An overview of the preclinical toxicity and potential carcinogenicity of sitaxentan (Thelin®), a potent endothelin receptor antagonist developed for pulmonary arterial hypertension
Abstract
Sitaxentan (Thelin®), an endothelin receptor antagonist with a long duration of action and high specificity for the endothelin receptor A subtype, was used to treat pulmonary arterial hypertension. It was withdrawn from the market due to an idiosyncratic risk of drug-induced liver injury identified from emerging clinical trial data and clinical case reports. The preclinical safety profile of sitaxentan is presented, including single- and repeat-dose toxicity in mice, rats, and dogs and carcinogenicity in mice and rats. Sitaxentan-related adverse effects included coagulopathy in rats and dogs, increased serum alkaline phosphatase activity in mice and dogs, and hepatic hypertrophy in all species. Decreased albumin, erythrocyte count, hemoglobin concentration and hematocrit, and increased coagulation times and liver weight were also noted. These effects generally occurred at systemic exposures (AUC(0-24)) that were substantially greater than those seen in humans. Twice-daily (vs. once daily) dosing resulted in increased toxicity, which correlated with increased trough plasma sitaxentan concentrations. Sitaxentan appeared to have a low potential for testicular and hepatic toxicity and was not carcinogenic. These studies suggested that sitaxentan would have a reasonable margin of safety when used as directed in humans and supported a positive benefit:risk assessment at the time of marketing approval.
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Sitaxentan caused no explicit liver injury in animal experiments, whereas hepatotoxicity was prominent in humans.
“Sitaxentan caused no explicit liver injury in animal experiments [8], whereas the hepatotoxicity was prominent in humans [4,5].”
From Machine Learning Based Toxicity Prediction: From Chemical Structural Description to Transcriptome Analysis (2018) · cites this paper as [8]
Cites
Guidelines for the diagnosis and treatment of pulmonary hypertension
Galiè, N., Hoeper, M. M., Humbert, M. J. C., Torbicki, A., Vachiéry, J., Barberà, J. A., Beghetti, M., Corris, P. A., Gaine, S., Gibbs, J. S. R., et al. (2009) · European Heart Journal · doi:10.1093/eurheartj/ehp297 · Cited by 3,841 · see citing works
Primary Pulmonary Hypertension
Rubin, L. J. (1997) · New England Journal of Medicine · doi:10.1056/nejm199701093360207 · Cited by 1,726 · see citing works
Treatment of Pulmonary Arterial Hypertension
Humbert, M., Sitbon, O., & Simonneau, G. (2004) · New England Journal of Medicine · doi:10.1056/nejmra040291 · Cited by 1,724 · see citing works
Stepan, A. F., Walker, D. P., Bauman, J. N., Price, D. A., Baillie, T. A., Kalgutkar, A. S. S., & Aleo, M. D. (2011) · Chemical Research in Toxicology · doi:10.1021/tx200168d · Cited by 711 · see citing works
Krum, H., Viskoper, R. J., Lacourcière, Y., Budde, M., & Charlon, V. (1998) · New England Journal of Medicine · doi:10.1056/nejm199803193381202 · Cited by 567 · see citing works
Fattinger, K. (2001) · Clinical Pharmacology & Therapeutics · doi:10.1067/mcp.2001.114667 · Cited by 509 · see citing works
Morgan, R. E., Trauner, M. A., van Staden, C. J., Lee, P. H., Ramachandran, B., Eschenberg, M. J., Afshari, C. A., Qualls, C. W., Lightfoot-Dunn, R. M., & Hamadeh, H. K. (2010) · Toxicological Sciences · doi:10.1093/toxsci/kfq269 · Cited by 337 · see citing works
Mechanisms of drug-induced liver injury: from bedside to bench
Tujios, S. R., & Fontana, R. J. (2011) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2011.22 · Cited by 277 · see citing works
Barst, R. J., Rich, S., Widlitz, A. C., et al. (2002) · CHEST Journal · doi:10.1378/chest.121.6.1860 · Cited by 242 · see citing works
Endothelin receptor antagonists in pulmonary arterial hypertension
Dupuis, J., & Hoeper, M. M. (2008) · European Respiratory Journal · doi:10.1183/09031936.00078207 · Cited by 235 · see citing works
Bile Salt Export Pump (BSEP/ABCB11) Can Transport a Nonbile Acid Substrate, Pravastatin
Hirano, M., Maeda, K., Hayashi, H., Kusuhara, H., & Sugiyama, Y. (2005) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.105.084830 · Cited by 180 · see citing works
Carducci, M. A., Nelson, J. B., Bowling, M. K., Rogers, T., Eisenberger, M. A., Sinibaldi, V. J., Donehower, R. C., Leahy, T. L., Carr, R. A., Isaacson, J. D., et al. (2002) · Journal of Clinical Oncology · doi:10.1200/jco.2002.08.028 · Cited by 159 · see citing works
Wu, C., Chan, M. F., Stavros, F. D., Raju, B. G., Okun, I. M., Mong, S., Keller, K. M., Brock, T. A., Kogan, T. P., & Dixon, R. A. F. (1997) · Journal of Medicinal Chemistry · doi:10.1021/jm9700068 · Cited by 125 · see citing works
Self-citationLiver toxicity of sitaxentan in pulmonary arterial hypertension
Galiè, N., Hoeper, M. M., Gibbs, J. S. R., & Simonneau, G. (2011) · European Respiratory Journal · doi:10.1183/09031936.00194810 · Cited by 76 · see citing works
Tilton, R. G., Munsch, C. L., Sherwood, S. J., et al. (2000) · Pulmonary Pharmacology & Therapeutics · doi:10.1006/pupt.2000.0237 · Cited by 75 · see citing works
Hartman, J. C., Brouwer, K. R., Mandagere, A., Melvin, L., & Gorczynski, R. J. (2010) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y10-060 · Cited by 71 · see citing works
Role of Endothelin Receptor Antagonists in the Treatment of Pulmonary Arterial Hypertension
Abman, S. H. (2008) · Annual Review of Medicine · doi:10.1146/annurev.med.59.110106.212434 · Cited by 67 · see citing works
Liver toxicity: the Achilles' heel of endothelin receptor antagonist therapy?
Hoeper, M. M. (2009) · European Respiratory Journal · doi:10.1183/09031936.00094409 · Cited by 47 · see citing works
Diagnosis and Management of Pulmonary Arterial Hypertension
Houtchens, J., Martin, D., & Klinger, J. R. (2011) · Pulmonary Medicine · doi:10.1155/2011/845864 · Cited by 37 · see citing works
Sitaxentan-related acute liver failure in a patient with pulmonary arterial hypertension
Lee, W.-T. N., Kirkham, N., Johnson, M., et al. (2011) · European Respiratory Journal · doi:10.1183/09031936.00091610 · Cited by 28 · see citing works
Scott, L. J. (2007) · Drugs · doi:10.2165/00003495-200767050-00007 · Cited by 26 · see citing works
Wu, C., Decker, E. R., Blok, N., et al. (1999) · Journal of Medicinal Chemistry · doi:10.1021/jm9900063 · Cited by 26 · see citing works
Smith, D. A., Harrison, A. C., & Morgan, P. (2011) · Chemical Research in Toxicology · doi:10.1021/tx100408v · Cited by 18 · see citing works
Novel approaches to the pharmacotherapy of pulmonary arterial hypertension
Olsson, K. M., & Hoeper, M. M. (2009) · Drug Discovery Today · doi:10.1016/j.drudis.2008.12.003 · Cited by 13 · see citing works
Mucke, H. A. (2009) · Clinical Medicine Therapeutics · doi:10.4137/cmt.s2344 · Cited by 1 · see citing works
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Wu, Y., & Wang, G. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19082358 · Cited by 193 · see citing works
Kenna, J. G., Stahl, S. H., Eakins, J. A., Foster, A. J., Andersson, L. C., Bergare, J., Billger, M., Elebring, M., Elmore, C. S., & Thompson, R. A. (2015) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.114.220491 · Cited by 48 · see citing works
Erve, J. C. L., Gauby, S., Maynard, J. W., Svensson, M. A., Tonn, G., & Quinn, K. P. (2013) · Chemical Research in Toxicology · doi:10.1021/tx4001144 · Cited by 48 · see citing works
- Authors
- Owen, K., Cross, D. M., Derzi, M., Horsley, E., & Stavros, F. L.
- Affiliations
- Pfizer (United Kingdom) (GB)
- Pfizer (United States) (US)
- Pocatello High School (US)
- Venue
- Regulatory Toxicology and Pharmacology
- Publisher
- Elsevier BV
- Published
- 2012-10
- Volume
- 64
- Issue
- 1
- Pages
- 95-103
- ISSN
- 0273-2300 (ISSN-L)
- OpenAlex
- W2022087062
- Cited by
- 27
- References
- 25
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 2 · 2019: 2 · 2018: 2 · 2017: 1 · 2016: 3 · 2015: 4 · 2014: 1 · 2013: 2 · 2012: 2
- FWCI
- 2.32
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Regulatory Toxicology and Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- sitaxentan, endothelin receptor antagonists, pulmonary arterial hypertension, preclinical toxicity, carcinogenicity, drug-induced liver injury, hepatic hypertrophy, coagulopathy, alkaline phosphatase, testicular toxicity, dosing frequency, risk-benefit assessment
- MeSH terms
- Alkaline Phosphatase, Animals, Antihypertensive Agents, Blood Coagulation, Carcinogens, Dogs, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Erythrocyte Indices, Female, Hypertension, Pulmonary, Hypertrophy, Isoxazoles, Liver, Liver Function Tests, Male, Mice, Inbred Strains, Organ Size, Species Specificity, Thiophenes, Carcinogenicity Tests, Rats, Sprague-Dawley, Risk Assessment, Mice, Rats, Chemical and Drug Induced Liver Injury, Chronic, Endothelin Receptor Antagonists
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