Phase I dose-escalation study of the safety and pharmacokinetics of atrasentan: An endothelin receptor antagonist for refractory prostate cancer

Evidence suggests that endothelin (ET)-1 and its primary receptor, the ET(A) receptor, may contribute to the progression of prostate and other cancers. Atrasentan (ABT-627) is a highly potent, selective ET(A) receptor antagonist. This study assessed safety, maximum tolerated dose, and pharmacokineti...

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Bibliographic Details
Published in:Clinical cancer research 2003-08, Vol.9 (8), p.2965-2972
Main Authors: ZONNENBERG, Bernard A, GROENEWEGEN, Gerard, JANUS, Todd J, LEAHY, Terri W, HUMERICKHOUSE, Rod A, ISAACSON, Jeffrey D, CARR, Robert A, VOEST, Emile
Format: Article
Language:English
Subjects:
Aged
Aged, 80 and over
Antineoplastic agents
Antineoplastic Agents - adverse effects
Antineoplastic Agents - pharmacokinetics
Area Under Curve
Biological and medical sciences
Carcinoma - metabolism
Chemotherapy
Cohort Studies
Disease Progression
Dose-Response Relationship, Drug
Endothelin Receptor Antagonists
Female
Humans
Male
Medical sciences
Middle Aged
Pharmacology. Drug treatments
Prostatic Neoplasms - drug therapy
Prostatic Neoplasms - metabolism
Pyrrolidines - adverse effects
Pyrrolidines - pharmacokinetics
Time Factors
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Summary:Evidence suggests that endothelin (ET)-1 and its primary receptor, the ET(A) receptor, may contribute to the progression of prostate and other cancers. Atrasentan (ABT-627) is a highly potent, selective ET(A) receptor antagonist. This study assessed safety, maximum tolerated dose, and pharmacokinetics (PK) in patients with refractory adenocarcinomas, primarily prostate cancer. This 28-day, single-center Phase I trial evaluated the safety and PK of escalating oral atrasentan doses (2.5-95 mg) given daily (except day 2) to eligible patients >/==" BORDER="0">18 years old with an adenocarcinoma proven resistant to standard therapy. Priority was given to patients with hormone-refractory prostate cancer. After 28 days, patients without objective signs of tumor progression were eligible to continue atrasentan in an extension study. Thirty-nine patients (30 of whom had prostate cancer) were treated in cohorts of three patients each with escalating atrasentan doses (2.5, 5, 10, 20, 30, 45, 60, 75, and 95 mg). The most common adverse events were rhinitis, headache, and peripheral edema. Anemia consistent with a reversible hemodilution effect was observed. No maximum tolerated dose was found in the dose range studied. Atrasentan PK were characterized by rapid absorption (mean T(max) = 0.9 h), mean +/- SD oral clearance of 24 +/- 15 liters/h, and volume distribution of 726 +/- 477 liters. PK were approximately dose-proportional and time independent across doses. Atrasentan is well tolerated, with no dose-limiting adverse events observed up to 95 mg. Adverse events are consistent with the vasodilatory effect of the drug. PK are linear and dose-proportional; the half-life is appropriate for once-daily dosing.
ISSN:1078-0432
1557-3265