Oxaliplatin Pharmacokinetics and Pharmacodynamics in Adult Cancer Patients with Impaired Renal Function
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- Chris H. Takimoto
- 1Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas;
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- Martin A. Graham
- 4Department of Global Metabolism and Pharmacokinetics, Sanofi-Aventis, Malvern; Pennsylvania;
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- Graham Lockwood
- 4Department of Global Metabolism and Pharmacokinetics, Sanofi-Aventis, Malvern; Pennsylvania;
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- Chee M. Ng
- 1Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas;
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- Andrew Goetz
- 1Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas;
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- Dennis Greenslade
- 4Department of Global Metabolism and Pharmacokinetics, Sanofi-Aventis, Malvern; Pennsylvania;
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- Scot C. Remick
- 5Case Western Reserve University, Cleveland, Ohio;
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- Sunil Sharma
- 6Memorial Sloan-Kettering Cancer Center;
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- Sridhar Mani
- 8Montifiore Hospital, Albert Einstein College of Medicine, Bronx, New York;
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- Ramesh K. Ramanathan
- 9Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania;
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- Timothy W. Synold
- 10City of Hope, Duarte, California; and
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- James H. Doroshow
- 10City of Hope, Duarte, California; and
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- Anne Hamilton
- 7New York University, New York, New York;
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- Daniel L. Mulkerin
- 11University of Wisconsin, Madison, Wisconsin
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- Percy Ivy
- 3Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Centers, National Cancer Institute, Bethesda, Maryland;
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- Merrill J. Egorin
- 8Montifiore Hospital, Albert Einstein College of Medicine, Bronx, New York;
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- Jean L. Grem
- 2Medicine Branch at Navy, National Naval Medical Center, National Cancer Institute;
説明
<jats:title>Abstract</jats:title> <jats:p>Purpose: To characterize the pharmacokinetics and pharmacodynamics of oxaliplatin in cancer patients with impaired renal function.</jats:p> <jats:p>Experimental Design: Thirty-four patients were stratified by 24-h urinary creatinine clearance (CrCL) into four renal dysfunction groups: group A (control, CrCL, ≥60 mL/min), B (mild, CrCL, 40-59 mL/min), C (moderate, CrCL, 20-39 mL/min), and D (severe, CrCL, <20 mL/min). Patients were treated with 60 to 130 mg/m2 oxaliplatin infused over 2 h every 3 weeks. Pharmacokinetic monitoring of platinum in plasma, plasma ultrafiltrates, and urine was done during cycles 1 and 2.</jats:p> <jats:p>Results: Plasma ultrafiltrate platinum clearance strongly correlated with CrCL (r2 = 0.712). Platinum elimination from plasma was triphasic, and maximal platinum concentrations (Cmax) were consistent across all renal impairment groups. However, only the β-half-life was significantly prolonged by renal impairment, with values of 14.0 ± 4.3, 20.3 ± 17.7, 29.2 ± 29.6, and 68.1 h in groups A, B, C, and D, respectively (P = 0.002). At a dose level of 130 mg/m2, the area under the concentration time curve increased in with the degree of renal impairment, with values of 16.4 ± 5.03, 39.7 ± 11.5, and 44.6 ± 14.6 μg·h/mL, in groups A, B, and C, respectively. However, there was no increase in pharmacodynamic drug-related toxicities. Estimated CrCL using the Cockcroft-Gault method approximated the measured 24-h urinary CrCL (mean prediction error, −5.0 mL/min).</jats:p> <jats:p>Conclusions: Oxaliplatin pharmacokinetics are altered in patients with renal impairment, but a corresponding increase in oxaliplatin-related toxicities is not observed.</jats:p>
収録刊行物
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- Clinical Cancer Research
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Clinical Cancer Research 13 (16), 4832-4839, 2007-08-15
American Association for Cancer Research (AACR)