Pharmacokinetics of oxaliplatin in patients with normal versus impaired renal function

Massari, Claire; Brienza, S.; Rotarski, M.; Gastiaburu, J; Misset, Jean-Louis; Cupissol, Didier; Alafaci, Elisabetta; Dutertre-Catella, H.; Bastian, Gerard

doi:10.1007/s002800050024

Cited by 85 publications

(56 citation statements)

References 12 publications

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“…In patients with mild-to-moderate renal impairment, as defined by measured CrCL >20 mL/min, full doses of oxaliplatin at 130 mg/m 2 were well tolerated with no increase in drug-related toxicity (8). Despite this clinical tolerability, the overall clearance of unbound platinum from plasma ultrafiltrates was markedly reduced in patients with renal failure, an observation noted in prior pharmacokinetic studies of oxaliplatin (7). Overall, the clearance of unbound platinum from plasma ultrafiltrates and the total urinary platinum excreted over 24 h both strongly correlated with measured CrCL (Fig.…”

Section: Discussionmentioning

confidence: 76%

“…Furthermore, in the only previously published study of oxaliplatin in renal dysfunction, 10 patients with an estimated CrCL <60 mL/min (median CrCL, 42 mL/min; range, 27-57 mL/min) were compared with 13 control patients with an estimated CrCL >60 mL/min (median CrCL, 70.5 mL/min; range, 63-136 mL/min; ref. 7). Following a single dose of oxaliplatin at 130 mg/m 2 , the renally impaired patients had a lower systemic clearance of unbound platinum compared with controls (14.23 F 6.04 versus 25.70 F 8.53 L/h, respectively; P = 0.005).…”

Section: Discussionmentioning

confidence: 99%

“…Within the first 48 h after drug administration, over 50% of the administered platinum is excreted into the urine, consistent with the kidneys being a major route of platinum elimination (4). After repeated dosing, oxaliplatin can accumulate in erythrocytes; however, this intracellular binding within RBC is thought to be irreversible (6,7).…”

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confidence: 99%

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

Takimoto

Graham

Lockwood

et al. 2007

Clinical Cancer Research

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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.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

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

Takimoto

Graham

Lockwood

et al. 2007

Clinical Cancer Research

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“…Moreover, our population pharmacokinetic analysis identified significant covariates associated with PUF platinum similar to those identified in analogous adult studies, including BSA, weight, age, sex, and renal function quantified by serum creatinine or calculated creatinine clearance. [41][42][43][44] These findings suggest that a patient's weight and renal function may be important considerations for dosing oxaliplatin in pediatric patients, and that a dosage individualization nomogram incorporating such covariates could be developed.…”

Section: Discussionmentioning

confidence: 99%

Phase II study of oxaliplatin in children with recurrent or refractory medulloblastoma, supratentorial primitive neuroectodermal tumors, and atypical teratoid rhabdoid tumors

Fouladi

Blaney

Poussaint

et al. 2006

Cancer

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BACKGROUND.An open‐label Phase II study of oxaliplatin was conducted to evaluate its safety and efficacy in children with recurrent or refractory medulloblastoma (MB), supratentorial primitive neuroectodermal tumors (SPNET), and atypical teratoid rhabdoid tumor (ATRT).METHODS.Patients were stratified as follows: stratum IA, first recurrence MB with measurable disease; IB, recurrent MB with only cerebral spinal fluid (CSF) positivity or linear leptomeningeal disease (LLD); IC, MB ≥second recurrence; stratum II, recurrent SPNET; stratum III, recurrent ATRT. Patients received oxaliplatin, 130 mg/m2 intravenously over 2 hours every 3 weeks. The primary objective was to estimate the sustained response rate in stratum 1A. Plasma ultrafiltrate platinum pharmacokinetics were evaluated.RESULTS.A total of 43 patients with a median age of 8.5 years (range, 0.6–18.9 years) were enrolled. In stratum 1A, 2 of 15 had partial responses (PRs, 1 sustained PR). No responses were observed in other strata. The most frequent Grade 3 and 4 toxicities included thrombocytopenia (25.6%), neutropenia (16.3%), leukopenia (12%), increase in serum alanine transaminase (ALT) (7%), vomiting (4.7%), and sensory neuropathy (4.7%). No severe ototoxicity or nephrotoxicity was reported. Plasma ultrafiltrate platinum pharmacokinetic parameters were similar to adults, with a median clearance of 12.2 L/hr (range, 4.4–30 L/hr) and median area under the curve (AUC0‐∞) of 9.4 μg/mL/hr (range, 6.2–13.9 μg/mL/hr).CONCLUSIONS.Oxaliplatin was well tolerated in children but has limited activity in children with recurrent CNS embryonal tumors previously treated with platinum compounds. Cancer 2006. © 2006 American Cancer Society.

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“…Several phase I dose-escalation studies in PC patients treated with CRS have characterized the HIO pharmacokinetics in both the peritoneum and plasma (14)(15)(16). Following 460 mg/m 2 dosing, the maximum HIO concentration (C max ) in the peritoneum (330 mg/L) (16) was 130-fold higher than plasma C max (2.59 mg/L) after intravenous (IV) administration of 130 mg/m 2 (17), indicating that, relative to IV dosing, HIO administration after CRS delivers a higher peritoneal oxaliplatin exposure with a minimum access to the systemic circulation, that limits the hematological toxicities, such as thrombocytopenia and neutropenia, which are the oxaliplatin dose-limiting toxicities after IV dosing (18). In a previous pharmacokinetic and pharmacodynamic (PK/PD) analysis, we characterized the immediate neutrophilia response induced by CRS and the HIO-induced myelosuppression (19).…”

Section: Introductionmentioning

confidence: 99%

Platelet Dynamics in Peritoneal Carcinomatosis Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Oxaliplatin

Pérez-Ruixo

Valenzuela

Peris

et al. 2015

AAPS J

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Abstract. The aim of the study was to characterize the platelet count (PLT) dynamics in peritoneal carcinomatosis patients treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal oxaliplatin (HIO). Data from patients treated with CRS alone (N=18) or CRS and HIO (N=62) were used to estimate the baseline platelet count (PLT 0 ), rate constants for platelet maturation (k tr ) and platelet random destruction (k s ), feedback on progenitor cell proliferation (γ), and the drug-specific model parameters (α, β). Plasma oxaliplatin concentrations, C p , reduced the proliferation rate of progenitor cells (k prol ) according to a power function α×C p β . The surgery effect on k prol and k s was explored. The typical values (between subject variability) of the PLT 0 , k tr , k s , γ, α, and β were estimated to be 237×10 9 cells/L (32.9%), 7.09×10 −3 h −1 (47.1%), 8.86×10 −3 h −1 (80.0%), 0.621, 0.88 L/mg (56.9%), and 2.63. Surgery induced a maximal 2.09-fold increase in k prol that was attenuated with a half-life of 8.42 days. Splenectomy decreased k s by 47.5%. Age, sex, body surface area, sex, total proteins, and HIO carrier solution did not impact the model parameters. The model developed suggests that, following CRS and HIO, thrombocytopenia and thrombocytosis were reversible and short-lasting; the severity of the thrombocytopenia and thrombocytosis was inversely correlated, with splenectomized patients having thrombocytopenia of lower severity and thrombocytosis of higher severity; and the HIO dose and treatment duration determine the severity and duration of the thrombocytopenia. Higher HIO dose or longer treatment duration could be used without substantially increasing the risk of major hematological toxicity.

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Pharmacokinetics of oxaliplatin in patients with normal versus impaired renal function

Cited by 85 publications

References 12 publications

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

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

Phase II study of oxaliplatin in children with recurrent or refractory medulloblastoma, supratentorial primitive neuroectodermal tumors, and atypical teratoid rhabdoid tumors

Platelet Dynamics in Peritoneal Carcinomatosis Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Oxaliplatin

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