat micro-nucleus assays nor did it provoke safety concerns when evaluated for behavioral effects in rats or cardiovascular safety effects in dogs. These results support the transition of Oxfendazole to First in Human safety studies preliminary to its evaluation in human helminth diseases
-
preclinical studies on the pharmacokinetics safety and toxicology of Oxfendazole toward first in human studies
International Journal of Toxicology, 2015Co-Authors: Ellen E. Codd, John R. Horton, Armando E. Gonzalez, Hector H. Garcia, Claire Mcfarlane, Edward S Riccio, Rupa S Doppalapudi, Jon C Mirsalis, Robert H. GilmanAbstract:A 2-week study in rats identified target organs of Oxfendazole toxicity to be bone marrow, epididymis, liver, spleen, testis, and thymus. Female rats had greater Oxfendazole exposure and exhibited toxicities at lower doses than did males. Decreased white blood cell levels, a class effect of benzimidazole anthelmintics, returned to normal during the recovery period. The no observed adverse effect level was determined to be >5 but <25 mg/kg/d and the maximum tolerated dose 100 mg/kg/d. The highest dose, 200 mg/kg/d, resulted in significant toxicity and mortality, leading to euthanization of the main study animals in this group after 7 days. Oxfendazole did not exhibit genetic toxicology signals in standard Ames bacterial, mouse lymphoma, or rat micronucleus assays nor did it provoke safety concerns when evaluated for behavioral effects in rats or cardiovascular safety effects in dogs. These results support the transition of Oxfendazole to First in Human safety studies preliminary to its evaluation in human helminth diseases.
Thanh Bach - One of the best experts on this subject based on the ideXlab platform.
-
Population Pharmacokinetic Model of Oxfendazole and Metabolites in Healthy Adults following Single Ascending Doses.
Antimicrobial agents and chemotherapy, 2021Co-Authors: Thanh Bach, Daryl J. Murry, Larissa V. Stebounova, Gregory A. Deye, Patricia L. WinokurAbstract:Oxfendazole is a potent veterinary benzimidazole anthelmintic under transition to human for the treatment of multiple parasitic infectious diseases. The first-in-human study evaluating the disposition of Oxfendazole and its metabolites in healthy adults following single ascending oral doses from 0.5 to 60 mg/kg 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 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 to the significance of pre-systemic metabolism in Oxfendazole and metabolites 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 L/h and 35.2 L, 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 one-compartment model with formation-rate limited elimination. Fenbendazole formation from Oxfendazole was primarily through systemic metabolism while both pre-systemic 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.
-
population pharmacokinetic model of Oxfendazole and metabolites in healthy adults following single ascending doses
Antimicrobial Agents and Chemotherapy, 2021Co-Authors: Thanh Bach, Daryl J. Murry, Larissa V. Stebounova, Gregory A. Deye, Patricia L. WinokurAbstract:Oxfendazole is a potent veterinary benzimidazole anthelmintic under transition to humans for the treatment of multiple parasitic infectious diseases. The first-in-human 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 35.2 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.
-
Pharmacokinetics, Safety, and Tolerability of Oxfendazole in Healthy Adults in an Open-Label Phase 1 Multiple Ascending Dose and Food Effect Study.
Antimicrobial agents and chemotherapy, 2020Co-Authors: Thanh Bach, Gregory A. Deye, Ellen E. Codd, John R. Horton, Hector H. Garcia, Shirley Galbiati, Jessie K Kennedy, Effie Nomicos, Robert H. Gilman, Armando E. GonzalezAbstract: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.).
-
Development and validation of a simple, fast, and sensitive LC/MS/MS method for the quantification of Oxfendazole in human plasma and its application to clinical pharmacokinetic study.
Journal of pharmaceutical and biomedical analysis, 2019Co-Authors: Thanh Bach, Sohyun Bae, Ronilda D'cunha, Patricia L. WinokurAbstract:Abstract The most popular standard treatments for soil transmitted helminths in humans including mebendazole, albendazole, levamisole, and pyrantel pamoate, show greatly variable efficacy against different species of parasites and have unfavorable pharmacokinetic characteristics, such as short half-life. The transition of Oxfendazole, a potent broad-spectrum anthelmintic with long half-life, from veterinary medicine to human use has been considered as a promising approach. However, analytical methods for the quantitative detection of Oxfendazole in human matrix are very limited and lack sensitivity. In this study, we have developed a high-performance liquid chromatography-tandem mass spectrometry (LC/MS/MS) method for the quantification of Oxfendazole in human plasma using albendazole as an internal standard. The established method was fully validated with lower limit of quantitation (LLOQ) of 0.5 ng/mL and linearity in the range of 0.5–1000 ng/mL; intra-day and inter-day accuracies ranged from 2.6 to 9.5% for 3 quality control levels (1.5 ng/mL, 75 ng/mL, and 750 ng/mL) and LLOQ; intra-day and inter-day precision was ≤13.6% for quality controls and ≤15.1% for LLOQ; matrix factor and extraction recovery were consistent with coefficient of variation of less than 15.0%. Other parameters including matrix selectivity, injection carryover, reinjection reproducibility, hemolysis effect, interference of analyte with internal standard, dilution integrity, freeze/thaw stability, whole blood stability, and stock solution stability were also validated and met the acceptance criteria. The assay was successfully applied to quantify Oxfendazole plasma concentration in healthy adult volunteers after the administration of multiple oral doses of Oxfendazole.
-
Pharmacokinetics, Safety, and Tolerability of Oxfendazole in Healthy Volunteers: a Randomized, Placebo-Controlled First-in-Human Single-Dose Escalation Study.
Antimicrobial agents and chemotherapy, 2019Co-Authors: Daryl J. Murry, Thanh Bach, Larissa V. Stebounova, Kiran Gajurel, Greg Deye, Ellen E. Codd, John R. Horton, Armando E. Gonzalez, Hector H. GarciaAbstract: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.).
Christian Friis - One of the best experts on this subject based on the ideXlab platform.
-
Pathway of Oxfendazole from the host into the worm: Trichuris suis in pigs.
International journal for parasitology. Drugs and drug resistance, 2017Co-Authors: Tina V.a. Hansen, Andrew R. Williams, Matthew J. Denwood, Peter Nejsum, Stig Milan Thamsborg, Christian FriisAbstract:Abstract It is well known that the efficacy of a single oral dose of benzimidazoles against Trichuris spp. infections in humans and animals is poor, but is currently still used in control programmes against human trichuriasis. However, the route of the benzimidazoles from the treated host to Trichuris remains unknown. As parts of adult Trichuris are situated intracellularly in the caecum, they might be exposed to anthelmintic drugs in the intestinal content as well as the mucosa. In this study, the pathway of Oxfendazole and its metabolites was explored using a T. suis-pig infection model, by simultaneously measuring drug concentrations within the worms and the caecal mucosa, caecal tissue, caecal content and plasma of pigs over time after a single oral dose of 5 mg/kg Oxfendazole. Additionally, for comparison to the in vivo study, drug uptake and metabolism of Oxfendazole by T. suis was examined after in vitro incubation. Oxfendazole and metabolites were quantified by High Performance Liquid Chromatography. Multivariate linear regression analysis showed a strong and highly significant association between OFZ concentrations within T. suis and in plasma, along with a weaker association between OFZ concentrations in caecal tissue/mucosa and T. suis, suggesting that Oxfendazole reaches T. suis after absorption from the gastrointestinal tract and enters the worms by the blood-enterocyte pathway. The fenbendazole sulfone level in T. suis was highly affected by the concentrations in plasma. In addition, correlations between drug concentrations in the host compartments, were generally highest for this metabolite. In comparison to Oxfendazole, the correlation between plasma and content was particularly high for this metabolite, suggesting a high level of drug movement between these compartments and the possible involvement of the enterohepatic circulation.
-
Pathway of Oxfendazole from the host into the worm: Trichuris suis in pigs
Elsevier, 2017Co-Authors: Tina V.a. Hansen, Andrew R. Williams, Matthew J. Denwood, Peter Nejsum, Stig Milan Thamsborg, Christian FriisAbstract:It is well known that the efficacy of a single oral dose of benzimidazoles against Trichuris spp. infections in humans and animals is poor, but is currently still used in control programmes against human trichuriasis. However, the route of the benzimidazoles from the treated host to Trichuris remains unknown. As parts of adult Trichuris are situated intracellularly in the caecum, they might be exposed to anthelmintic drugs in the intestinal content as well as the mucosa. In this study, the pathway of Oxfendazole and its metabolites was explored using a T. suis-pig infection model, by simultaneously measuring drug concentrations within the worms and the caecal mucosa, caecal tissue, caecal content and plasma of pigs over time after a single oral dose of 5 mg/kg Oxfendazole. Additionally, for comparison to the in vivo study, drug uptake and metabolism of Oxfendazole by T. suis was examined after in vitro incubation. Oxfendazole and metabolites were quantified by High Performance Liquid Chromatography.Multivariate linear regression analysis showed a strong and highly significant association between OFZ concentrations within T. suis and in plasma, along with a weaker association between OFZ concentrations in caecal tissue/mucosa and T. suis, suggesting that Oxfendazole reaches T. suis after absorption from the gastrointestinal tract and enters the worms by the blood-enterocyte pathway. The fenbendazole sulfone level in T. suis was highly affected by the concentrations in plasma. In addition, correlations between drug concentrations in the host compartments, were generally highest for this metabolite. In comparison to Oxfendazole, the correlation between plasma and content was particularly high for this metabolite, suggesting a high level of drug movement between these compartments and the possible involvement of the enterohepatic circulation. Keywords: Trichuris, Benzimidazole, Drug efficacy, Drug pathwa
-
Glucose uptake in Oesophagostomum dentatum and the effect of Oxfendazole.
Veterinary parasitology, 1998Co-Authors: Mads Bjelke Petersen, Christian FriisAbstract:Abstract The uptake of 14 C -glucose by adult Oesophagostomum dentatum was characterised. The uptake was a non-linear function of external glucose concentration. The maximum velocity of uptake (Vmax) was 0.964 nmol/100 mg dry weight (dw)/5 min, and the transport constant (Kt) was 10.02 μM. When phlorizin, phloretin and 3-O-methylglucose were tested for their effects on the uptake of 14 C -glucose, phloretin and 3-O-methylglucose produced significant inhibitions, indicating that the uptake was mediated and occurred by facilitated diffusion. Exposure of the worms to Oxfendazole prior to incubation with 14 C -glucose did not affect the uptake of glucose. In another experiment worms were incubated with unlabelled glucose and the external glucose concentration was measured enzymatically. During a 7 h incubation period, the quantity of glucose remaining in the incubation medium of Oxfendazole exposed worms was significantly greater than in the control group. It was concluded that Oxfendazole did not influence the process of 14 C -glucose uptake, but might induce changes in the parasite leading to a reduced ability to deplete the incubation medium of glucose.
-
A new in vitro assay of benzimidazole activity against adult Oesophagostomum dentatum
International journal for parasitology, 1997Co-Authors: Mads Bjelke Petersen, Christian Friis, Henrik BjørnAbstract:A new in vitro assay of benzimidazole activity against adult Oesophagostomum dentatum is described. The method is based on the ability of O. dentatum to migrate through polyamide nets after exposure to various concentrations of benzimidazole. To determine an appropriate mesh size, control worms and worms exposed to 10 microM Oxfendazole for 24 h were allowed to migrate through nets with various mesh sizes (300-500 microns) for up to 1 h. A mesh size of 350 microns and migration periods of 10, 20 and 30 min were selected. Exposure to Oxfendazole at 10 microM for 24, 48 and 72 h inhibited the migration in a time-dependent manner. After 72 h of exposure and with a 20-min migration period, the EC50 of Oxfendazole for O. dentatum was 0.564 microM. In further studies the activities of albendazole sulphoxide, albendazole, cambendazole, fenbendazole, flubendazole, luxabendazole, mebendazole, Oxfendazole, oxibendazole, parbendazole and thiabendazole were compared. The worms were exposed to each drug at two concentrations (0.1 and 3.16 microM) for 72 h. At 3.16 microM there were no significant differences in the activity of the drugs. At 0.1 microM significant differences in activity were found. Albendazole sulphoxide and Oxfendazole were poor inhibitors of migration compared with their parent compounds, albendazole and fenbendazole.
