The main outcome parameters of this study were predicted carboplatin AUC compared to measured carboplatin AUC, i.e., carboplatin exposure. Estimated Clearance Equations Cockcroft and Gault equation: Male: CrCl (ml/min) = (140 - age) x wt (kg) / (serum creatinine x 72) Female: Multiply above result by 0.85 Reference: Cockcroft DW, Gault MH. Renal function was assessed before each course of carboplatin. The target AUC of carboplatin used in this study was 7.42 mg/mL.min and was based on previously published data by Newell et al [6]. Calvert formula Carboplatin dose = AUC (GFR + 25). Carboplatin dosage: prospective evaluation of a simple formula based on renal function. Prediction of total body water in infants and children. Gynecol Oncol Res Pract. [41]. Briefly, a two-compartment model was developed with first-order elimination which describes carboplatin concentrationtime profiles: clearance was 8.38 L/h; volume of distribution was 15.4 L and the distribution micro-constants k12 and k21 were 0.135 h-1 and 0.215 h-1, respectively. 1 Original Cockcroft-Gault equation: CrCl = (140age)(weight in kg) (0.85, if female) 72*SCr These numbers are roughly interpolated from the information provided at the . This method, however, underestimates serum creatinine values compared to previous approaches when serum creatinine values are low, at approximately 0.7 mg/dL. Soveri I., Berg U.B., Bjrk J., Elinder C.-G., Grubb A., Mejare I., Sterner G., Bck S.-E. MR When deciding what factors to incorporate into the calculation of carboplatin dosing, one generally utilizes existing clinical trial data that targeted a speci fic area under the concentration-time curve (AUC). Nephron 1976;16 (1):31-41. Dodgshun A.J., Quinlan C., Sullivan M.J. Cystatin C based equation accurately estimates glomerular filtration rate in children with solid and central nervous system tumours: Enough evidence to change practice? The percentage of body mass is used as follows: Foot 1.35%, at the knee 6.2%, at the hip 18%, hand 0.6%, at elbow 2.25%, at shoulder 5%. The drug was administered by study physicians or nurses, who punctually recorded dosing and sampling times in case report forms. 1. Different dosing regimens were compared in terms of accuracy, bias and precision. Estimated Clearance Equations Cockcroft and Gault equation: Male: CrCl (ml/min) = (140 - age) x wt (kg) / (serum creatinine x 72) Female: Multiply above result by 0.85 Reference: Cockcroft DW, Gault MH. MeSH Den Bakker E., Gemke R.J.B.J., Bkenkamp A. Endogenous markers for kidney function in children: A review. 2012 Jul;32(7):604-12. doi: 10.1002/j.1875-9114.2012.01098.x. Therefore, taking the patients kidney function into account to calculate the adequate dose of carboplatin might result in a better exposure of carboplatin within a patient. CALVERT FORMULA: Total Dose (mg) = (target AUC) x (GFR + 25); Note: With the Calvert formula, the total dose of carboplatin is calculated in mg, not mg/m2 Comments: This drug is usually administered by an infusion lasting 15 minutes or longer. Of note, only four infants participated in the development of the Newell equation [6]. Clipboard, Search History, and several other advanced features are temporarily unavailable. Licensee MDPI, Basel, Switzerland. Calvert A.H., Newell D.R., A Gumbrell L., OReilly S., Burnell M., E Boxall F., Siddik Z.H., Judson I.R., E Gore M., Wiltshaw E. Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. Cancer Chemother Pharmacol. 8600 Rockville Pike Doz F., Pinkerton R. What is the place of carboplatin in paediatric oncology? US Food & Drug Administration. In overweight and obese patients, body weight applied to serum creatinine-based formulas may overestimate glomerular filtration rate. . The equation is: carboplatin dose (mg) = AUC x [GFR + 25]. Measured versus estimated glomerular filtration rate in the Calvert equation: influence on carboplatin dosing. The weight used in the above equations is IBW. Unable to load your collection due to an error, Unable to load your delegates due to an error. Improving carboplatin dosing based on estimated GFR. The average between a cystatin C- and a creatinine-based equation improves estimation of GFR in both children and adults and enables diagnosing Shrunken Pore Syndrome. Best performed the combination of Cockcroft-Gault with adjusted body weight. Carboplatin dosing using eGFR may therefore be a more practical alternative to calculate the appropriate carboplatin dose. Patients with creatinine clearance values below 60 mL/min are at increased risk of severe bone marrow suppression. A lot of the variability in calculating the carboplatin dose is due to physicians utilizing results of serum creatinine tests to estimate the glomerular filtration rate (GFR), as based on one of various formulas, many of which have not been sufficiently prospectively evaluated. 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. Hjorth L., Wiebe T., Karpman D. Correct evaluation of renal glomerular filtration rate requires clearance assays. In this article, the development and application of a simple equation, known as the Calvert formula, are discussed. Levin A., Stevens P.E., Bilous R.W., Coresh J., De Francisco A.L., De Jong P.E., Griffith K.E., Hemmelgarn B.R., Iseki K., Lamb E.J., et al. Appropriate patient weight and serum creatinine should be used when estimating GFR for use in the Calvert equation. Mirjam E. van de Velde, Emil den Bakker, [], and Arend Bkenkamp. HHS Vulnerability Disclosure, Help The linear relationship between carboplatin clearance and glomerular filtration rate (GFR) initiated the development of carboplatin dosing equations based on renal function in adults [4] as well as children [6,7]. Carboplatin exposure using cystatin C-based eGFR equations tended to be more accurate compared to creatinine-based eGFR (30% accuracy 76.389.5% versus 76.378.9%, respectively), which led to significant overexposure, especially in younger (aged 2 years) children. FOIA These formulas typically include creatinine level, age, weight, and sex (Table 1). 1994 Jun;12(6):1251-8 Qaddoumi I., Bass J., Wu J., Billups C.A., Wozniak A.W., Merchant T.E., Haik B.G., Wilson M.W., Rodriguez-Galindo C. Carboplatin-associated ototoxicity in children with retinoblastoma. Performance of the different eGFR equations in predicting carboplatin exposure was compared using the following parameters: As limits of overdosing by more than 25% and underdosing by more than 10% appear to be clinically relevant in oncology patients [19], we also calculated the proportion of predictions between 125% and 90% of measured AUC (P10 to +25) in analogy to the study by Millisor et al [15]. Would you like email updates of new search results? 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. Prediction of carboplatin clearance calculated by patient characteristics or 24-hour creatinine clearance: a comparison of the performance of three formulae. The equation for females is: $$ CrCl \ (females) = {CrCl \ for \ males \times 0.85} $$. The different dosing equations were developed using gold standard GFR measurements (i.e., 51Chromium ethylenediamine tetraacetic acid (51Cr-EDTA) clearance and technetium-99 m diethylenetriaminepentacetic acid (99mTc-DTPA) clearance). The formulae used in this study are listed below. Performance of predicted carboplatin AUC values based on different estimates of GFR and anthropometric dosing. van Warmerdam LJ, Rodenhuis S, ten Bokkel Huinink WW, Maes RA, Beijnen JH. and transmitted securely. Fourth, calculation of the observed carboplatin AUC was based on the publication by Ekhart et al. Vera N.G., Villarreal L.P., Vargas J.U. The https:// ensures that you are connecting to the In this study we sought to validate a carboplatin dosing method based on kidney function and compare several methods for kidney function-based carboplatin dosing in children suffering from retinoblastoma. While performing well in the overall analysis, anthropometric dosing is hampered by a weight-dependent change in bias. Please note that dose is provided in mg not mg/m 2. However, the only study so far evaluating eGFR for carboplatin dosing in pediatric oncology patients compared eGFR with a gold standard GFR measurement and extrapolated these findings to drug exposure [15]. Cockcroft DW, Gault MH. Carboplatin dosing. 2007;12:913-923. The most commonly used body . Pottel H., Dubourg L., Schaeffner E., Eriksen B.O., Melsom T., Lamb E.J., Rule A.D., Turner S.T., Glassock R.J., De Souza V., et al. We only included retinoblastoma patients resulting in a very homogenous and young population without much comorbidity. Time flies! Leon O. Jacobson Professor of Medicine Director, Center for Personalized Therapeutics Associate Director for Clinical Sciences Cancer Research Center For the treatment of solid tumors in adults, carboplatin dosing based on renal function is recommended since carboplatin is almost exclusively (up to 80%) eliminated by glomerular filtration. Although highly accurate, these methods are not widely available and often too invasive and time-consuming for routine measurement of GFR [15]. The site is secure. Setting an upper limit on renal function may help avoid this problem. Verschraagen M., van der Born K., Zwiers T., van der Vijgh W.J. Validation of standardized creatinine and cystatin C GFR estimating equations in a large multicentre European cohort of children. The site is secure. ; data curation, L.M.B. Bookshelf an overprediction of the creatinine clearance and, by applying a modied Calvert formula with creatinine clearance as GFR to calculate the dose, produced a higher than expected carboplatin area under the concentration- time curve [7, 8]. 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. and R.J.H. What is creatinine clearance? An official website of the United States government. 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. The assistance of the nurses on the pediatric oncology (outpatient) ward is also greatly appreciated. As illustrated by Beumer et al. Population pharmacokinetics of carboplatin in children. 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]. 1989;23(6):367-72 The formula is: dose (mg) = AUC (mg ml-1 min) x [GFR (ml/min) + 25 (ml/min)]. official website and that any information you provide is encrypted In 13 children with retinoblastoma 38 carboplatin clearance values were obtained from individual fits using MWPharm++. 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). Pottel H., Delanaye P., Schaeffner E., Dubourg L., Eriksen B.O., Melsom T., Lamb E.J., Rule A.D., Turner S.T., Glassock R.J., et al. The impact of this and other clinical factors on pCR rate, dose intensity (DI) and toxicity was assessed. ; supervision, A.B., G.J.P. Would you like email updates of new search results? In case the serum creatinine is given in mg/dL, the conversion from mg/dL to mol/L is: 1 mg/dL = 88.4 mol/L. Furthermore, since there was a dosing difference in children below and above 10 kg, these were also analyzed separately. Prevention of Chemotherapy-Induced Nephrotoxicity in Children with Cancer. It has been used extensively by us in other studies for which both methods were compared and showed to be similar as well [23,24], as described previously immediately after sample collection [25]. 2022 Jul 19;24(3):583. doi: 10.3892/etm.2022.11520. -, Ann Oncol. New model for estimating glomerular filtration rate in patients with cancer. These characteristics of the standard intrinsically influence the outcome of comparison of the different dosing methods. 2. official website and that any information you provide is encrypted and E.d.B. The population that is at greatest risk for an overdose is the group of patients with normal renal function, especially since there is little evidence of the value of AUC formulas to estimate dosing. Creatinine clearance (Ccr), calculated using the Cockroft-Gault, Jelliffe, Modified-Jelliffe or Wright formulae, has been used as a substitute for the GFR. 2016 Feb;81(2):349-61. doi: 10.1111/bcp.12817. This could be a most welcome follow-up study. of serum creatinine-based GFR estimations, the GFR or creatinine clearance should be directly measured in each patient whenever possible. Of all of the patients, 46.2% were female. MR Carboplatin is a platinum chemotherapy drug that is administered as an intravenous infusion. This formula is called the creatinine clearance and tends to exceed the true GFR by 10 to 20 percent or more depending upon the proportion of urinary creatinine that is derived from tubular secretion [ 4 ]. This has led to the development of a wide range of pediatric eGFR equations based on creatinine and cystatin C in recent years [20]. and G.L.K. All authors have read and agreed to the published version of the manuscript. ; validation, L.M.B., A.B. The ePub format is best viewed in the iBooks reader. After the sampling procedure, all samples were immediately placed in an ice bath and centrifuged (1500 g at 4 C for 10 min), to separate plasma from whole blood. An aliquot of plasma (0.5 mL) was thoroughly mixed with 1.5 mL of ice cold (20 C) ethanol and incubated for several hours at 20 C to denaturize the plasma proteins. 2013 Jul-Aug;47(7-8):1039-44. doi: 10.1345/aph.1S176. Blufpand H.N., Tromp J., Abbink F.C., Stoffel-Wagner B., Bouman A.A., Meeteren A.Y.S.-V., van Wijk J.A., Kaspers G.J., Bkenkamp A. Cystatin C more accurately detects mildly impaired renal function than creatinine in children receiving treatment for malignancy. Carboplatin dose is based on the Calvert formula: Dosage = Target AUC x (GFR* + 25) *Where the GFR is provided by the eCrCl. Because of these challenges, questions arise as to what should be done by agencies like the US Food and Drug Administration (FDA) or the National Cancer Institute, or by pharmaceutical companies to combat this significant public health issue. Nephron. For patients with abnormal renal function, the usual formulas are less likely to be problematic. PMC Different studies employ different formulas or approaches to carboplatin dosing. Fluid electrolyte changes in physically healthy subjects during prolonged re-striction of motor activity and daily hyperhydration. and transmitted securely. Pharmacotherapy. eGFR: estimated glomerular filtration rate. Pharmacokinetics and preliminary clinical data of the novel chemoprotectant BNP7787 and cisplatin and their metabolites. This is a breakdown product of creatine, an important component found in muscles that is cleared through the kidneys so its clearance is an important indicator of the kidneys' filtering function. Ryan Pritchard E, Waddell JA, Solimando DA Jr. Hosp Pharm. H&O Can you provide some background on carboplatin? Mosteller R.D. The University of Chicago Go R.S., Adjei A.A. Review of the comparative pharmacology and clinical activity of cisplatin and carboplatin. 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]. This dosing calculator adjusts for renal . government site. All dosing methods resulted in a positive bias with median %PE values ranging from 4.1 to 21%. Cancer Chemother Pharmacol. First, we did not use a gold standard GFR technique for direct comparison with the eGFR equations and did not assess the most accurate CKiD-3 equation incorporating anthropometric data, creatinine, urea and cystatin C [29,43], as urea had not been measured. The original study published in 1976 used actual body weight, but it mentioned that a correction factor was likely needed for those who are obese. -. GFR = glomerular filtration rate, CL cr = creatinine clearance, TBW . This was adjusted for children by introducing a weight-dependent term of 0.36 (i.e., 25 divided by the weight of an average adult of 70 kg) to be added to GFR in the Newell equation [6]. Carboplatin dose (mg) = AUCx (GFR + 25) Carboplatin dose (mg) = 7 x (81.25 + 25) Carboplatin dose (mg) = 7 x 106.25 Carboplatin dose (mg) = 743.8 The carboplatin calculator can be used to find the exact dosage for patients of various age groups. Functional range of creatinine clearance for renal drug dosing: a practical solution to the controversy of which weight to use in the Cockcroft-Gault equation. If kidney function is impaired, this will slow down the clearance of drugs. In Figure 1, %PE of the different eGFR equations and anthropometric dosing in the individual studies is shown as waterfall plots. New standardized cystatin C and creatinine GFR equations in children validated with inulin clearance. ), 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; ed.nnobku@rengaW-leffotS.tigriB, 10Department of Epidemiology and Biostatistics, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands; ln.cmumadretsma@traffub.l. BMI: body mass index, BSA: body surface area, eGFR: estimated glomerular filtration rate. Best performed the combination of Cockcroft-Gault with adjusted body weight. The aim was to compare doses of carboplatin calculated using the Calvert formula and Chatelut formula and also to compare doses calculated using Calve Janowitz T., Williams E.H., Marshall A., Ainsworth N., Thomas P., Sammut S.J., Shepherd S., White J., Mark P., Lynch A., et al. Conceptualization, H.N.B., A.B. 2010;36:1-6. http://www.cancerletter.com. Discrepancies between the Cockcroft-Gault and Chronic Kidney Disease Epidemiology (CKD-EPI) Equations: Implications for Refining Drug Dosage Adjustment Strategies. Still, this did not improve accuracy of carboplatin exposure in the present study because all equations had a positive bias. Prediction of creatinine clearance from serum creatinine. This model was implemented in MWPharm++ 1.35 (Mediware a.s., Praha, Czech Republic). Serum creatinine cut-off values ranged from 0.36 mg/dL to 1 mg/dL. Cockcroft-Gault equation takes into account the age of the patient as well, since muscle mass decreases with age. Concomitant chemotherapeutic drugs were vincristine 1.5 mg/m2 and etoposide 150 mg/m2, administration of which are part of the local standard treatment protocol. -, J Clin Oncol. Although largely eliminated renally, roughly 20% of carboplatin is non-renally cleared, which to a large extent is due to tissue binding, with a small proportion excreted through the liver [11,44]. http://www.nkdep.nih.gov/professionals/gfr_calculators/idms_con.htm. The Brandt equation had the highest positive bias of all creatinine-based equations. Kidneys play an important role in clearing (excreting) drugs. In the older children, Schwartzcrea, Schwartzcys and Millisor had the least bias and highest precision and yielded high P30 accuracy. Creatinine clearance calculator If you need medical care or advice that is urgent but not an immediate, genuine emergency, please visit https://111.nhs.uk/ or call 111 first so that trained NHS 111 advisors can tell you the best place to be seen quickly. The percentage prediction error (%PE), defined as: The absolute percentage prediction error (APE), Accuracy assessed by calculating the proportion of predicted AUC values within 30% of measured AUC (P. Received 2021 Oct 8; Accepted 2021 Nov 19. Given the physiological differences in body dimensions and renal function [20] between young infants and older children, we analyzed patients under two years separately from older children. 2016 Jun;51(6):442-9. doi: 10.1310/hpj5106-442. This is remarkable as both Schwartzcys and FAScys were developed in children above the age of one [29,42], while the youngest patient in the cohort of Brandt et al. Still, none of the patients here showed hyperfiltration as all eGFR measurements were below 140 mL/min/1.73 m2. This was not observed with any of the eGFR-based dosing methods. Choice of equations was based on performance in validation studies using gold standard GFR measurements [33]. H&O What factors are considered when determining the dose of carboplatin? While anthropometric dosing based on BSA or weight performed reasonably well overall, we observed significant underdosing of carboplatin in studies performed at a bodyweight below 10 kg, although patient numbers were small. Dose rounding based on the drug vial size must be in accordance to the maximum limit of 10%. The creatinine clearance used to calculate the carboplatin dose will be from PHYS 75 at Emory University All but two patients were studied during multiple courses (two during two courses, four during three courses and five during four courses). [10] demonstrated that GFR-based dosing can lead to overdosing in children with hyperfiltration, a not uncommon finding in patients with malignancy undergoing hyperhydration [51]. and G.J.P. and G.L.K. -, Cancer Chemother Pharmacol. Flat Dosing of carboplatin is justified in adult patients with normal renal function. The carboplatin clearance was also calculated directly by using Chatelut formula. 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. For the study purpose doses were recalculated using Cockcroft-Gault with adjusted body weight and predicted normal weight and CKD-EPI. 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. 2019 Jan;75(1):51-57. doi: 10.1007/s00228-018-2552-z. The present study is the first external evaluation of carboplatin dosing using estimated rather than measured GFR in the pediatric Newell equation. The performance of all six eGFR-based equations as well as anthropometric dosing in predicting carboplatin AUC is presented in Table 3. 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. By contrast, the anthropometric dosing regimen based on weight in small children and BSA in children above 10 kg was associated with underdosing in the former. eCollection 2022 Sep. McDannold N, Zhang Y, Supko JG, Power C, Sun T, Peng C, Vykhodtseva N, Golby AJ, Reardon DA. the clearance is typically calculated using the cockcroft and gault (C-G) formula. In renally-impaired patients who received single agent Carboplatin Injection therapy, the incidence of severe leukopenia, neutropenia, or thrombocytopenia has been about 25% when the dosage modifications in the table below have . Carboplatin dose is based on the Calvert formula: Dosage = Target AUC x (GFR* + 25) *Where the GFR is provided by the eCrCl. Details of these equations can be found in Table 1. 2. We acknowledge a number of limitations in our study. 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. National Kidney Disease Education Program. Residual error was assumed to be distributed normally with a standard deviation according to SD = 0.1 C, in which C is platinum plasma concentration. It should be borne in mind that the Calvert equation and, by extension, the Newell equation, are based on measured GFR in mL/min. The use of the Calvert formula to calculate carboplatin doses allows clinicians to achieve the appropriate carboplatin area under the concentration (AUC) curve. 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. Bouquegneau A, Vidal-Petiot E, Moranne O, Mariat C, Boffa JJ, Vrtovsnik F, Scheen AJ, Krzesinski JM, Flamant M, Delanaye P. Br J Clin Pharmacol. These were deemed the optimal timepoints to cover the expected distributionelimination curve. Creatinine clearance (Ccr), calculated using the Cockroft-Gault, Jelliffe, Modified-Jelliffe or Wright formulae . sharing sensitive information, make sure youre on a federal and E.d.B. and E.d.B. How to find Ideal body weight (IBW)? Written informed consent was signed by all patients or parents/guardians, as appropriate, before participating in the study. The United Kingdom Childrens Cancer Study Group. http://www.fda.gov/ AboutFDA/CentersOffices/CDER/ucm228974.htm. The formula is: dose (mg) = AUC (mg ml-1 min) x [GFR (ml/min) + 25 (ml/min)]. Simplified calculation of body-surface area. already built in. Filler G., Huang S.-H.S., Yasin A. 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. In total, 13 children were included. About. It is most commonly used to treat lung and ovarian cancers, but has been used off-label in many other diseases.

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