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

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, z60 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/m 2 oxaliplatin infused over 2 h every 3 weeks. Pharmacokinetic monitoring of platinum in plasma, plasma ultrafiltrates, and urine was done during cycles 1and 2. Results: Plasma ultrafiltrate platinum clearance strongly correlated with CrCL (r 2 = 0.712). Platinum elimination from plasma was triphasic, and maximal platinum concentrations (C max ) were consistent across all renal impairment groups. However, only the h-half-life was significantly prolonged by renal impairment, with values of 14.0 F 4.3, 20.3 F 17.7, 29.2 F 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 F 5.03, 39.7 F 11.5, and 44.6 F 14.6 AgÁh/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.

Pharmacokinetics of Oxaliplatin in a Hemodialyzed Patient: Chemotherapy Dose Adjustment and Timing of Dialysis

“…1 Oxaliplatin is mainly eliminated through the kidneys and its pharmacokinetic profile is altered in patients with renal insufficiency, with a strong correlation between glomerular filtration rate (GFR) and drug clearance and also between GFR and oxaliplatin area under the curve (AUC) in patients with different degrees of impaired renal function. 2 However, only limited data are available on oxaliplatin pharmacokinetics, efficacy, and safety in cancer patients who are dependent on hemodialysis. [3][4][5] Therefore, it is still unclear if oxaliplatin can be safely prescribed and if a dose reduction is necessary in hemodialysis patients.…”

Oxaliplatin: A Review in the Era of Molecularly Targeted Therapy

“…In a study examining the pharmacokinetics of oxaliplatin in the setting of renal function impairment 39 , 34 patients were stratified according to creatinine clearance and received oxaliplatin at various dose levels.…”

Pharmacokinetics of miriplatin in experimental dog models of hepatic or renal impairment

“…Renal dysfunction may lead to increase of plasma-free platinum concentration as is well documented in cases of other platinum complexes in man (Massari et al 2000;Takimoto et al 2007;Ishibashi et al2003). However, retrospective analysis using the information obtained in the clinical trials of miriplatin is difficult because the patients with renal dysfunction were not recruited.…”