Atrasentan, an endothelin-receptor antagonist for refractory adenocarcinomas: safety and pharmacokinetics.
OBJECTIVE
Endothelin receptors, particularly the ET(A) receptor, have been shown to participate in the pathophysiology of prostate and other cancers. Atrasentan, an endothelin antagonist, binds selectively to the ET(A) receptor. This study evaluated the safety, pharmacokinetics, and maximum-tolerated dose of atrasentan in cancer patients.


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.


CONCLUSIONS
Adverse events were consistent with atrasentan's pharmacologic vasodilatory effect. Linear, dose-proportional pharmacokinetics suggest that atrasentan can be easily and consistently dosed.
Carducci
Michael A
MA
Division of Medical Oncology, The Johns Hopkins Oncology Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. carducci@jhmi.edu
Nelson
Joel B
JB
Bowling
M Kathy
MK
Rogers
Theresa
T
Eisenberger
Mario A
MA
Sinibaldi
Victoria
V
Donehower
Ross
R
Leahy
Terri L
TL
Carr
Robert A
RA
Isaacson
Jeffrey D
JD
Janus
Todd J
TJ
Andre
Amy
A
Hosmane
Balakrishna S
BS
Padley
Robert J
RJ
D000230:Adenocarcinoma / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077868:Atrasentan; D065128:Endothelin Receptor Antagonists; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011759:Pyrrolidines; D016879:Salvage Therapy
D000970:Antineoplastic Agents; D065128:Endothelin Receptor Antagonists; D011759:Pyrrolidines; D000077868:Atrasentan