Dose-Ranging Study of the Safety and Pharmacokinetics of Atrasentan in Patients with Refractory Malignancies

Abstract

Purpose: 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.Experimental Design: 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.

Clinical pharmacology of an atrasentan and docetaxel regimen in men with hormone-refractory prostate cancer

“…This finding is consistent with previous knowledge that docetaxel does not induce or inhibit CYP3A4, the major CYP450 involved in the metabolism of atrasentan [17-18]. Furthermore, atransentan pharmacokinetic parameters observed on this study were similar to those reported using the drug as a single agent in both volunteers and patients with cancer [19-21]. …”

Phase I safety study of escalating doses of atrasentan in adults with recurrent malignant glioma

“…The safety profile of atrasentan in these patients was consistent with that observed in healthy volunteers and prostate cancer patients, even at the higher doses in this study, and it reflects the physiologic antagonism of ET A receptors. 13,21 The two patients with partial responses and several patients with prolonged stable disease reflect similar activity rates as those seen in relief of cancer pain and reduction in prostate-specific antigen and other tumor markers in prostate cancer. 22 In addition, the 6-month PFS rate of 13% in patients with GBM is comparable to previous phase II studies of cytotoxic chemotherapy in recurrent GBM, but with less toxicity.…”

Effects of 2-amino-8-hydroxyquinoline interaction on the conformation of physiological isomers of human serum albumin

“…Similar moderate binding parameters and energetics of many established drug molecules to serum albumin have been observed, suggesting that A8HQ can be a good example to understand the binding mode of similar drug candidates. Since the B isomer of HSA predominates under increased Ca 2+ concentration in blood plasma, it has been suggested that N-B transition has physiological significance (Ryan et al 2004). Increase in the association constant of the B isomer can modify its distribution and bioavailability in the body, and therefore this study also provides information about the dose-response relationship and rate of elimination of drugs derived from hydroxyquinoline in patients with increased Ca 2+ blood plasma concentration.…”