2. Furthermore, accuracy of carboplatin exposure in the present study compares surprisingly well to published data comparing eGFR equations with gold standard GFR measurements as reported in pediatric oncology studies [15,49]. Filler G., Huang S.-H.S., Yasin A. The main outcome parameters of this study were predicted carboplatin AUC compared to measured carboplatin AUC, i.e., carboplatin exposure. A weighted mean of 40% eGFRcreat and 60% eGFRcys has been suggested to be optimal for patients with malignancy [43]. Therefore, the creatinine clearance is 0.67mL/ min. Therefore, it is assumed there is limited additional value of adding urea in an equation for this specific population. This carboplatin dosing calculator uses the Calvert method to calculate the total carboplatin dose needed to achieve a given AUC (area under the free carboplatin plasma concentration versus time curve) while taking into account renal function. Bjrk J., Nyman U., Berg U., Delanaye P., Dubourg L., Goffin K., Grubb A., Hansson M., Littmann K., sling-Monemi K., et al. We acknowledge a number of limitations in our study. Federal government websites often end in .gov or .mil. Different studies employ different formulas or approaches to carboplatin dosing. The additional proximal tubule secretion falsely elevates the CrCl estimate of GFR. and Creatinine clearance (CrCl) values range from 1.24-2.24 mL/second. Consequently, some patients undergo a higher systemic exposure, expressed as the area under the plasma concentration/time curve (AUC), than others when dosages of carboplatin are given on the basis of the body surface area. 2022 Jul 19;24(3):583. doi: 10.3892/etm.2022.11520. found a relatively stable extra-renal clearance of carboplatin equivalent to about 25 mL/min in adults [4]. In Figure 2, %PE in anthropometric dosing appears to be directly related to body weight, leading to significant underdosing in the youngest children, while %PE is mostly positive in studies above 10 kg. Improved equations estimating GFR in children with chronic kidney disease using an immunonephelometric determination of cystatin C. Brandt J.R., Wong C., Jones D.R., Qualls C., McAfee N., Brewer E., Watkins S.L. the clearance is typically calculated using the cockcroft and gault (C-G) formula. After administration of carboplatin, the central venous line was flushed with 0.9% NaCl for 15 min and all connectors were changed to prevent contamination during blood sampling from the indwelling line. Common estimation equations for creatinine clearance or gfr. Percentage prediction error (%PE) of the different dosing methods. These time points were determined using WinPOPT version 1.1 (Otago, New Zealand). MR Because of the potential safety issue with carbopla- tin dosing, all laboratories in the United States are now required to use a new standardized method to measure serum creatinine called isotope dilution mass spectrom- etry (IDMS). Clearance is the rate at which an indicator substance is removed from the plasma and specifies a volume from which all of a substance is removed per unit time: for a substance X, clearance = urinary concentration of x (Ux) multiplied by the urine flow rate (V)/plasma concentration of X (Px). Kidney Disease: Improving Global Outcomes (KDIGO) CKD Workgroup. 1998;42(4):307-12. doi: 10.1007/s002800050822. The patient characteristics are summarized in Table 2. In unselected populations, creatinine-based eGFR equations perform comparably to cystatin C-based equations and the arithmetic mean of the two yields the best results [28,33]. MR The main challenge in accurate carboplatin dos- ing is determining how to estimate renal function. These different eGFR equations might be used instead of a gold standard GFR measurement in the widely used Newell equation to calculate carboplatin clearance [6]. H&O How can we overcome the challenges faced with carboplatin dosing? Licensee MDPI, Basel, Switzerland. The https:// ensures that you are connecting to the Presented at the International Oncology Conference in Kathmandu, Nepal 2014. Carboplatin clearance (ml/min) = GFR + 25. This is due to the fact that carboplatin is associated with less renal and neurological toxicity than cisplatin [3]. Adaptive dosing and platinumDNA adduct formation in children receiving high-dose carboplatin for the treatment of solid tumours. was 2.8 months of age [30] and 1 month in Millisors cohort [15]. Creatinine clearance (Ccr), calculated using the Cockroft-Gault, Jelliffe, Modified-Jelliffe or Wright formulae . However, gold standard GFR measurements using inulin, 51Cr-EDTA, 99Tc-DTPA, 125I-iothalamate or iohexol [14,36,37] are invasive, costly and cumbersome, thereby precluding widespread use in clinical practice. 2. In Figure 1, %PE of the different eGFR equations and anthropometric dosing in the individual studies is shown as waterfall plots. Substitution of the GFR in this formula by an estimate of creatinine clearance or GFR as calculated by formulae using serum creatinine (SCR; Cockcroft-Gault, Jelliffe, and Wright) is . 2012 Jul;32(7):604-12. doi: 10.1002/j.1875-9114.2012.01098.x. Carboplatin dosing for adult Japanese patients. In children, a number of eGFR equations have been developed using either creatinine and/or cystatin C [ 20 ]. The https:// ensures that you are connecting to the Results This research was funded by Fonds Nuts Ohra, grant number 1302-005. Measuring serum creatinine Historically - colorimetric 'Jaffe' method used. At various time points, venous blood (2 mL) was collected into tubes containing lithium heparin anticoagulant. This site needs JavaScript to work properly. Cockcroft-Gault CrCl = [ (140-age) x (Wt in kg) x (0.85 if female)] / (72 x Cr) Note: The original Cockroft-Gault Equation listed here provides an estimate of creatinine clearance, but this original formula is not adjusted for body surface area and may be less accurate in obese patients. CrCl mL/minute (males) = (140 - age) x weight (kg) / 0.814 x serum creatinine (micromol/L), for females, multiply result by 0.85 Practice points Formulas References History Disclaimer: The Cancer Institute NSW does not warrant or represent that the Information is free from errors or omission. Results: and E.d.B. It would therefore be useful to recalibrate the Newell equation in children using eGFR instead of measured GFR and also re-evaluate the extra-renal clearance of carboplatin. Qualitative variables are displayed as numbers (%). Ekhart C, Rodenhuis S, Schellens JH, Beijnen JH, Huitema AD. Renal function-based carboplatin dosing using measured glomerular filtration rate (GFR) results in more consistent drug exposure than anthropometric dosing. Measuring GFR: A systematic review. In overweight and obese patients they were superior in reducing mean overdose from 24% to roughly 15% (predicted normal weight, CKD-EPI) and 10% (adjusted body weight) and from 25% to 9%, 8% and 4%, respectively. Marina N.M., Rodman J.H., Murry D.J., Shema S.J., Bowmans L.C., Jones D.P., Furman W., Meyer W.H., Pratt C.B. You multiply the result by 0.85 to get creatinine clearance for a woman. We were able to show that carboplatin dosing based on a marker of kidney function (cystatin C) resulted in more adequate dosing than dosing on body surface area or weight. P30 accuracy of carboplatin exposure prediction using FAScys and Schwartzcys was well above the 80% benchmark used for eGFR equations [33]. This can result in suboptimal treatment [40] since underestimation of creatinine will lead to an overestimation of GFR and overdosing of carboplatin with the potential of increased toxicity. Mosteller R.D. A large simulation study compared eGFR by MDRD Study equation and estimated creatinine clearance (eCrCl) by the Cockcroft-Gault equation calculated from standardized creatinine values to each other and to measured GFR for the purpose of drug dosing. 1. Nephron 1976;16 (1):31-41. Although anthropometric dosing performed comparably to many of the eGFR equations overall, we observed a weight-dependent change in bias leading to underdosing in the smallest patients. ), 8Department of Biochemistry, Medical University of Gdansk, 80-210 Gdansk, Poland, 9Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn-Medical Center, 53127 Bonn, Germany; [email protected], 10Department of Epidemiology and Biostatistics, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands; [email protected]. Epub 2012 May 10. 1 Original Cockcroft-Gault equation: CrCl = (140age)(weight in kg) (0.85, if female) 72*SCr Careers. 2001 May;47(5):373-9. doi: 10.1007/s002800000260. Gynecol Oncol Res Pract. In this study, the CKD-EPI equation was found to have better performance than the MDRD equation; however, further research is needed to determine if widespread use of CKD-EPI is appropriate. The delivered area under the curve (dAUC) was calculated [ (actual carboplatin dose at cycle 1 dose calculated with uncapped/unbanded eGFR) 6] and dichotomized at the median value. This carboplatin dosing calculator uses the Calvert method to calculate the total carboplatin dose needed to achieve a given AUC (area under the free carboplatin plasma concentration versus time curve) while taking into account renal function. To be eligible for study participation, patients had to be between 0 and 18 years old and scheduled to receive carboplatin for the treatment of retinoblastoma. A recent study, reported in the Clinical Journal of the American Society of Nephrology, compared the MDRD formula to a new chronic kidney disease epidemiology collaboration (CKD-EPI) equation, which was developed by using data from numerous studies. Its pharmacokinetics are therefore mainly determined by the patients renal function [4,5]. The Brandt equation had the highest positive bias of all creatinine-based equations. Calvert formula Carboplatin dose = AUC (GFR + 25). Measured carboplatin clearance obtained from these individual fits were compared with predicted carboplatin clearance using the Newell equation [6]: As most eGFR equations yield standardized GFR in mL/min/1.73 m2 GFR was converted to absolute GFR in mL/min before use in the Newell formula. Historically, this error was balanced by an error of almost equal magnitude in the measurement of the serum creatinine. All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Review Board of Amsterdam UMC, location VUmc (formerly known as VUmc) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. 1984 Feb;4(1):61-74 Rounding in the Calculator; Carboplatin Dosing Tips; ASCO on Dosing Chemo in Obesity: Equations and Conversions; Leucovorin Nomogram; Amputee Calculator Info; Vial Sizes and Concentrations ; writingoriginal draft preparation, M.E.v.d.V., E.d.B., A.B., G.L.K. Continuous variables are presented as median (interquartile range; IQR). Combining GFR estimates from cystatin C and creatininewhat is the optimal mix? In total, 13 children were included. Renal function was assessed before each course of carboplatin. Morrow A, Garland C, Yang F, De Luna M, Herrington JD. Epub 2008 Nov 7. The present study is the first external evaluation of carboplatin dosing using estimated rather than measured GFR in the pediatric Newell equation. This formula has proven to be, in both retrospective and prospective studies, a reliable tool to calculate the optimal dose of carboplatin Future studies should determine the value of the creatinine clearance as a measure for the GFR. Using cystatin C-based eGFR equations for carboplatin dosing in children leads to more accurate carboplatin-exposure in patients with normal renal function compared to anthropometric dosing. One of the most common types of toxicity is ototoxicity, which is particularly relevant in children with retinoblastoma, who may also suffer from impaired vision following treatment of their underlying illness [2]. Evaluation of formulas using the serum creatinine level to calculate the optimal dosage of carboplatin. GFR = glomerular filtration rate, CL cr = creatinine clearance, TBW . Epub 2018 Sep 15. In a study in adults, Ekhart et al. Methods: Leion F., Hegbrant J., den Bakker E., Jonsson M., Abrahamson M., Nyman U., Bjrk J., Lindstrm V., Larsson A., Bkenkamp A., et al. The predicted creatinine production rate in females is 85% of the calculated value because they have a smaller muscle mass per kilogram, and it is muscle mass that determines creatinine production. The .gov means its official. Accessibility official website and that any information you provide is encrypted 1992 Apr;3(4):291-6 In the majority of circumstances dose calculations for carboplatin are based solely on renal function. There is another formula for renal function that has been suggested to be more accuratethe modification of diet in renal disease (MDRD) formula. Delanaye P, Guerber F, Scheen A, Ellam T, Bouquegneau A, Guergour D, Mariat C, Pottel H. Clin Pharmacokinet. Carboplatin dosing. If kidney function is impaired, this will slow down the clearance of drugs. A retrospective analysis and review. We conducted a retrospective analysis applying the CKD-EPI formula and the alternate size descriptors adjusted body weight and predicted normal weight in the Cockcroft-Gault equation for calculating the carboplatin dose. Discrepancies between the Cockcroft-Gault and Chronic Kidney Disease Epidemiology (CKD-EPI) Equations: Implications for Refining Drug Dosage Adjustment Strategies. Carboplatin Dosing in Children Using Estimated Glomerular Filtration Rate: Equation Matters, predicted carboplatin clearance (mL/min) = eGFR (mL/min) + 0.36 body weight (kg), AUC (mg/mL.min) = dose (mg)/clearance (mL/min). The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Committee) of Amsterdam UMC location VUmc (formerly known as VU University Medical Center) (protocol code Farmacokinetiek van Carboplatine 2.0, date: 10-02-2011). This is more marked for the creatinine-based than the cystatin C-based eGFR equations and anthropometric dosing. Veal G.J., Errington J., Tilby M.J., Pearson A.D.J., Foot A.B.M., McDowell H., Ellershaw C., Pizer B., Nowell G.M., Pearson D.G., et al. Geurtsen M.L., Kors W.A., Moll A.C., Smits C. Long-term audiologic follow-up of carboplatin-treated children with retinoblastoma. and R.J.H. and transmitted securely. Chicago, Illinois. [30] and Millisor et al. Creatinine clearance ( CrCl) is an estimate of Glomerular Filtration Rate ( GFR ); however, CrCl is slightly higher than true GFR because creatinine is secreted by the proximal tubule (in addition to being filtered by the glomerulus). This leads to a particular shortcoming in pediatric oncology patients, where muscle wasting from treatment and malignancy may cause inappropriately low creatinine values thereby masking kidney failure. Estimated GFR was calculated using six equations, which were developed in pediatric populations [28]: the creatinine-based Schwartzcrea [29], Brandt [30] and Millisor [15] equations and the cystatin C-based Schwartzcys [29], FAScys [31] and Berg [32] equations.

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