Dose-ranging study of the safety and pharmacokinetics of atrasentan in patients with refractory malignances

Christopher Ryan, Nicholas J. Vogelzang, Everett E. Vokes, Hedy L. Kindler, Samir D. Undevia, Rod Humerickhouse, Amy K. André, Qiang Wang, Robert A. Carr, Mark J. Ratain

    Research output: Contribution to journalArticle

    38 Citations (Scopus)

    Abstract

    Purpose: Atrasentan is an orally bioavailable selective antagonist of the endothelin receptor ETA. 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.

    Original languageEnglish (US)
    Pages (from-to)4406-4411
    Number of pages6
    JournalClinical Cancer Research
    Volume10
    Issue number13
    DOIs
    StatePublished - Jul 1 2004

    Fingerprint

    Pharmacokinetics
    Safety
    Rhinitis
    Drug-Related Side Effects and Adverse Reactions
    Headache
    Edema
    atrasentan
    Neoplasms
    Withholding Treatment
    Hyponatremia
    Sex Characteristics
    Hypotension
    Oral Administration
    Half-Life
    Prostatic Neoplasms
    Research Design
    Population

    ASJC Scopus subject areas

    • Cancer Research
    • Oncology

    Cite this

    Ryan, C., Vogelzang, N. J., Vokes, E. E., Kindler, H. L., Undevia, S. D., Humerickhouse, R., ... Ratain, M. J. (2004). Dose-ranging study of the safety and pharmacokinetics of atrasentan in patients with refractory malignances. Clinical Cancer Research, 10(13), 4406-4411. https://doi.org/10.1158/1078-0432.CCR-04-0083

    Dose-ranging study of the safety and pharmacokinetics of atrasentan in patients with refractory malignances. / Ryan, Christopher; Vogelzang, Nicholas J.; Vokes, Everett E.; Kindler, Hedy L.; Undevia, Samir D.; Humerickhouse, Rod; André, Amy K.; Wang, Qiang; Carr, Robert A.; Ratain, Mark J.

    In: Clinical Cancer Research, Vol. 10, No. 13, 01.07.2004, p. 4406-4411.

    Research output: Contribution to journalArticle

    Ryan, C, Vogelzang, NJ, Vokes, EE, Kindler, HL, Undevia, SD, Humerickhouse, R, André, AK, Wang, Q, Carr, RA & Ratain, MJ 2004, 'Dose-ranging study of the safety and pharmacokinetics of atrasentan in patients with refractory malignances', Clinical Cancer Research, vol. 10, no. 13, pp. 4406-4411. https://doi.org/10.1158/1078-0432.CCR-04-0083
    Ryan, Christopher ; Vogelzang, Nicholas J. ; Vokes, Everett E. ; Kindler, Hedy L. ; Undevia, Samir D. ; Humerickhouse, Rod ; André, Amy K. ; Wang, Qiang ; Carr, Robert A. ; Ratain, Mark J. / Dose-ranging study of the safety and pharmacokinetics of atrasentan in patients with refractory malignances. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 13. pp. 4406-4411.
    @article{794b4ae854894f0c95a21b4e1611f5e1,
    title = "Dose-ranging study of the safety and pharmacokinetics of atrasentan in patients with refractory malignances",
    abstract = "Purpose: Atrasentan is an orally bioavailable selective antagonist of the endothelin receptor ETA. 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.",
    author = "Christopher Ryan and Vogelzang, {Nicholas J.} and Vokes, {Everett E.} and Kindler, {Hedy L.} and Undevia, {Samir D.} and Rod Humerickhouse and Andr{\'e}, {Amy K.} and Qiang Wang and Carr, {Robert A.} and Ratain, {Mark J.}",
    year = "2004",
    month = "7",
    day = "1",
    doi = "10.1158/1078-0432.CCR-04-0083",
    language = "English (US)",
    volume = "10",
    pages = "4406--4411",
    journal = "Clinical Cancer Research",
    issn = "1078-0432",
    publisher = "American Association for Cancer Research Inc.",
    number = "13",

    }

    TY - JOUR

    T1 - Dose-ranging study of the safety and pharmacokinetics of atrasentan in patients with refractory malignances

    AU - Ryan, Christopher

    AU - Vogelzang, Nicholas J.

    AU - Vokes, Everett E.

    AU - Kindler, Hedy L.

    AU - Undevia, Samir D.

    AU - Humerickhouse, Rod

    AU - André, Amy K.

    AU - Wang, Qiang

    AU - Carr, Robert A.

    AU - Ratain, Mark J.

    PY - 2004/7/1

    Y1 - 2004/7/1

    N2 - Purpose: Atrasentan is an orally bioavailable selective antagonist of the endothelin receptor ETA. 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.

    AB - Purpose: Atrasentan is an orally bioavailable selective antagonist of the endothelin receptor ETA. 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.

    UR - http://www.scopus.com/inward/record.url?scp=3042851918&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=3042851918&partnerID=8YFLogxK

    U2 - 10.1158/1078-0432.CCR-04-0083

    DO - 10.1158/1078-0432.CCR-04-0083

    M3 - Article

    C2 - 15240529

    AN - SCOPUS:3042851918

    VL - 10

    SP - 4406

    EP - 4411

    JO - Clinical Cancer Research

    JF - Clinical Cancer Research

    SN - 1078-0432

    IS - 13

    ER -