Toxicity of High‐Dose Carboplatin: Ultrafiltered and Not Total Plasma Pharmacokinetics Is of Clinical Relevance

Kloft, Charlotte; Siegert, W.; Beyer, Jörg; Jaehde, Ulrich

doi:10.1177/009127002401102704

Cited by 15 publications

(8 citation statements)

References 24 publications

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“…Carboplatin is mainly eliminated by the kidneys, as indicated by the fact that about 65% of the administered dose is excreted into the urine within the first 24 h after administration [1]. A small fraction of the drug binds irreversibly to plasma proteins and the free, ultrafilterable platinum fraction is considered pharmacologically active [2]. Carboplatin clearance appears to be directly related to the glomerular filtration rate (GFR) and several dosing formulae have been suggested to calculate an a priori carboplatin dose based upon renal function.…”

Section: Introductionmentioning

confidence: 99%

Carboplatin dosing in overweight and obese patients with normal renal function, does weight matter?

Ekhart

Rodenhuis

Schellens

et al. 2008

Cancer Chemother Pharmacol

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Purpose The purpose of this study was to determine the potential utility of alternative weight descriptors in the Cockcroft-Gault equation to more accurately predict carboplatin clearance in underweight, normal weight, overweight and obese patients.Methods Clearance values obtained from individual fits using NONMEM were compared to predicted carboplatin clearances calculated using the modified Calvert formula in which creatinine clearance was calculated with the Cockcroft-Gault equation using diverse weight descriptors. Results This study indicated that lean body mass was the best weight descriptor in underweight and normal weight patients, while adjusted ideal body weight was the best weight descriptor in overweight and obese patients. However, a flat dose based on the population carboplatin clearance performed better in all weight categories than the use of the Cockcroft-Gault equation with diverse weight descriptors. Conclusion These results suggest that in overweight and obese patients, with a normal renal function, a flat carboplatin dose should be administered, based on the population carboplatin clearance (8.38 l/h = 140 mL/min). Thus, in case an AUC of 5 mg min/mL is desired, the appropriate dose for carboplatin would be 5 9 140 = 700 mg.

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Section: Introductionmentioning

confidence: 99%

Carboplatin dosing in overweight and obese patients with normal renal function, does weight matter?

Ekhart

Rodenhuis

Schellens

et al. 2008

Cancer Chemother Pharmacol

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“…The remainder of the drug binds irreversibly to proteins and tissue (1,2). The free, ultrafilterable carboplatin fraction is considered pharmacologically active (3).…”

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confidence: 99%

Flat Dosing of Carboplatin Is Justified in Adult Patients with Normal Renal Function

Ekhart

Jonge

Huitema

et al. 2006

Clinical Cancer Research

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Purpose: The Calvert formula is a widely applied algorithm for the a priori dosing of carboplatin based on patients glomerular filtration rate (GFR) as accurately measured using the 51 Cr-EDTA clearance. Substitution of the GFR in this formula by an estimate of creatinine clearance or GFR as calculated by formulae using serum creatinine (S CR ; Cockcroft-Gault, Jelliffe, and Wright) is, however, routine clinical practice in many hospitals. The goal of this study was to validate this practice retrospectively in a large heterogeneous adult patient population. Experimental Design: Concentration-time data of ultrafilterable platinum of 178 patients (280 courses, 3,119 samples) with different types of cancer receiving carboplatin-based chemotherapy in conventional and high doses were available. Data were described with a linear two-compartment population pharmacokinetic model. Relations between S CR -based formulae for estimating renal function and carboplatin clearance were investigated.Results: None of the tested S CR -based estimates of renal function were relevantly related to the pharmacokinetic variables of carboplatin. Neither S CR (median, 51; range, 18-124 Amol/L) nor the estimated GFR using the three different formulae was related to carboplatin clearance. Conclusions: Our data do not support the application of modifications of the Calvert formula by estimating GFR from S CR in the a priori dosing of carboplatin in patients with relatively normal renal function (creatinine clearance, >50 mL/min). For targeted carboplatin exposures, the original Calvert formula, measuring GFR using the 51 Cr-EDTA clearance, remains the method of choice. Alternatively, in patients with normal renal function, a flat dose based on the mean population carboplatin clearance should be administered.

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“…In comparison, estimated carboplatin exposures of 65 -213% of the target AUC values would have been attained without dose adjustment, with 32% of patients (9/28) receiving carboplatin AUC values above 25 mg ml À1 .min. The likelihood of dose adjustment was not influenced by the method of showing correlations between carboplatin AUC and drug toxicity following high-dose chemotherapy, it is likely that patients with an AUC greater than 25 mg ml À1 .min would have experienced serious side effects if therapeutic monitoring had not been implemented (Huitema et al, 2002;Kloft et al, 2002). Indeed, significantly increased frequencies of nephrotoxicity, ototoxicity and peripheral nervous system toxicities were observed in patients with AUC above 24.2 mg ml À1 .min in a recently published study in patients with germ-cell cancer (Kloft et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Adaptive dosing and platinum–DNA adduct formation in children receiving high-dose carboplatin for the treatment of solid tumours

et al. 2007

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A pharmacokinetic -pharmacodynamic study was carried out to investigate the feasibility and potential importance of therapeutic monitoring following high-dose carboplatin treatment in children. High-dose carboplatin was administered over 3 or 5 days, with the initial dose based on renal function, to achieve target area under the plasma concentration -time curve (AUC) values of 21 or 20 mg ml À1 .min, respectively. Dose adjustment was carried out based on observed individual daily AUC values, to obtain the defined target exposures. Platinum -DNA adduct levels were determined in peripheral blood leucocytes and toxicity data were obtained. Twenty-eight children were studied. Based on observed AUC values, carboplatin dose adjustment was performed in 75% (21 out of 28) patients. Therapeutic monitoring resulted in the achievement of carboplatin exposures within 80 -126% of target AUC values, as compared to estimated exposures of 65 -213% of target values without dose adjustment. The carboplatin AUC predicted with no dose modification was positively correlated with pretreatment glomerular filtration rate (GFR) values. Higher GFR values were observed in those patients who would have experienced AUC values 425% above the target AUC than those patients attaining AUC values 425% below the target AUC, following renal function-based dosing. Platinum -DNA adduct levels correlated with observed AUC values on day 1 of carboplatin and increased over a 5-day course of treatment. Real-time monitoring of carboplatin pharmacokinetics with adaptive dosing is both feasible and necessary for the attainment of consistent AUC values in children receiving high-dose carboplatin treatment. Pharmacodynamic data suggest a strong correlation between carboplatin pharmacokinetics and the drug -target interaction.

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Toxicity of High‐Dose Carboplatin: Ultrafiltered and Not Total Plasma Pharmacokinetics Is of Clinical Relevance

Cited by 15 publications

References 24 publications

Carboplatin dosing in overweight and obese patients with normal renal function, does weight matter?

Carboplatin dosing in overweight and obese patients with normal renal function, does weight matter?

Flat Dosing of Carboplatin Is Justified in Adult Patients with Normal Renal Function

Adaptive dosing and platinum–DNA adduct formation in children receiving high-dose carboplatin for the treatment of solid tumours

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