Phase I study to assess the pharmacokinetics and the effect on cardiac repolarization of amrubicin and amrubicinol in patients with advanced solid tumors

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• 作者：Nianhang Chen (1)
  Sant P. Chawla (2)
  Elena Gabriela Chiorean (3)
  William L. Read (4)
  Mayer Gorbaty (5)
  Alain C. Mita (6)
  Lotus Yung (1)
  Peter Bryan (1)
  Richard McNally (1)
  Markus F. Renschler (1)
  Sunil Sharma (7)
  
• 关键词：Pharmacokinetics ; Cardiac effects ; Anthracyclines ; Amrubicin ; Advanced solid tumors
• 刊名：Cancer Chemotherapy and Pharmacology
• 出版年：2013
• 出版时间：April 2013
• 年：2013
• 卷：71
• 期：4
• 页码：1083-1094
• 全文大小：600KB
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• 作者单位：Nianhang Chen (1)
  Sant P. Chawla (2)
  Elena Gabriela Chiorean (3)
  William L. Read (4)
  Mayer Gorbaty (5)
  Alain C. Mita (6)
  Lotus Yung (1)
  Peter Bryan (1)
  Richard McNally (1)
  Markus F. Renschler (1)
  Sunil Sharma (7)
  
  1. Celgene Corporation, 86 Morris Avenue I-212C, Summit, NJ, 07901, USA
  2. Sarcoma Oncology Center, 2811 Wilshire Blvd, Suite 414, Santa Monica, CA, 90403, USA
  3. Indiana University Melvin and Bren Simon Cancer Center, 535 Barnhill Drive, RT 473, Indianapolis, IN, 46202, USA
  4. UC San Diego, Moores Cancer Center, 3855 Health Sciences Drive, La Jolla, CA, 92093, USA
  5. Sinai Hospital of Baltimore, 5401 Old Court Road, Randallstown, MD, 21133, USA
  6. University of Texas Health Science Center at San Antonio, 703 Floyd Curl Drive, San Antonio, TX, 78229, USA
  7. Huntsman Cancer Institute, 1950 Circle of Hope, Salt Lake City, UT, 84112, USA
  
• ISSN：1432-0843

文摘

Purpose To evaluate the pharmacokinetics and cardiac repolarization effect (measured by QT/QTc interval) of amrubicin and its active metabolite amrubicinol in non-Japanese patients with advanced solid tumors. Methods Patients received amrubicin 40?mg/m2/day as a 5-min infusion on days 1- of a 21-day cycle. During cycle 1, serial blood and plasma samples were collected on days 1- and time-matched triplicate electrocardiograms on the “off-drug-visit (1-?days prior to start of treatment) and days 1-. Results Twenty-four patients were treated. Amrubicinol reached peak concentration 2-?h after amrubicin administration and had a terminal half-life of 53?h. Distribution of amrubicinol into erythrocytes was fivefold greater than into plasma. The molar ratio of amrubicinol to amrubicin in blood was 0.67 on day 3. The presence of an NQO1 polymorphism did not alter drug exposure. The upper bound of the one-sided 95?% confidence interval for the time-matched, baseline-adjusted change from the off-drug day in QTcI (individual correction) was <10?ms at all times and was only >10?ms (10.20?ms) at a single time point for QTcF (Fridericia correction). No relationship was observed between blood amrubicin or amrubicinol concentrations and QTcF changes. All QTcF measurements were <480?ms, and none increased by >60?ms from baseline. Conclusions Data suggest that amrubicinol is an important active metabolite in humans and that both compounds were not associated with clinically relevant QTc interval prolongation at the dose regimen studied.