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Oxaliplatin Pharmacokinetics and Pharmacodynamics in Adult Cancer Patients with Impaired Renal Function

Authors' Affiliations: ¹ Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas; ² Medicine Branch at Navy, National Naval Medical Center, National Cancer Institute; ³ Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Centers, National Cancer Institute, Bethesda, Maryland; ⁴ Department of Global Metabolism and Pharmacokinetics, Sanofi-Aventis, Malvern; Pennsylvania; ⁵ Case Western Reserve University, Cleveland, Ohio; ⁶ Memorial Sloan-Kettering Cancer Center; ⁷ New York University, New York, New York; ⁸ Montifiore Hospital, Albert Einstein College of Medicine, Bronx, New York; ⁹ Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania; ¹⁰ City of Hope, Duarte, California; and ¹¹ University of Wisconsin, Madison, Wisconsin

Requests for reprints: Chris H. Takimoto, Institute for Drug Development, Cancer Therapy and Research Center, 14960 Omicron Drive, San Antonio, TX 78245-3217. Phone: 210-450-3800; Fax: 210-677-0058; E-mail: ctakimot{at}idd.org.

Purpose: To characterize the pharmacokinetics and pharmacodynamics of oxaliplatin in cancer patients with impaired renal function.

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.

Results: Plasma ultrafiltrate platinum clearance strongly correlated with CrCL (r² = 0.712). Platinum elimination from plasma was triphasic, and maximal platinum concentrations (C_max) were consistent across all renal impairment groups. However, only the ß-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).

Conclusions: Oxaliplatin pharmacokinetics are altered in patients with renal impairment, but a corresponding increase in oxaliplatin-related toxicities is not observed.

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