Dose-ranging study of the safety and pharmacokinetics of atrasentan in patients with refractory malignancies.
OBJECTIVE
Atrasentan is an orally bioavailable selective antagonist of the endothelin receptor ET(A). Due to the potential activity of this agent against prostate cancer, the majority of subjects enrolled in prior studies had been male. This Phase I study sought to determine the toxicity and pharmacokinetics of daily atrasentan in a population of both female and male subjects with advanced malignancies.


METHODS
Patients with refractory malignancies received atrasentan once daily at doses ranging from 5 mg to 75 mg. At least 3 subjects were treated at each dose level before enrollment began at the next higher dose level. Enrollment for specific dose levels was expanded if any subject experienced serious drug-related toxicity. Plasma concentration profiles for atrasentan were determined after dosing on days 1 and 28.


RESULTS
Thirty-five patients received atrasentan at doses from 5 mg to 75 mg. The most frequent drug-related adverse events were headache (60%), rhinitis (49%), and peripheral edema (31%). These toxicities were mild to moderate in severity and reversible on cessation of treatment. Dose escalation was stopped at the 75-mg dose level due to the occurrence of three severe adverse events (2 hyponatremia and 1 hypotension). Atrasentan was rapidly absorbed after oral administration; mean time to maximum observed concentration ranged from 0.3 to 1.7 h. Terminal elimination half-life averaged 26 h. No significant difference between sexes was found in any atrasentan pharmacokinetic parameter tested, including maximum observed plasma concentration, time to maximum observed concentration, minimum observed plasma concentration, area under the plasma concentration-time curve, and elimination rate constant.


CONCLUSIONS
Atrasentan is well tolerated in both female and male cancer patients at doses of up to 60 mg/day with dose-limiting toxicity observed at 75 mg/day. The most frequently observed toxicities were headache, rhinitis, and edema. There was no statistically significant difference in atrasentan pharmacokinetics between sexes.
Ryan
Christopher W
CW
Section of Hematology/Oncology, Department of Medicine, Cancer Research Center, and Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, and Abbott Laboratories, Abbott Park, Illinois, USA. ryanc@ohsu.edu
Vogelzang
Nicholas J
NJ
Vokes
Everett E
EE
Kindler
Hedy L
HL
Undevia
Samir D
SD
Humerickhouse
Rod
R
André
Amy K
AK
Wang
Qiang
Q
Carr
Robert A
RA
Ratain
Mark J
MJ
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D019540:Area Under Curve; D000077868:Atrasentan; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011471:Prostatic Neoplasms / Q000378:metabolism; D011759:Pyrrolidines / Q000493:pharmacokinetics*; D017466:Receptors, Endothelin / Q000378:metabolism; D012737:Sex Factors; D013997:Time Factors
D000970:Antineoplastic Agents; D011759:Pyrrolidines; D017466:Receptors, Endothelin; D000077868:Atrasentan