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Variability of carboplatin dose calculation methods in Spain
Abstract
Objective:
To describe and analyze the variability in carboplatin dosing strategies in Spanish hospitals.
Methods:
We designed a questionnaire consisting of 19 multiple-choice items structured in two sections (hospital characteristics and carboplatin dosing data). The questionnaire was sent by e-mail to all the oncology pharmacists included in the register of the Spanish Oncology Pharmacy Group (GEDEFO), and we analyzed the completed questionnaires.
Results:
Response rate was 33.5% from a total of 185 pharmacy services invited to take part in the survey. All hospitals used the Calvert formula to calculate carboplatin dose with glomerular filtration rate estimated by a formula, most commonly the Cockcroft-Gault equation (80.7%). Carboplatin doses were capped in most hospitals (91.9%): 54.8% capped creatinine clearance at 125 mL/min, 11.3% capped serum creatinine, and 19.3% capped both creatinine clearance and serum creatinine. Serum creatinine cut-off values ranged from 0.36 mg/dL to 1 mg/dL. The most commonly used body weight was actual body weight for underweight, normal weight, and overweight patients. The use of adjusted ideal body weight increased in obese and especially in morbidly obese patients.
Conclusion:
The results from this survey show the variability that exists in carboplatin dose calculation methods among Spanish hospitals and the need to continue investigating to find the optimum dose calculation method and unify criteria to avoid differences between sites that can affect effectiveness and toxicity of carboplatin-containing treatments.
Objective
Carboplatin is a cytotoxic chemotherapy drug developed in the 1980s which is still widely used today across various tumour types. Despite its common application, there remains a significant controversy and practice variation on its unique method of dosing by area under the curve (AUC). One potential reason for this variability stems from the reliance of using an estimated glomerular filtration rate (eGFR) as an extrapolation of the measured GFR (mGFR) which the commonly used Calvert equation was originally validated for. This review takes a novel and collaborative nephro-oncology approach to highlight the historical evolution of carboplatin dosing, methods for estimating GFR and its relative performance in the application of carboplatin dosing for adult patients.
Data sources
We reviewed all pertinent publications comparing carboplatin AUC-based dosing in adult patients based on the various methods of GFR measurements or estimations in order to provide a comprehensive description of each method’s advantages and risks.
Data summary and conclusions
The Cockcroft-Gault equation has been widely studied but newer eGFR equations, such as the CKD-Epidemiology Collaboration (CKD-EPI) or Janowitz-Williams equation have outperformed the Cockcroft-Gault in recent studies.
Purpose
The glomerular filtration rate (GFR) is essential for carboplatin chemotherapy dosing; however, the best method to estimate GFR in patients with cancer is unknown. We identify the most accurate and least biased method.
Methods
We obtained data on age, sex, height, weight, serum creatinine concentrations, and results for GFR from chromium-51 (⁵¹Cr) EDTA excretion measurements (⁵¹Cr-EDTA GFR) from white patients ≥ 18 years of age with histologically confirmed cancer diagnoses at the Cambridge University Hospital NHS Trust, United Kingdom. We developed a new multivariable linear model for GFR using statistical regression analysis. ⁵¹Cr-EDTA GFR was compared with the estimated GFR (eGFR) from seven published models and our new model, using the statistics root-mean-squared-error (RMSE) and median residual and on an internal and external validation data set. We performed a comparison of carboplatin dosing accuracy on the basis of an absolute percentage error > 20%.
Results
Between August 2006 and January 2013, data from 2,471 patients were obtained. The new model improved the eGFR accuracy (RMSE, 15.00 mL/min; 95% CI, 14.12 to 16.00 mL/min) compared with all published models. Body surface area (BSA)–adjusted chronic kidney disease epidemiology (CKD-EPI) was the most accurate published model for eGFR (RMSE, 16.30 mL/min; 95% CI, 15.34 to 17.38 mL/min) for the internal validation set. Importantly, the new model reduced the fraction of patients with a carboplatin dose absolute percentage error > 20% to 14.17% in contrast to 18.62% for the BSA-adjusted CKD-EPI and 25.51% for the Cockcroft-Gault formula. The results were externally validated.
Conclusion
In a large data set from patients with cancer, BSA-adjusted CKD-EPI is the most accurate published model to predict GFR. The new model improves this estimation and may present a new standard of care.
A formula has been developed to predict creatinine clearance (Ccr) from serum creatinine (Scr) in adult males: (see article)(15% less in females). Derivation included the relationship found between age and 24-hour creatinine excretion/kg in 249 patients aged 18-92. Values for Ccr were predicted by this formula and four other methods and the results compared with the means of two 24-hour Ccr's measured in 236 patients. The above formula gave a correlation coefficient between predicted and mean measured Ccr's of 0.83; on average, the difference predicted and mean measured values was no greater than that between paired clearances. Factors for age and body weight must be included for reasonable prediction.
To provide recommendations for appropriate cytotoxic chemotherapy dosing for obese adult patients with cancer.
The American Society of Clinical Oncology convened a Panel of experts in medical and gynecologic oncology, clinical pharmacology, pharmacokinetics and pharmacogenetics, and biostatistics and a patient representative. MEDLINE searches identified studies published in English between 1996 and 2010, and a systematic review of the literature was conducted. A majority of studies involved breast, ovarian, colon, and lung cancers. This guideline does not address dosing for novel targeted agents.
Practice pattern studies demonstrate that up to 40% of obese patients receive limited chemotherapy doses that are not based on actual body weight. Concerns about toxicity or overdosing in obese patients with cancer, based on the use of actual body weight, are unfounded.
The Panel recommends that full weight-based cytotoxic chemotherapy doses be used to treat obese patients with cancer, particularly when the goal of treatment is cure. There is no evidence that short- or long-term toxicity is increased among obese patients receiving full weight-based doses. Most data indicate that myelosuppression is the same or less pronounced among the obese than the non-obese who are administered full weight-based doses. Clinicians should respond to all treatment-related toxicities in obese patients in the same ways they do for non-obese patients. The use of fixed-dose chemotherapy is rarely justified, but the Panel does recommend fixed dosing for a few select agents. The Panel recommends further research into the role of pharmacokinetics and pharmacogenetics to guide appropriate dosing of obese patients with cancer.
Study objective: Different equations used to estimate creatinine clearance (Cl cr ) in obese oncology patients can produce divergent estimated creatinine clearance values, which in turn can result in significantly different calculated carboplatin doses. Standardization of the calculation of creatinine clearance in patients of all body types is a desirable goal. The objective of our study was to examine the impact of increasing body mass index on the accuracy of creatinine clearance estimation methods and to determine the optimal equation for creatinine clearance estimation in the obese adult female cancer patient.
Design: Retrospective data analysis.
Patients: We compared the estimated creatinine clearance values produced by each of 11 equations to 24-hour creatinine clearance values measured in 119 adult female patients with gynecologic cancers grouped according to body composition.
Measurements and main results: We applied simple linear regression and Tukey mean-difference analysis to assess the relationship between estimated creatinine clearance values produced by these equations and measured creatinine clearance values for each patient. The relationship between measured creatinine clearance and estimated creatinine clearance produced by all equations displayed lower linear regression R ² values and higher limits of agreement in obese patients than in nonobese groups. Agreement between measured and estimated creatinine clearance produced by the Cockcroft-Gault equation is sensitive to the particular weight parameter incorporated and is lowest using ideal weight or actual body weight. The Cockcroft-Gault equation incorporating an intermediate weight value reduced estimation bias. The Jelliffe equation produced the lowest R ² values.
Conclusion: Available model equations are less reliable for predicting creatinine clearance in obese female cancer patients (body mass index >30) than in nonobese patients. A measured glomerular filtration rate or creatinine clearance value is most accurate in obese female cancer patients. When using Cockcroft-Gault equation for estimation in this patient population, however, an intermediate weight value (adjusted or modified-adjusted) rather than ideal or actual body weight should be used.
Dosing adjustments for patients with impaired kidney function are often based on estimated creatinine clearance (eCrCl) because measuring kidney function is not always possible for dose adjustment. However, there is no consensus on the body size descriptor that should be used in the estimation equations.
To compare the use of alternative body size descriptors (ABSDs) on the performance of kidney function estimation equations compared with measured CrCl (mCrCl).
We combined 2
a Food and Drug Administration clinical trial database that includes subjects with body mass index (BMI) less than 40 kg/m(2) and published data from those 40 kg/m(2) or more. The 3 parent equations (Cockcroft-Gault [CG], Modification of Diet in Renal Disease [MDRD], Chronic Kidney Disease-Epidemiology Collaboration [CKDEPI]), and 14 ABSD-modified equations were compared with mCrCl for accuracy, bias, agreement, goodness of fit (R(2)), and prediction error. These equations were also compared across mCrCl and BMI strata.
Subjects (n = 590) were aged 19-80 years; 33.9% were female and BMI ranged from 17.2 to 95.6 kg/m(2). Compared with mCrCl, the use of total weight in the CG equation yielded low accuracy (12.5%) and significant bias (-107 mL/min) in the morbidly obese group. In contrast, the use of lean body weights (BMI ≥40 kg/m(2)) and total ± adjusted weights (BMI <40 kg/m(2)) with the CG equation yielded higher accuracy, greater than or equal to 60.7% across all BMI strata, and was unbiased. Transforming the MDRD or CKDEPI equations with body surface area improved accuracy only at mCrCl of 30-80 mL/min and increased the overall prediction error.
No kidney function equation was consistently accurate and unbiased across weight, mCrCl, and estimate ranges. The accuracy and overestimation bias of the CG equation in obese subjects was improved through the selective use of total, adjusted, and lean body weight by BMI strata.
A formula has been developed to predict creatinine clearance (Ccr) from serum creatinine (Scr) in adult males: (see article)(15% less in females). Derivation included the relationship found between age and 24-hour creatinine excretion/kg in 249 patients aged 18-92. Values for Ccr were predicted by this formula and four other methods and the results compared with the means of two 24-hour Ccr's measured in 236 patients. The above formula gave a correlation coefficient between predicted and mean measured Ccr's of 0.83; on average, the difference predicted and mean measured values was no greater than that between paired clearances. Factors for age and body weight must be included for reasonable prediction.
We previously proposed a formula to predict carboplatin clearance (CL) from four patient characteristics: plasma creatinine level, body weight, age, and sex (J Natl Cancer Inst 1995; 87: 573). Its accuracy was studied in a subpopulation of obese patients.
Twenty-five patients (16 male and 9 female, 23 to 82 years old) were studied. They were 20% to 67% (median 36%) over the ideal weight which was calculated according to the Lorentz equation. Their actual CL was obtained individually by the Siphar program. The pharmacokinetic population program NONMEM was used to determine the best value of substitution for weight in the formula.
By using the actual weight, CL was significantly over predicted (by more than 20% for 7 of 25 patients). By using the mean value between the ideal and the actual weight, a good prediction of CL was obtained: the percentage of error ranged from -21% to +22%.
The formula is applicable to obese patients if both ideal and actual weights are taken into account.
When determining the carboplatin dosage from the Calvert formula, there are a lack of data when evaluating patients with cachexia or body mass index (BMI)>or=27. If the Cockcroft and Gault (C-G) creatinine clearance (CrCl) equation is utilized and substituted for glomerular filtration rate in the Calvert formula, the chance for inaccurate dosing occurs especially in these populations. Therefore, the purpose of this study is to evaluate and compare the target carboplatin area under the concentration (AUC) with the actual AUC achieved in cachectic or BMI>or=27 patients. In a prospective manner, we evaluated 19 patients with a BMI>or=27 and nine cachectic patients. In the C-G equation to determine creatinine clearance, the adjusted body weight was used for BMI>or=27 patients and serum creatinine value of 70.7 microM (0.8 mg/dl) for the cachectic patients. The carboplatin dose was calculated, administered to the patients, and subsequent carboplatin blood samples were obtained for pharmacokinetic determination. Once the AUC was determined, the results were compared with the expected outcomes from the modified C-G CrCl equation for the Calvert formula, Chatelut and Bénézet equations. The results demonstrated that the modified C-G CrCl equation for the Calvert formula had less bias and more precision than using actual weight in the C-G CrCl equation or using the Chatelut and Bénézet equations. Using the actual weight in overweight and especially obese patients and using a serum creatinine<70.7 microM in cachectic patients will lead to overestimation of the carboplatin clearance and thus AUC.
Aim:
For drug dosing adaptation, the KDIGO guidelines recommend using estimated glomerular filtration rate (eGFR) with the CKD-EPI equation, after de-indexation to the body surface area (BSA). In pharmacology, the Cockcroft & Gault (CG) equation is still recommended to adapt drug dosage. In the context of obesity, adjusted ideal body weight (AIBW) is sometimes preferred to actual body weight (ABW) for the CG equation. The aim of our study was to compare the performances of the different GFR estimating equations non-indexed or de-indexed by BSA for the purpose of drug-dosage adaptation in obese patients.
Methods:
We analysed data from patients with a body mass index (BMI) higher than 30 kg/m(2) who underwent a GFR measurement. eGFR was calculated with the CKD-EPI and MDRD equations, « de-indexed » by BSA, and the CG equation, using either ABW, AIBW or lean body weight (LBW) for the weight variable and compared with measured GFR, expressed in ml/min.
Results:
In our population of obese patients, using the AIBW instead of the ABW in the CG equation, markedly improved the overall accuracy of this equation (57% for CGABW and 79% for CGAIBW (p < 0.05)). For high BMI (over 40kg/m(2) ), accuracies of the CG equations are not different when using LBW than when using AIBW. The MDRD and CKD-EPI equations deindexed by the BSA also displayed good performances with an overall higher accuracy for the MDRD deindexed equation (80% and 76% respectively (p < 0.05)).
Conclusions:
De-indexed MDRD appear the most suitable to estimate non-indexed GFR for the purpose of drug dosage adaptation in obese patients.
Background: Serum creatinine concentration is widely used as an index of renal function, but this concentration is affected by factors other than glomerular filtration rate (GFR). Objective: To develop an equation to predict GFR from serum creatinine concentration and other factors. Design: Cross-sectional study of GFR, creatinine clearance, serum creatinine concentration, and demographic and clinical characteristics in patients with chronic renal disease. Patients: 1628 patients enrolled in the baseline period of the Modification of Diet in Renal Disease (MDRD) Study, of whom 1070 were randomly selected as the training sample ; the remaining 558 patients constituted the validation sample. Methods: The prediction equation was developed by stepwise regression applied to the training sample. The equation was then tested and compared with other prediction equations in the validation sample. Results: To simplify prediction of GFR, the equation included only demographic and serum variables. Independent factors associated with a lower GFR included a higher serum creatinine concentration, older age, female sex, nonblack ethnicity, higher serum urea nitrogen levels, and lower serum albumin levels (P < 0.001 for all factors). The multiple regression model explained 90.3% of the variance in the logarithm of GFR in the validation sample. Measured creatinine clearance overestimated GFR by 19%, and creatinine clearance predicted by the Cockcroft-Gault formula overestimated GFR by 16%. After adjustment for this overestimation, the percentage of variance of the logarithm of GFR predicted by measured creatinine clearance or the Cockcroft-Gault formula was 86.6% and 84.2%, respectively. Conclusion: The equation developed from the MDRD Study provided a more accurate estimate of GFR in our study group than measured creatinine clearance or other commonly used equations.
Background
Equations to estimate glomerular filtration rate (GFR) are routinely used to assess kidney function. Current equations have limited precision and systematically underestimate measured GFR at higher levels.
Background:
It is not unusual to find obese and cachectic patients in the hematology oncology setting. However, information on dosage in these groups is scarce.
Objective:
The objectives of our study were to explore the dosing strategies applied in the treatment of obese and cachectic cancer patients and to determine whether these strategies are applied in clinical trials.
Setting:
Members of the Spanish Group for the Development of Hematology-Oncology Pharmacy (GEDEFO).
Methods:
We invited all cancer hospital pharmacists to participate in a survey.
Main outcome measure:
Descriptive statistics of the dosing strategies approaches.
Results:
We invited 159 eligible hospitals to participate, and 38 responded to the survey. A total of 50 surveys were received: different strategies were applied by different physicians from the same hospital and by hematology and oncology departments. Body mass index was used to define obesity and cachexia in 40 and 30 % of the cases, respectively. Capping the body surface area (BSA) was the approach most commonly followed (64.1 %) in obese patients, whereas no specific approach was adopted in cachectic patients. In hematology patients, the BSA calculation was based on ideal body weight or adjusted body weight in 16.0 % of cases (n = 2) and 50.0 % of cases (n = 6), respectively; in oncology patients, use of adjusted or ideal body weight was negligible. Actual body weight was the main approach in obese patients (35 surveys) and cachectic patients (48 surveys). Creatinine clearance was assessed mainly using the Cockcroft and Gault equation (around 76.0 % of responses). As for clinical trials, 64.1 % of the respondents (n = 25 hospitals) considered the criteria from each clinical trial individually.
Conclusions:
Dose adjustments are more frequent in obese patients than in cachectic patients. In cancer oncology patients, dose is adjusted mainly by hematology and hematopoietic cell transplant teams. Capping BSA is the most frequent strategy, followed by calculating actual body weight.
Single cycle carboplatin, dosed by glomerular filtration rate (GFR), is standard adjuvant therapy for stage 1 seminoma. Accurate measurement of GFR is essential for correct dosing. Isotopic methods remain the gold standard for the determination of GFR. Formulae to estimate GFR have improved the assessment of renal function in non-oncological settings. We assessed the utility of these formulae for carboplatin dosing.
We studied consecutive subjects receiving adjuvant carboplatin for stage 1 seminoma at our institution between 2007 and 2012. Subjects underwent 51Cr-ethylene diamine tetra-acetic acid (EDTA) measurement of GFR with carboplatin dose calculated using the Calvert formula. Theoretical carboplatin doses were calculated from estimated GFR using Chronic Kidney Disease-Epidemiology (CKD-EPI), Management of Diet in Renal Disease (MDRD) and Cockcroft-Gault (CG) formulae with additional correction for actual body surface area (BSA). Carboplatin doses calculated by formulae were compared with dose calculated by isotopic GFR; a difference <10% was considered acceptable.
115 patients were identified. Mean isotopic GFR was 96.9ml/min/1.73m(2). CG and CKD-EPI tended to overestimate GFR whereas MDRD tended to underestimate GFR. The CKD-EPI formula had greatest accuracy. The CKD-EPI formula, corrected for actual BSA, performed best; 45.9% of patients received within 10% of correct carboplatin dose. Patients predicted as underdosed (13.5%) by CKD-EPI were more likely to be obese (p=0.013); there were no predictors of the 40.5% receiving an excess dose.
Our data support further evaluation of the CKD-EPI formula in this patient population but clinically significant variances in carboplatin dosing occur using non-isotopic methods of GFR estimation. Isotopic determination of GFR should remain the recommended standard for carboplatin dosing when accuracy is essential.
The aim was to compare doses of carboplatin calculated using the Calvert formula and Chatelut formula and also to compare doses calculated using Calvert formula, modified with non-isotopic estimation of GFR, using the Cockcroft and Gault formula or the Jelliffe formula. For formulae comparison, doses were calculated to target an AUC of 7 mg/ml.min. When compared with the dose derived from the Calvert formula, the doses calculated in 122 adult cancer patients using the Chatelut formula were significantly higher for males and significantly lower for females. There was a statistically significant difference between the dose per kg calculated for males and females (P
To evaluate the performance of kidney function estimation equations and to determine the frequency of drug dose discordance in an older population.
Cross-sectional analysis of data from community-dwelling volunteers randomly selected from the Baltimore Longitudinal Study of Aging from January 1, 2005, to December 31, 2010.
A total of 269 men and women with a mean ± SD age of 81 ± 6 years, mean serum creatinine concentration (Scr) of 1.1 ± 0.4 mg/dl, and mean 24-hour measured creatinine clearance (mClcr) of 53 ± 13 ml/minute.
Kidney function was estimated by using the following equations: Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). The performance of each equation was assessed by measuring bias and precision relative to mClcr. Dose calculation errors (discordance) were determined for 10 drugs requiring renal dosage adjustments to avoid toxicity when compared with the dosages approved by the Food and Drug Administration. The CG equation was the least biased estimate of mClcr. The MDRD and CKD-EPI equations were significantly positively biased compared with CG (mean ± SD 34 ± 20% and 22 ± 15%, respectively, p<0.001) and mClcr (29 ± 47% and 18 ± 40%, respectively, p<0.001). Rounding low Scr values (less than 1.0 mg/dl) up to an arbitrary value of 1.0 mg/dl resulted in CG values (44 ± 10 ml/minute) that were significantly lower than mClcr (56 ± 12 ml/minute, p<0.001) and CG (56 ± 15 ml/minute, p<0.001). The MDRD and CKD-EPI equations had median dose discordance rates of 28.6% and 22.9%, respectively.
The MDRD and CKD-EPI equations significantly overestimated creatinine clearance (mClcr and CG) in elderly individuals. This leads to dose calculation errors for many drugs, particularly in individuals with severe renal impairment. Thus equations estimating glomerular filtration rate should not be substituted in place of the CG equation in older adults for the purpose of renal dosage adjustments. In addition, the common practice of rounding or replacing low Scr values with an arbitrary value of 1.0 mg/dl for use in the CG equation should be avoided. Additional studies that evaluate alternative eGFR equations in the older populations that incorporate pharmacokinetic and pharmacodynamic outcomes measures are needed.
To evaluate the impact of various body weights and serum creatinine (S(c) (r) ) concentrations on the bias and accuracy of the Cockcroft-Gault creatinine clearance (C-G Cl(c) (r) ) equation compared with measured 24-hour Cl(c) (r) .
Retrospective analysis.
Tertiary care hospital.
A total of 3678 patients with stable renal function and who underwent a 24-hour urine collection between July 1, 1996, and June 30, 2010.
For each patient, C-G Cl(c) (r) was calculated and compared with a measured 24-hour Cl(c) (r) . Body weight adjustments to the calculation were performed based on the following weight classifications: underweight, normal weight, overweight, obese, and morbidly obese. In addition, C-G Cl(c) (r) was calculated by using rounded S(c) (r) values based on two S(c) (r) thresholds-0.8 mg/dl and 1 mg/dl-for patients with measured S(c) (r) values below those thresholds. Those patients were then evaluated after stratification into two age groups: all ages and a subgroup of patients aged 65 years or older. The S(c) (r) -rounded C-G Cl(c) (r) values were compared with the C-G Cl(c) (r) values using actual S(c) (r) values. Mean differences were calculated, and accuracy was evaluated. Use of actual body weight in the calculations for underweight patients resulted in an unbiased Cl(c) (r) of -0.22 ml/minute (p=0.898). Use of ideal body weight in the calculations of patients of normal weight returned an unbiased Cl(c) (r) of -1.3 ml/minute (p=0.544). An unbiased C-G Cl(c) (r) could not be calculated for other weight categories. In those patients, adjusted body weight using a factor of 0.4 (ABW(0.4) ) was the least biased and most accurate. In patients aged 65 years or older with an S(c) (r) less than 0.8 mg/dl and less than 1 mg/dl, actual S(c) (r) was unbiased (-3 ml/min [p=1] and -9 ml/min [p=0.279], respectively) and more accurate than rounded S(c) (r) . In patients of all ages with an S(c) (r) less than 0.8 mg/dl and less than 1 mg/dl, actual S(c) (r) proved less biased (-4.5 ml/min [p=0.038] and -5.5 ml/min [p<0.001], respectively) and more accurate than rounded S(c) (r) .
An unbiased C-G Cl(c) (r) can be calculated using actual body weight in underweight patients and ideal body weight in patients of normal weight. Using ABW(0.4) for overweight, obese, and morbidly obese patients appears to be the least biased and most accurate method for calculating their C-G Cl(c) (r) . Rounding S(c) (r) in patients with low S(c) (r) did not improve accuracy or bias of the Cl(cr) calculations.
The aim was to evaluate the accuracy of Cockcroft-Gault, Jelliffe, Wright and Modification of Diet in Renal Disease (MDRD) formulae as a substitute for the gold standard measure of glomerular filtration rate (GFR) using chromium 51 EDTA.
Retrospective analysis of GFR measurements in oncology patients from a University Teaching Hospital over 3 years was carried out. Bias and precision of estimates of GFR were compared with measured GFR.
Six hundred and sixty patients with measured GFR (median 90 ml/min, range 23-179 ml/min) were identified. Cockcroft-Gault produced the smallest bias (median percentage error -1.4%) and highest precision (median absolute percentage error 14.0%) and was the most accurate for carboplatin dosing. For patients>30% over their ideal body weight (IBW), using IBW+30% in the Cockcroft-Gault formula was more precise than using actual body weight or IBW. The Wright formula was most accurate for patients aged 70+years and patients with a body mass index (BMI)≥30 but overestimated GFR when GFR<50 ml/min.
When measured GFR is unavailable, we advise estimating GFR using the Cockcroft-Gault formula and using IBW+30% for patients weighing>30% over their IBW. If the GFR is ≥50 ml/min and the patient is >70 years and/or BMI≥30, the Wright formula gives the best estimate of GFR.
Accurate assessment of kidney function is an important component of determining appropriate drug dosing regimens. Nearly all manufacturer-recommended dosage adjustments are based on creatinine clearance ranges derived from clinical pharmacokinetic studies performed during the drug development process. The Cockcroft-Gault (CG) equation provides an estimate of creatinine clearance and is the equation most commonly used to determine drug dosages in patients with impaired kidney function. The Modification of Diet in Renal Disease (MDRD) study equation has also been proposed for this purpose. Published studies report that drug dosages determined by the two equations do not agree in 10-40% of cases. However, interpretation and comparison of these studies are complicated by the variable creatinine methods used for calculating CG and MDRD estimates, the patient populations studied, and a lack of outcomes data demonstrating the clinical significance of dosing discrepancies. Moreover, the impact of reporting standardized serum creatinine values on the accuracy of the CG equation and corresponding drug dosing regimens have been questioned. Currently, no prospective pharmacokinetic studies have been conducted with use of the MDRD equation to generate dosing recommendations, and limited data are available to support its use in some patient populations representing demographic extremes. Collectively, these issues have resulted in considerable confusion among clinicians and have fueled a healthy debate on whether or not to use the MDRD equation to determine drug dosages. Each of these issues is reviewed, and a proposed algorithm for using creatinine-based kidney function assessments in drug dosing is provided. Knowledge of the advantages, limitations, and clinical role of each equation will facilitate their safe and effective use in drug dosing.
To determine which body weight descriptor most accurately predicts measured creatinine clearance (Cl(cr)) and whether rounding serum creatinine concentration (S(cr)) to 1 mg/dl when it is less than 1 mg/dl accurately predicts measured Cl(cr).
Meta-analysis of 13 English-language trials comparing 24-hour measured Cl(cr) with Cockcroft-Gault estimated Cl(cr) by using various body weights or rounded S(cr) values.
A total of 1197 patients (mean age 53.3 yrs, 48.7% male) were included in the meta-analysis.
A thorough literature search of the PubMed, MEDLINE, and the Cochrane Library databases was performed (1976-June 2010) to identify relevant clinical trials. Patient population, number of subjects, age, and 24-hour measured and estimated Cl(cr) were extracted independently by two investigators by using standardized data collection forms. Mean difference (MD) between estimated and measured Cl(cr) was assessed. Thirteen studies met all selection criteria. A random-effects model was applied secondary to a high level of heterogeneity among the studies (I(2)>50%). Total body weight in the Cockcroft-Gault equation overestimated measured Cl(cr) (MD 15.91 ml/min, 95% confidence interval [CI] 7.17-24.65 ml/min). Ideal body weight underestimated Cl(cr) (MD-5.15 ml/min, 95% CI -9.92 to -0.38 ml/min). No body weight (i.e., assumes body weight is 72 kg, thus removing the factor of 72 from the denominator of the equation) closely estimated Cl(cr) (MD 0.43 ml/min, 95% CI -5.42-6.27 ml/min). Adjusted body weight with correction factors of 0.3 or 0.4 also closely estimated Cl(cr) (MD 4.55 ml/min, 95% CI -11.41-20.50 ml/min, and MD 19.94 ml/min, 95% CI -9.6-49.49 ml/min, respectively). Total body weight with a rounded S(cr) value closely estimated measured Cl(cr) (MD 3.51 ml/min, 95% CI -17.18-24.20 ml/min). Ideal body weight with a rounded S(cr) value underestimated Cl(cr) (MD -29.45 ml/min, 95% CI -48.46 to -10.43).
Using the Cockcroft-Gault equation with no body weight and actual S(cr) value most closely estimated measured Cl(cr). In obese patients, it may be reasonable to use actual body weight with a correction factor of 0.3 or 0.4 and actual S(cr) value in the Cockcroft-Gault equation. Based on this analysis, the use of total body weight, ideal body weight, and a rounded S(cr) value cannot be recommended.
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.
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.
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.
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 x 140 = 700 mg.
Hematologic toxicity of an antineoplastic drug, carboplatin, is largely dependent on its pharmacokinetics. Its therapeutic efficacy may be related to plasma drug exposure. Dosage adjustment based on isotopic determination of glomerular filtration rate has been proposed, but its ambulatory use is not yet conceivable. The dosage adjustment based on a patient's creatinine clearance relies on accurate measurement of urine volume per unit time and can be done with ease.
A population pharmacokinetics study was undertaken to determine a relationship between carboplatin clearance and patient characteristics. A predictive formula was derived that was then prospectively evaluated, and its outcome was compared with that obtained by other methods available to predict carboplatin clearance.
Plasma carboplatin pharmacokinetics determined as ultrafilterable platinum in 70 patients (age range, 23-84 years) treated with different combination regimens that included carboplatin at doses ranging from 184 mg to 950 mg (1-hour intravenous infusion) for various tumor types. Data were analyzed using the nonlinear mixed effects model (NONMEM). The data from 34 patients (46 cycles) were utilized to derive the most predictive formula. The reliability of the formula was subsequently evaluated by analyzing the data obtained from 36 other patients (49 cycles).
Carboplatin clearance (mL/min) was found to be best predicted by the following formula: 0.134.weight + [218.weight.(1-0.00457.age).(1-0.314.sex)]creatinine expressed in micromolar concentration (with weight in kg, age in years, and sex = 0 if male and sex = 1 if female). Prospectively, this formula predicted the carboplatin clearance with good precision (median absolute percent error of 10% [range, 0% to 30%]) and minimal bias (median percent error of 2% [range, -25% to 30%]). This method of prediction was as accurate as the one derived from the measurement of glomerular filtration rate following the injection of 51 chromium-EDTA.
This formula for the determination of carboplatin clearance can permit individualized determination of carboplatin dosage in adults by simply multiplying the calculated carboplatin clearance by the area under the curve for the desired dosage administration.
Serum creatinine concentration is widely used as an index of renal function, but this concentration is affected by factors other than glomerular filtration rate (GFR).
To develop an equation to predict GFR from serum creatinine concentration and other factors.
Cross-sectional study of GFR, creatinine clearance, serum creatinine concentration, and demographic and clinical characteristics in patients with chronic renal disease.
1628 patients enrolled in the baseline period of the Modification of Diet in Renal Disease (MDRD) Study, of whom 1070 were randomly selected as the training sample; the remaining 558 patients constituted the validation sample.
The prediction equation was developed by stepwise regression applied to the training sample. The equation was then tested and compared with other prediction equations in the validation sample.
To simplify prediction of GFR, the equation included only demographic and serum variables. Independent factors associated with a lower GFR included a higher serum creatinine concentration, older age, female sex, nonblack ethnicity, higher serum urea nitrogen levels, and lower serum albumin levels (P < 0.001 for all factors). The multiple regression model explained 90.3% of the variance in the logarithm of GFR in the validation sample. Measured creatinine clearance overestimated GFR by 19%, and creatinine clearance predicted by the Cockcroft-Gault formula overestimated GFR by 16%. After adjustment for this overestimation, the percentage of variance of the logarithm of GFR predicted by measured creatinine clearance or the Cockcroft-Gault formula was 86.6% and 84.2%, respectively.
The equation developed from the MDRD Study provided a more accurate estimate of GFR in our study group than measured creatinine clearance or other commonly used equations.
The frequent need to obtain an estimate of renal function in cancer patients, not least for targeting carboplatin dose, has led to a number of approaches to estimate glomerular filtration rate (GFR). This study aimed to develop a simple and reliable method to estimate GFR using readily-available patient characteristics. Data from 62 patients with estimates of 51Cr-EDTA clearance were analysed to determine the most appropriate formula relating this method of measuring GFR to patient characteristics. The population pharmacokinetics of 51Cr-EDTA were analysed using NONMEM to evaluate the influence of each covariate. The formulae derived were then validated using a further 38 patients and compared with those obtained using existing formulae. 51Cr-EDTA clearance (GFR) was positively related to Dubois surface area, negatively related to age, and inversely related to serum creatinine (SCr). Females had lower 51Cr-EDTA clearance than males. The enzymatic method of SCr assay gave more reliable results than the Jaffe colorimetric method. A measure of creatine kinase significantly improved the estimation of GFR. The new formula produced estimates of GFR which were less biased (Mean Prediction Error = -3%) and more precise (Mean Absolute Prediction Error = 12%) than Cockcroft and Gault (-8% and 16%) or Jelliffe (-15% and 19%) estimates. The formulae developed here can be used to provide reliable estimates of GFR, particularly in regard to targeted dosing of carboplatin.
The aim was to compare doses of carboplatin calculated using the Calvert formula and Chatelut formula and also to compare doses calculated using Calvert formula, modified with non-isotopic estimation of GFR, using the Cockcroft and Gault formula or the Jelliffe formula. For formulae comparison, doses were calculated to target an AUC of 7 mg/ml x min. When compared with the dose derived from the Calvert formula, the doses calculated in 122 adult cancer patients using the Chatelut formula were significantly higher for males and significantly lower for females. There was a statistically significant difference between the dose per kg calculated for males and females (P<0.0001). The mean percentage difference in dose calculated with substituted measures of renal function with the Cockcroft and Gault formula and Jelliffe formula was -8% (standard deviation (S.D.) 17%) and -14% (S.D. 16%), respectively. Further prospective evaluation of the Chatelut formula is required before it can be recommended for routine clinical application.
Prediction of carboplatin clearance from standard morphological and biological patient characteristics
- E Chatelut
- P Canal
- Brumner
The controversy remains, a consensus is needed: how to assess renal function for dosing carboplatin
- J A Smith
K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification
Documento de consenso: recomendaciones sobre la utilización de ecuaciones para la estimación del filtrado glomerular en adultos
- S Gracia
- R Montañés
- Bover
- Documento De
- Consenso
Appropriate chemotherapy dosing for obese adult patients with cáncer: American Society of Clinical Oncology clinical practice guideline
- J J Griggs
- P B Mangu
- H American
An analysis of measured and estimated creatinine clearance rates in normal weight, overweight, and obese patients with gynecologic cancers
- W K Nelson
- Formica
- Jr
- D L Cooper
The influence of body size descriptors on the estimation of kidney function in normal weight, overweight, obese, and morbidly obese adults
- E J Park
- Pai
- Mp
- T Dong