Atrasentan, an Endothelin-Receptor Antagonist for Refractory Adenocarcinomas: Safety and Pharmacokinetics

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

doi:10.1200/jco.2002.08.028

Cited by 150 publications

(98 citation statements)

References 29 publications

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“…Previous clinical studies of atrasentan have suggested a mild hemodilution effect as manifested by a decrease in hemoglobin/hematocrit as well as serum albumin and total protein (20,21). In the current study, no statistically significant changes from baseline across all of the dose levels occurred for hemoglobin or hematocrit after 2 or 4 weeks of atrasentan treatment.…”

Section: Resultsmentioning

confidence: 99%

“…The frequently observed adverse events of rhinitis, headache, and edema have been reported previously with ET receptor antagonists and are likely attributable to the vasoactive properties of these agents. Data from a previous Phase I study of atrasentan supported 60 mg as the maximum tolerated dose due to increased incidence of headache coincident with higher dose levels (20). Another Phase I study treated patients with doses of up to 95 mg/day without achieving protocol-defined maximum tolerated dose (21).…”

Section: Discussionmentioning

confidence: 99%

“…The initial dose level was 5 mg/day, with subsequent planned dose levels of 10,20,30,45,60,75,95,115, and 140 mg/day. Three subjects were to be enrolled at each dose level.…”

Section: Methodsmentioning

confidence: 99%

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

Ryan

Vogelzang

Vokes

et al. 2004

Clinical Cancer Research

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Ryan

Vogelzang

Vokes

et al. 2004

Clinical Cancer Research

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“…Indeed, chemical inhibitors of HDACs have been shown to inhibit tumor cell growth and induce differentiation and cell death. [5] Several such inhibitory agents, including suberoyanilide hydroxamic acid (SAHA, aka virinostat) and depsipeptide (FR901228) have reached clinical trials, [6][7][8] and SAHA has been approved by the FDA for use in cutaneous T-cell lymphoma (CTCL). The HDAC inhibitors (HDACIs) also enhance the cytotoxic effects of both radiation and chemotherapeutic drugs.…”

Section: Introductionmentioning

confidence: 99%

Chemistry, Biology, and QSAR Studies of Substituted Biaryl Hydroxamates and Mercaptoacetamides as HDAC Inhibitors—Nanomolar‐Potency Inhibitors of Pancreatic Cancer Cell Growth

et al. 2008

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The histone deacetylases (HDACs) are able to regulate gene expression and inhibitors of the HDACs (HDACIs) hold promise in the treatment of cancer as well as a variety of neurodegenerative diseases. To investigate the possibility to achieve some measure of isoform selectivity in the inhibition of the HDACs, we prepared a small series of 2,4′-diaminobiphenyl ligands functionalized at the para-amino group with an appendage containing either a hydroxamate or a mercaptoacetamide group and coupled to an amino acid residue at the ortho-amino group. A smaller series of substituted phenylthiazoles was also explored. Some of these newly synthesized ligands show low nM potency in the HDAC inhibition assays and display micromolar to low nanomolar IC 50 values when tested against five pancreatic cancer cell lines. The isoform selectivity of these ligands for the Class I HDACs (HDAC1-3 and 8) and Class IIb HDACs (HDAC6 and HDAC10) together with QSAR studies of their correlation with the lipophilicity are presented. Of particular interest is the HDAC6 selectivity of the mercaptoacetamides.

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“…Phase I clinical trials suggested a favorable safety profile, and the most common adverse effects were headache, rhinitis, peripheral edema, and asthenia. 11,12 Phase II studies in prostate cancer suggested that atrasentan had modest clinical activity, with statistically significant improvement in time to disease progression, time to prostatespecific antigen (PSA) progression, and changes in bone turnover markers compared with placebo. 9,13 Men with metastatic HRPC treated with placebo exhibited a continued increase in bone alkaline phosphatase (BAP), a marker of osteoblast activity, and N-telopeptide (NTX), a marker of osteoclast activity.…”

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confidence: 99%

Randomized phase II study of atrasentan alone or in combination with zoledronic acid in men with metastatic prostate cancer

Michaelson

Kaufman

Kantoff

et al. 2006

Cancer

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BACKGROUND. Metastatic prostate cancer is characterized by the presence of osteoblastic bone metastases. Bone metastases account for most of the morbidity from this disease. Inhibition of osteoclast activity with the potent bisphosphonate zoledronic acid reduces skeletal complications and decreases serum levels of biochemical bone turnover markers compared with placebo. Atrasentan is an investigational agent that inhibits endothelin‐1 receptor, resulting in decreased osteoblast activity. METHODS. The effects of atrasentan alone versus combination therapy with atrasentan and zoledronic acid were investigated on bone turnover markers in men with bone metastases from prostate cancer. Forty‐four men were randomized to receive either atrasentan alone or combination therapy, and 33 completed at least 12 weeks of treatment and were included in the primary analysis. RESULTS. Treatment with the combination resulted in significantly lower serum levels of N‐telopeptide, a marker of bone resorption, compared with treatment with atrasentan alone. There was no difference between groups in serum levels of bone‐specific alkaline phosphatase, a marker of bone formation, at 12 weeks. Commonly observed adverse effects were edema, rhinitis, fatigue, and shortness of breath, most of which were NCI CTC (version 3.0) Grade 1. No Grade 4 or 5 treatment‐related toxicities were observed. There was minimal clinical efficacy, with no objective responses and only 1 prostate‐specific antigen (PSA) response. CONCLUSIONS. There is no evidence for additive or synergistic effects of combination therapy with atrasentan and zoledronic acid on bone turnover markers in men with metastatic prostate cancer. Cancer 2006. © 2006 American Cancer Society.

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Atrasentan, an Endothelin-Receptor Antagonist for Refractory Adenocarcinomas: Safety and Pharmacokinetics

Abstract: Adverse events were consistent with atrasentan's pharmacologic vasodilatory effect. Linear, dose-proportional pharmacokinetics suggest that atrasentan can be easily and consistently dosed.

Cited by 150 publications

References 29 publications

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

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

Chemistry, Biology, and QSAR Studies of Substituted Biaryl Hydroxamates and Mercaptoacetamides as HDAC Inhibitors—Nanomolar‐Potency Inhibitors of Pancreatic Cancer Cell Growth

Randomized phase II study of atrasentan alone or in combination with zoledronic acid in men with metastatic prostate cancer

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