Atrasentan, an endothelin-receptor antagonist for refractory adenocarcinomas: Safety and pharmacokinetics

Michael A Carducci, Joel B. Nelson, M. Kathy Bowling, Theresa Rogers, Mario Eisenberger, Victoria Sinibaldi, Ross C Donehower, Terri L. Leahy, Robert A. Carr, Jeffrey D. Isaacson, Todd J. Janus, Amy Andre, Balakrishna S. Hosmane, Robert J. Padley

Research output: Contribution to journalArticle

Abstract

Purpose: Endothelin receptors, particularly the ETA receptor, have been shown to participate in the pathophysiology of prostate and other cancers. Atrasentan, an endothelin antagonist, binds selectively to the ETA receptor. This study evaluated the safety, pharmacokinetics, and maximum-tolerated dose of atrasentan in cancer patients. Patients and Methods: Patients who were 18 years or older and had histologically confirmed adenocarcinoma refractory to therapy enrolled in this 28-day, open-label, phase I study. Enrollment was planned for cohorts of three patients at doses escalating from 10 to 140 mg/d. When any patient had dose-limiting toxicity, that cohort was expanded. The primary outcome variable was safety; secondary outcome variables were pharmacokinetics, tumor response, and pain relief. Results: Thirty-one cancer patients (14 prostate) were treated at daily atrasentan doses of 10, 20, 30, 45, 60, and 75 mg (n = 3 to 8 per cohort). The most common adverse events, such as rhinitis, headache, asthenia, and peripheral edema, were reversible on drug discontinuation and responded to symptom-specific treatment. Reversible hemodilution was apparent in laboratory findings and weight gain. Clinically significant headache was the dose-limiting adverse event; the maximum-tolerated dose was 60 mg/d. Pharmacokinetics were dose-proportional across the 10- to 75-mg dose range. Atrasentan was rapidly absorbed; the time to maximum observed concentration was approximately 1.5 hours. The terminal elimination half-life was approximately 24 hours, and steady-state plasma concentrations were achieved within 7 days. Decreases in prostate-specific antigen and pain relief were noted in a patient subset. Conclusion: Adverse events were consistent with atrasentan's pharmacologic vasodilatory effect. Linear, dose-proportional pharmacokinetics suggest that atrasentan can be easily and consistently dosed.

Original languageEnglish (US)
Pages (from-to)2171-2180
Number of pages10
JournalJournal of Clinical Oncology
Volume20
Issue number8
DOIs
StatePublished - Apr 15 2002

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Adenocarcinoma
Pharmacokinetics
Safety
Maximum Tolerated Dose
Headache
Asthenia
Pain
Endothelin Receptors
Neoplasms
Hemodilution
Prostate-Specific Antigen
Rhinitis
atrasentan
Endothelin Receptor Antagonists
Weight Gain
Half-Life
Prostate
Edema
Prostatic Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Atrasentan, an endothelin-receptor antagonist for refractory adenocarcinomas : Safety and pharmacokinetics. / Carducci, Michael A; Nelson, Joel B.; Bowling, M. Kathy; Rogers, Theresa; Eisenberger, Mario; Sinibaldi, Victoria; Donehower, Ross C; Leahy, Terri L.; Carr, Robert A.; Isaacson, Jeffrey D.; Janus, Todd J.; Andre, Amy; Hosmane, Balakrishna S.; Padley, Robert J.

In: Journal of Clinical Oncology, Vol. 20, No. 8, 15.04.2002, p. 2171-2180.

Research output: Contribution to journalArticle

Carducci, MA, Nelson, JB, Bowling, MK, Rogers, T, Eisenberger, M, Sinibaldi, V, Donehower, RC, Leahy, TL, Carr, RA, Isaacson, JD, Janus, TJ, Andre, A, Hosmane, BS & Padley, RJ 2002, 'Atrasentan, an endothelin-receptor antagonist for refractory adenocarcinomas: Safety and pharmacokinetics', Journal of Clinical Oncology, vol. 20, no. 8, pp. 2171-2180. https://doi.org/10.1200/JCO.2002.08.028
Carducci, Michael A ; Nelson, Joel B. ; Bowling, M. Kathy ; Rogers, Theresa ; Eisenberger, Mario ; Sinibaldi, Victoria ; Donehower, Ross C ; Leahy, Terri L. ; Carr, Robert A. ; Isaacson, Jeffrey D. ; Janus, Todd J. ; Andre, Amy ; Hosmane, Balakrishna S. ; Padley, Robert J. / Atrasentan, an endothelin-receptor antagonist for refractory adenocarcinomas : Safety and pharmacokinetics. In: Journal of Clinical Oncology. 2002 ; Vol. 20, No. 8. pp. 2171-2180.
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abstract = "Purpose: Endothelin receptors, particularly the ETA receptor, have been shown to participate in the pathophysiology of prostate and other cancers. Atrasentan, an endothelin antagonist, binds selectively to the ETA receptor. This study evaluated the safety, pharmacokinetics, and maximum-tolerated dose of atrasentan in cancer patients. Patients and Methods: Patients who were 18 years or older and had histologically confirmed adenocarcinoma refractory to therapy enrolled in this 28-day, open-label, phase I study. Enrollment was planned for cohorts of three patients at doses escalating from 10 to 140 mg/d. When any patient had dose-limiting toxicity, that cohort was expanded. The primary outcome variable was safety; secondary outcome variables were pharmacokinetics, tumor response, and pain relief. Results: Thirty-one cancer patients (14 prostate) were treated at daily atrasentan doses of 10, 20, 30, 45, 60, and 75 mg (n = 3 to 8 per cohort). The most common adverse events, such as rhinitis, headache, asthenia, and peripheral edema, were reversible on drug discontinuation and responded to symptom-specific treatment. Reversible hemodilution was apparent in laboratory findings and weight gain. Clinically significant headache was the dose-limiting adverse event; the maximum-tolerated dose was 60 mg/d. Pharmacokinetics were dose-proportional across the 10- to 75-mg dose range. Atrasentan was rapidly absorbed; the time to maximum observed concentration was approximately 1.5 hours. The terminal elimination half-life was approximately 24 hours, and steady-state plasma concentrations were achieved within 7 days. Decreases in prostate-specific antigen and pain relief were noted in a patient subset. Conclusion: Adverse events were consistent with atrasentan's pharmacologic vasodilatory effect. Linear, dose-proportional pharmacokinetics suggest that atrasentan can be easily and consistently dosed.",
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T1 - Atrasentan, an endothelin-receptor antagonist for refractory adenocarcinomas

T2 - Safety and pharmacokinetics

AU - Carducci, Michael A

AU - Nelson, Joel B.

AU - Bowling, M. Kathy

AU - Rogers, Theresa

AU - Eisenberger, Mario

AU - Sinibaldi, Victoria

AU - Donehower, Ross C

AU - Leahy, Terri L.

AU - Carr, Robert A.

AU - Isaacson, Jeffrey D.

AU - Janus, Todd J.

AU - Andre, Amy

AU - Hosmane, Balakrishna S.

AU - Padley, Robert J.

PY - 2002/4/15

Y1 - 2002/4/15

N2 - Purpose: Endothelin receptors, particularly the ETA receptor, have been shown to participate in the pathophysiology of prostate and other cancers. Atrasentan, an endothelin antagonist, binds selectively to the ETA receptor. This study evaluated the safety, pharmacokinetics, and maximum-tolerated dose of atrasentan in cancer patients. Patients and Methods: Patients who were 18 years or older and had histologically confirmed adenocarcinoma refractory to therapy enrolled in this 28-day, open-label, phase I study. Enrollment was planned for cohorts of three patients at doses escalating from 10 to 140 mg/d. When any patient had dose-limiting toxicity, that cohort was expanded. The primary outcome variable was safety; secondary outcome variables were pharmacokinetics, tumor response, and pain relief. Results: Thirty-one cancer patients (14 prostate) were treated at daily atrasentan doses of 10, 20, 30, 45, 60, and 75 mg (n = 3 to 8 per cohort). The most common adverse events, such as rhinitis, headache, asthenia, and peripheral edema, were reversible on drug discontinuation and responded to symptom-specific treatment. Reversible hemodilution was apparent in laboratory findings and weight gain. Clinically significant headache was the dose-limiting adverse event; the maximum-tolerated dose was 60 mg/d. Pharmacokinetics were dose-proportional across the 10- to 75-mg dose range. Atrasentan was rapidly absorbed; the time to maximum observed concentration was approximately 1.5 hours. The terminal elimination half-life was approximately 24 hours, and steady-state plasma concentrations were achieved within 7 days. Decreases in prostate-specific antigen and pain relief were noted in a patient subset. Conclusion: Adverse events were consistent with atrasentan's pharmacologic vasodilatory effect. Linear, dose-proportional pharmacokinetics suggest that atrasentan can be easily and consistently dosed.

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