Oxaliplatin pharmacokinetics and pharmacodynamics in adult cancer patients with impaired renal function

Chris H. Takimoto, Martin A. Graham, Graham Lockwood, Chee M. Ng, Andrew Goetz, Dennis Greenslade, Scot C. Remick, Sunil Sharma, Sridhar Mani, Ramesh K. Ramanathan, Timothy W. Synold, James H. Doroshow, Anne Hamilton, Daniel L. Mulkerin, Percy Ivy, Merrill J. Egorin, Jean L. Grem

Research output: Contribution to journalArticle

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Abstract

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, 40-59mL/min), C (moderate, CrCL, 20-39mL/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 platinumin 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 (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 68.1h in groups A, B, C, and D, respectively (P = 0.002). At a dose level of 130 mg/m 2, 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 Ag μh/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.

Original languageEnglish (US)
Pages (from-to)4832-4839
Number of pages8
JournalClinical Cancer Research
Volume13
Issue number16
DOIs
StatePublished - Aug 15 2007

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oxaliplatin
Creatinine
Pharmacokinetics
Kidney
Neoplasms
Platinum
Drug-Related Side Effects and Adverse Reactions

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Oxaliplatin pharmacokinetics and pharmacodynamics in adult cancer patients with impaired renal function. / Takimoto, Chris H.; Graham, Martin A.; Lockwood, Graham; Ng, Chee M.; Goetz, Andrew; Greenslade, Dennis; Remick, Scot C.; Sharma, Sunil; Mani, Sridhar; Ramanathan, Ramesh K.; Synold, Timothy W.; Doroshow, James H.; Hamilton, Anne; Mulkerin, Daniel L.; Ivy, Percy; Egorin, Merrill J.; Grem, Jean L.

In: Clinical Cancer Research, Vol. 13, No. 16, 15.08.2007, p. 4832-4839.

Research output: Contribution to journalArticle

Takimoto, CH, Graham, MA, Lockwood, G, Ng, CM, Goetz, A, Greenslade, D, Remick, SC, Sharma, S, Mani, S, Ramanathan, RK, Synold, TW, Doroshow, JH, Hamilton, A, Mulkerin, DL, Ivy, P, Egorin, MJ & Grem, JL 2007, 'Oxaliplatin pharmacokinetics and pharmacodynamics in adult cancer patients with impaired renal function', Clinical Cancer Research, vol. 13, no. 16, pp. 4832-4839. https://doi.org/10.1158/1078-0432.CCR-07-0475
Takimoto, Chris H. ; Graham, Martin A. ; Lockwood, Graham ; Ng, Chee M. ; Goetz, Andrew ; Greenslade, Dennis ; Remick, Scot C. ; Sharma, Sunil ; Mani, Sridhar ; Ramanathan, Ramesh K. ; Synold, Timothy W. ; Doroshow, James H. ; Hamilton, Anne ; Mulkerin, Daniel L. ; Ivy, Percy ; Egorin, Merrill J. ; Grem, Jean L. / Oxaliplatin pharmacokinetics and pharmacodynamics in adult cancer patients with impaired renal function. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 16. pp. 4832-4839.
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abstract = "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, 40-59mL/min), C (moderate, CrCL, 20-39mL/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 platinumin 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 (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 68.1h in groups A, B, C, and D, respectively (P = 0.002). At a dose level of 130 mg/m 2, 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 Ag μh/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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T1 - Oxaliplatin pharmacokinetics and pharmacodynamics in adult cancer patients with impaired renal function

AU - Takimoto, Chris H.

AU - Graham, Martin A.

AU - Lockwood, Graham

AU - Ng, Chee M.

AU - Goetz, Andrew

AU - Greenslade, Dennis

AU - Remick, Scot C.

AU - Sharma, Sunil

AU - Mani, Sridhar

AU - Ramanathan, Ramesh K.

AU - Synold, Timothy W.

AU - Doroshow, James H.

AU - Hamilton, Anne

AU - Mulkerin, Daniel L.

AU - Ivy, Percy

AU - Egorin, Merrill J.

AU - Grem, Jean L.

PY - 2007/8/15

Y1 - 2007/8/15

N2 - 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, 40-59mL/min), C (moderate, CrCL, 20-39mL/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 platinumin 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 (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 68.1h in groups A, B, C, and D, respectively (P = 0.002). At a dose level of 130 mg/m 2, 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 Ag μh/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.

AB - 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, 40-59mL/min), C (moderate, CrCL, 20-39mL/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 platinumin 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 (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 68.1h in groups A, B, C, and D, respectively (P = 0.002). At a dose level of 130 mg/m 2, 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 Ag μh/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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