Development of an oral regimen of unithiol for the treatment of snakebite envenoming: a phase 1 open-label dose-escalation safety trial and pharmacokinetic analysis in healthy Kenyan adultsResearch in context
Summary: Background: Viperidae snakes are responsible for many of the 94,000 deaths caused by snakebite envenoming each year. The most pathological venom component of this globally diverse family of snakes are the zinc-dependent snake venom metalloproteinase (SVMP) enzymes, which can be inhibited b...
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Elsevier
2025-03-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396425000441 |
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| author | Michael Abouyannis Yvonne K. Nyambura Samson Ngome Debra Riako Jennifer Musyoki Charles Muiruri Benedict Orindi Laura Else Alieu Amara Laura Dickinson Rachel H. Clare Laura-Oana Albulescu Adam P. Westhorpe Jeroen Kool Ifedayo Adetifa Francis M. Ndungu Richard FitzGerald Saye Khoo David G. Lalloo Nicholas R. Casewell Mainga Hamaluba |
| author_facet | Michael Abouyannis Yvonne K. Nyambura Samson Ngome Debra Riako Jennifer Musyoki Charles Muiruri Benedict Orindi Laura Else Alieu Amara Laura Dickinson Rachel H. Clare Laura-Oana Albulescu Adam P. Westhorpe Jeroen Kool Ifedayo Adetifa Francis M. Ndungu Richard FitzGerald Saye Khoo David G. Lalloo Nicholas R. Casewell Mainga Hamaluba |
| author_sort | Michael Abouyannis |
| collection | DOAJ |
| description | Summary: Background: Viperidae snakes are responsible for many of the 94,000 deaths caused by snakebite envenoming each year. The most pathological venom component of this globally diverse family of snakes are the zinc-dependent snake venom metalloproteinase (SVMP) enzymes, which can be inhibited by the metal chelator, unithiol. A short-course oral regimen, readily available and rapidly deployed ahead of hospital admission is needed. Methods: This open-label, phase 1 clinical trial assessed the safety of single ascending oral, multiple ascending oral, and single ascending intravenous doses of unithiol in 64 healthy adult volunteers from Kilifi County, Kenya. The multiple dose stage was informed by an interim safety and pharmacokinetic analysis, and predefined target plasma concentrations. Plasma concentrations of unithiol were measured using high-performance liquid chromatography-mass spectrometry, and safety was described by full adverse event reporting. Findings: 175 individuals were screened, and 64 (median age 30 years, IQR 25–38 years) received the study drug. There were no dose limiting toxicities or serious adverse events. There were 61 solicited adverse events, 17 related unsolicited adverse events, and 53 laboratory adverse events, all of mild or moderate severity. The maximum oral dose of 1500 mg was well tolerated and associated with the following pharmacokinetic parameters: Cmax 14.7 μg/mL, Tmax 2.9 h, T1/2 18.4 h, and AUC0-∞ 204.5 μg.h/mL. Interpretation: The phase 2 recommended dose (1500 mg loading dose, followed by 900 mg doses at 6-h and 24-h) has no safety concerns, and has promising pharmacokinetic properties for clinical use. Unithiol is affordable, stable at room temperature, and has the potential to be given orally in remote rural clinics. Its further development for snakebite indication is warranted. Funding: Wellcome Trust, Bloomsbury Set, and Cures Within Reach. |
| format | Article |
| id | doaj-art-470613ea64d742e396e83a4c3c1fcb46 |
| institution | DOAJ |
| issn | 2352-3964 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj-art-470613ea64d742e396e83a4c3c1fcb462025-08-20T02:55:10ZengElsevierEBioMedicine2352-39642025-03-0111310560010.1016/j.ebiom.2025.105600Development of an oral regimen of unithiol for the treatment of snakebite envenoming: a phase 1 open-label dose-escalation safety trial and pharmacokinetic analysis in healthy Kenyan adultsResearch in contextMichael Abouyannis0Yvonne K. Nyambura1Samson Ngome2Debra Riako3Jennifer Musyoki4Charles Muiruri5Benedict Orindi6Laura Else7Alieu Amara8Laura Dickinson9Rachel H. Clare10Laura-Oana Albulescu11Adam P. Westhorpe12Jeroen Kool13Ifedayo Adetifa14Francis M. Ndungu15Richard FitzGerald16Saye Khoo17David G. Lalloo18Nicholas R. Casewell19Mainga Hamaluba20Centre for Snakebite Research & Interventions, Liverpool School of Tropical Medicine, Liverpool, UK; KEMRI-Wellcome Research Programme, Kilifi, Kenya; Corresponding author. Centre for Snakebite Research & Interventions, Liverpool School of Tropical Medicine, Liverpool, UK.KEMRI-Wellcome Research Programme, Kilifi, KenyaKEMRI-Wellcome Research Programme, Kilifi, KenyaKEMRI-Wellcome Research Programme, Kilifi, KenyaKEMRI-Wellcome Research Programme, Kilifi, KenyaKEMRI-Wellcome Research Programme, Kilifi, KenyaKEMRI-Wellcome Research Programme, Kilifi, KenyaDepartment of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UKDepartment of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UKDepartment of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UKCentre for Snakebite Research & Interventions, Liverpool School of Tropical Medicine, Liverpool, UKCentre for Snakebite Research & Interventions, Liverpool School of Tropical Medicine, Liverpool, UKCentre for Snakebite Research & Interventions, Liverpool School of Tropical Medicine, Liverpool, UKDivision of BioAnalytical Chemistry, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1085, 1081 HV, Amsterdam, the Netherlands; Centre for Analytical Sciences Amsterdam (CASA), 1098 XH, Amsterdam, the NetherlandsKEMRI-Wellcome Research Programme, Kilifi, Kenya; Department of Infectious Diseases Epidemiology, London School of Hygiene & Tropical Medicine, London, UKKEMRI-Wellcome Research Programme, Kilifi, KenyaNIHR Royal Liverpool and Broadgreen CRF, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UKDepartment of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK; NIHR Royal Liverpool and Broadgreen CRF, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UKCentre for Snakebite Research & Interventions, Liverpool School of Tropical Medicine, Liverpool, UKCentre for Snakebite Research & Interventions, Liverpool School of Tropical Medicine, Liverpool, UKKEMRI-Wellcome Research Programme, Kilifi, Kenya; Centre for Tropical Medicine & Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UKSummary: Background: Viperidae snakes are responsible for many of the 94,000 deaths caused by snakebite envenoming each year. The most pathological venom component of this globally diverse family of snakes are the zinc-dependent snake venom metalloproteinase (SVMP) enzymes, which can be inhibited by the metal chelator, unithiol. A short-course oral regimen, readily available and rapidly deployed ahead of hospital admission is needed. Methods: This open-label, phase 1 clinical trial assessed the safety of single ascending oral, multiple ascending oral, and single ascending intravenous doses of unithiol in 64 healthy adult volunteers from Kilifi County, Kenya. The multiple dose stage was informed by an interim safety and pharmacokinetic analysis, and predefined target plasma concentrations. Plasma concentrations of unithiol were measured using high-performance liquid chromatography-mass spectrometry, and safety was described by full adverse event reporting. Findings: 175 individuals were screened, and 64 (median age 30 years, IQR 25–38 years) received the study drug. There were no dose limiting toxicities or serious adverse events. There were 61 solicited adverse events, 17 related unsolicited adverse events, and 53 laboratory adverse events, all of mild or moderate severity. The maximum oral dose of 1500 mg was well tolerated and associated with the following pharmacokinetic parameters: Cmax 14.7 μg/mL, Tmax 2.9 h, T1/2 18.4 h, and AUC0-∞ 204.5 μg.h/mL. Interpretation: The phase 2 recommended dose (1500 mg loading dose, followed by 900 mg doses at 6-h and 24-h) has no safety concerns, and has promising pharmacokinetic properties for clinical use. Unithiol is affordable, stable at room temperature, and has the potential to be given orally in remote rural clinics. Its further development for snakebite indication is warranted. Funding: Wellcome Trust, Bloomsbury Set, and Cures Within Reach.http://www.sciencedirect.com/science/article/pii/S2352396425000441Phase 1 clinical trialSnakebiteEnvenomingUnithiol |
| spellingShingle | Michael Abouyannis Yvonne K. Nyambura Samson Ngome Debra Riako Jennifer Musyoki Charles Muiruri Benedict Orindi Laura Else Alieu Amara Laura Dickinson Rachel H. Clare Laura-Oana Albulescu Adam P. Westhorpe Jeroen Kool Ifedayo Adetifa Francis M. Ndungu Richard FitzGerald Saye Khoo David G. Lalloo Nicholas R. Casewell Mainga Hamaluba Development of an oral regimen of unithiol for the treatment of snakebite envenoming: a phase 1 open-label dose-escalation safety trial and pharmacokinetic analysis in healthy Kenyan adultsResearch in context EBioMedicine Phase 1 clinical trial Snakebite Envenoming Unithiol |
| title | Development of an oral regimen of unithiol for the treatment of snakebite envenoming: a phase 1 open-label dose-escalation safety trial and pharmacokinetic analysis in healthy Kenyan adultsResearch in context |
| title_full | Development of an oral regimen of unithiol for the treatment of snakebite envenoming: a phase 1 open-label dose-escalation safety trial and pharmacokinetic analysis in healthy Kenyan adultsResearch in context |
| title_fullStr | Development of an oral regimen of unithiol for the treatment of snakebite envenoming: a phase 1 open-label dose-escalation safety trial and pharmacokinetic analysis in healthy Kenyan adultsResearch in context |
| title_full_unstemmed | Development of an oral regimen of unithiol for the treatment of snakebite envenoming: a phase 1 open-label dose-escalation safety trial and pharmacokinetic analysis in healthy Kenyan adultsResearch in context |
| title_short | Development of an oral regimen of unithiol for the treatment of snakebite envenoming: a phase 1 open-label dose-escalation safety trial and pharmacokinetic analysis in healthy Kenyan adultsResearch in context |
| title_sort | development of an oral regimen of unithiol for the treatment of snakebite envenoming a phase 1 open label dose escalation safety trial and pharmacokinetic analysis in healthy kenyan adultsresearch in context |
| topic | Phase 1 clinical trial Snakebite Envenoming Unithiol |
| url | http://www.sciencedirect.com/science/article/pii/S2352396425000441 |
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