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Estimation of glomerular filtration rate in cancer patients

Estimation of glomerular filtration rate in cancer patients British Journal of Cancer (2001) 84(4), 452–459 © 2001 Cancer Research Campaign http://www.bjcancer.com doi: 10.1054/ bjoc.2000.1643, available online at http://www.idealibrary.com on Estimation of glomerular filtration rate in cancer patients 1 1 1 2 3 1 JG Wright , AV Boddy , M Highley , J Fenwick , A McGill and AH Calvert 1 2 3 Departments of Oncology, Medical Physics and Clinical Biochemistry, University of Newcastle, NE2 4HH, UK Summary 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 Cr-EDTA clearance were analysed to determine the most appropriate formula relating this method of measuring GFR to patient characteristics. The population pharmacokinetics of Cr-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. Cr-EDTA clearance (GFR) was positively related to Dubois surface area, negatively related to age, and inversely related to serum creatinine (SCr). Females had lower Cr-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. © 2001 Cancer Research Campaign http://www.bjcancer.com Keywords: glomerular filtration; renal function; EDTA; population pharmacokinetics It is frequently necessary to estimate the renal function of cancer monitoring for the toxicities of these agents is undertaken. patients. Many of the drugs used in treating cancer are, at least in Assessing renal function in such studies is additionally important part, excreted via the kidneys, so that renal impairment will lead to because impaired renal clearance of a drug can lead to toxicities in impaired drug elimination and potentially lethal toxicity. For most organs other than the kidney that are related to pre-treatment renal practical purposes, glomerular filtration rate (GFR) may be taken function (Gietema et al, 1995). as an indicator of overall kidney function and can be used to In the case of GFR-based dosing of carboplatin, a clear relation- modify drug dosing. The best-known example of this is carbo- ship has been demonstrated between the rate of drug elimination platin, which is eliminated almost entirely by glomerular filtration. (clearance – Cl) and overall systemic drug exposure, as quantified Dosing of carboplatin based on GFR has become the standard by the area under the plasma concentration time curve (AUC). practice and is indeed included on the data sheet for the product This is implemented in the Calvert formula (Calvert et al, 1989): sold in the USA (Egorin et al, 1984; Calvert et al, 1989). In addi- –1 –1 –1 Dose (mg) = AUC (mg ml min ) ´ (GFR (ml min ) + 25). tion, methotrexate is predominantly excreted by the kidneys and In using this equation, dose adjustment is important in avoiding an estimate of renal function is essential before the use of high- toxicity, which has been shown to be closely related to AUC dose therapy (Stoller et al, 1975). Many other drugs, such as (Egorin et al, 1984; Jodrell et al, 1992). Using GFR to achieve a etoposide (Pflüger et al, 1993), topotecan (O’Reilly et al, 1996) target AUC also ensures appropriate dosing for patients with and aminoglycoside antibiotics (Jelliffe et al, 1991), also have a higher-than-average GFR, who may otherwise receive inadequate large element of renal clearance. treatment. Retrospective studies have shown that response rate in Measurements of GFR are also essential in monitoring patients ovarian cancer (Jodrell et al, 1992) and relapse rate in testicular on treatment. The use of nephrotoxic drugs such as cisplatin cancer (Childs et al, 1992) are related to the area under the curve to requires that an index of renal function be obtained repeatedly which patients are exposed. during treatment (Reece et al, 1987). Chemotherapy may increase Despite the importance of measuring GFR, good methods of renal function in certain patients if there is a response in pelvic doing so are not readily available to many physicians treating disease, leading to relief of ureteric obstruction and this, in turn, cancer. The Cr-EDTA clearance method (Chantler et al, 1969) is may require an increase in the dose of a renally cleared agent such widely accepted as being accurate and reproducible and was used as carboplatin (Calvert et al, 1989). The evaluation of new anti- in many of the initial studies used to derive carboplatin dosing cancer agents in Phase I and II studies requires that careful formulae in Europe. Other isotope-based methods, such as those using iodothalamate or DTPA have been shown to be equivalent Received 17 May 2000 (Perrone et al, 1990; Millward et al, 1996). However, these Revised 11 October 2000 methods are relatively costly and are not available in many parts of Accepted 21 November 2000 the world ( Cr-EDTA is not licensed for this use in the USA). Correspondence to: A Boddy Alternative, more convenient, methods of estimating GFR have 452 Renal function in cancer patients 453 been in use for many years, usually based on a measure of serum a nonlinear hierarchical model in the computer program creatinine (SCr), the age, size and sex of the patient (Cockcroft- NONMEM. Two commonly used creatinine assays (kinetic Jaffe Gault (C&G) (Cockcroft and Gault, 1976) or Jelliffe (Jelliffe, and enzymatic) were investigated to determine the consequences 1973)). Although approximately 20% of creatinine elimination is for GFR prediction. The formulae derived here provide better, by tubular secretion (Perrone et al, 1992), use of these methods to assay-specific estimates for GFR, which are sufficiently precise predict GFR is based on the assumption that creatinine is elimin- and unbiased to be employed for carboplatin dose-optimization. ated entirely by glomerular filtration. Also, variations in the assay methods for creatinine introduce another source of variability PATIENTS AND METHODS (Hartman, 1985). These formulae were derived over 20 years ago using a 24-hour A total of 102 patients, all performance status 0 or 1, undergoing urinary creatinine clearance as the reference. Recent data on the treatment for cancer at the Northern Centre for Cancer Treatment, plasma pharmacokinetics of carboplatin when the doses were Newcastle General Hospital, UK were assessed. All patients gave calculated using the C&G formula as the estimate of GFR have informed consent and the study was approved by the local ethics shown that the AUCs obtained were significantly lower than those committee. Prior to analysis, one patient was excluded because of intended (Van Warmerdam et al, 1996; Ando et al, 1997). A direct acute renal failure, and another because of extremely high creatine 51 –1 comparison with Cr-EDTA clearance has shown that the C&G kinase (2048 units l ), secondary to chest wall invasion by method overestimates GFR in patients with normal renal function tumour. 38 patients were randomly assigned to the validation set, (Calvert, 1997). The use of weight as the index of body size can which played no part in the development of the models. The also lead to an overestimate of GFR in obese patients (Salazar and remaining 62 patients were used to develop formulae for predic- Corcoran, 1988). tion of GFR. The following covariates were recorded: age, weight, The measurement of creatinine clearance using a 24-hour urine height, sex, tumour type, weight change in the past month, pres- collection has given satisfactory results for carboplatin dosing in ence of nephrectomy, presence of pelvic disease (defined as the some trials (Egorin et al, 1984). However complete 24-hour urine presence of disease below the level of the renal pedicles), collections are notoriously difficult to achieve and the accuracy of chemotherapy and concomitant medication, previous chemo- the result also depends on the method used for creatinine estima- therapy, liver function tests (bilirubin, alanine transaminase, alka- tion (Perrone et al, 1992). line phosphatase and albumin), other blood chemistry (urea, We have developed a method to estimate GFR. In order to be sodium, chlorine, potassium, creatinine and creatine kinase) and widely applicable, it is based on the serum creatinine level and Cr-EDTA pharmacokinetics. Blood samples for biochemistry 51 51 other readily obtainable covariates. The pharmacokinetics of Cr- were taken at the same time as the first baseline sample in the Cr- EDTA and its relationship to patient covariates were studied using EDTA estimation of renal function. Table 1 Characteristics of all patients studied Population characteristics Model development Prospective validation No. of patients 62 38 Age (years) 58 (23–81) 56 (18–80) Weight (kg) 71 (41–113) 69 (36–93) Height (m) 1.64 (1.48–1.9) 1.64 (1.47–1.96) BSA Dubois (m ) 1.8 (1.34–2.37) 1.76 (1.31–2.18) 51 –1 CrEDTA clearance (ml min ) 73 (30–148) 91 (42–176) Serum creatinine (mmol) Enzymatic method 84 (50–190) 79 (45–195) Jaffe method 90 (60–167) 84 (56–174) –1 Creatine kinase (units l ) 44 (6–209) 56 (18–188) Sex (male/female) 20/42 13/25 Prior cisplatin therapy 10 5 Nephrectomies 2 1 Presence of pelvic disease 17 8 –1 Albumin (g l ) 40 (25–51) 41 (33–50) Diagnosis Ovarian 24 12 Urinary tract 11 4 Breast 5 2 Testicular 6 3 Colorectal 4 3 Mesothelioma 3 6 Melanoma 2 1 Lung 1 1 Sarcoma 4 1 Cervical 1 Brain 1 2 Adrenocortical 1 Unknown primary 2 Values given as median (range). © 2001 Cancer Research Campaign British Journal of Cancer (2001) 84(4), 452–459 454 JG Wright et al A Hitachi 717 auto-analyser was used for the analysis of creatine where y is the estimate and x is the observed value. In comparing kinase (CK-NAC activated kit, Boehringer-Mannheim) and serum the derived and existing formulae for GFR, the statistical signific- creatinine by kinetic Jaffe (HiCo creatinine, Boehringer-Mannheim) ance of differences in MPE and MAPE was assessed using the and enzymatic (Creatinine PAP, Boehringer-Mannheim) methods. paired t-test and the Wilcoxon signed rank test, respectively. Table 1 summarizes the characteristics of the patients studied. RESULTS Procedure for Cr-EDTA clearance assessment Comparison of serum creatinine assays Cr-EDTA was administered as an intravenous bolus and plasma samples were withdrawn from the opposite arm at approximately Systematic differences were found between the kinetic Jaffe and 2, 3, 4 and 5 hours. Linear regression on the logarithmically trans- enzymatic serum creatinine assays (Figure 1). The Jaffe method formed counts against time was used to estimate the elimination gave higher results than the enzymatic at lower concentrations –1 rate constant K, with volume of distribution V calculated by back (<100 micromoles l ). This is consistent with endogenous inter- extrapolation of this log-transformed data. Individual estimates of fering substances resulting in a higher value with the former assay. Cr-EDTA clearance were calculated from the product KxV. This At higher concentrations, the enzymatic assay produced larger is the routine practice of the Medical Physics department and is a values than the kinetic Jaffe. As serum creatinine measures are method widely employed for this purpose (Chantler et al, 1969). reciprocally related to renal function, the discrepancies at the These estimates of Cr-EDTA clearance were used for the evalua- lower end of the range (high GFR) would have a large impact on tion of the formula on the validation set and were consistent with GFR estimation. those calculated by nonlinear regression. The Cr-EDTA concen- –1 trations (cpm ml ) versus time data were used directly in the Development of formulae population analyses. Given these differences between assays, independent predictive formulae were derived for each assay. The formulae derived from Population pharmacokinetic analysis the initial 62 patients are shown in Table 2, together with those for Model development the most commonly used current methods, the Cockcroft and The pharmacokinetics of Cr-EDTA were analysed in the model Gault and Jelliffe formulae. The functional form of the newly development dataset (n = 62) using the first-order conditional es- derived formulae is identical to that of the Jelliffe formula, but the timation method in the computer program NONMEM V5 coefficients differ substantially. This format for the equation was (Boeckmann et al, 1997). The data were described accurately by a found to provide the best estimates of Cr-EDTA clearance, one compartment model with first-order elimination. This model although numerous other combinations of additive and multiplica- was parameterized in terms of clearance and volume of distribu- tive models were explored. Dubois Body surface area (Dubois and 0.425 0.725 tion, with an interindividual random effect on each parameter. A Dubois, 1916) (0.007184 ´ weight ´ height ) proved to be proportional error model best described interindividual and the most predictive body size variable. Weight, height, Gehan residual error. For interindividual error, this model is consistent and George surface area (Gehan and George, 1970) (0.02350 0.51456 0.42246 with the implied loss function, as percentage errors in dose are ´ weight ´ height ) or ideal body weight as body size closely related to percentage errors in AUC obtained. Although measures were inferior in the model development set. supported by the fit of the model without covariates, these assump- The covariate creatine kinase (CK) was also found to be import- tions were re-evaluated as the explanatory covariate model for ant in the model. Since accurate and reproducible measures of CK clearance was adjusted. As over 20 covariates were available, it activity may not be universally available, formulae without this was necessary to take a pragmatic approach to the selection of covariate were also derived. There was no detectable independent important covariates and their relationship to each other in the influence on EDTA clearance of prior cisplatin therapy, nephrec- formula. The inclusion of a covariate in the formula, and the tomy or presence of pelvic disease in the patients studied. appropriateness of the functional form chosen, were determined primarily by changes in residual plots, estimates of interindividual variability and the NONMEM objective function, although no statistical significance was attached to changes in the latter measure. Initial investigations were based on Efroymson’s algo- rithm (Efroymson, 1962), a subset selection procedure that altern- Y=0.76X + 24.4 ates between forward selection and backward elimination, commencing from covariate models selected randomly and also those suggested from prior considerations. Comparisons on the validation set Bias was assessed by the mean percentage error (MPE) and preci- sion by mean absolute percentage error (MAPE). Respectively, 0 50 100 150 200 these are calculated for n patients as: –1 Enzymatic (micromolesl ) Figure 1 Plot of serum creatinine estimates obtained by the enzymatic or 1 1 Jaffe methods. Both model development and validation data sets are yx yx MPE = () and MAPE = included. Solid line represents the regression of Jaffe on enzymatic S S1 n x n x 1 1 - 1 determinations. Dotted line is the line of identity British Journal of Cancer (2001) 84(4), 452–459 © 2001 Cancer Research Campaign –1 l ) Jaffe (micromoles Renal function in cancer patients 455 Table 2 Formulae for the estimation of GFR. Comparison of equations developed here and those routinely used Formulae for the prediction of creatinine clearance (140 – Age) ´ Wt ´ (1 – 0.15 ´ Sex) CrCl = Cockcroft and Gault (1976): 72 ´ SCr ´ 0.0113 (98 – 0.8 ´ (Age – 20)) ´ (1 – 0.1 ´ Sex) ´ (BSA/1.73) CrCl = Jelliffe and Jelliffe (1973): SCr ´ 0.0113 Formulae derived for GFR in a cancer population Using enzymatic serum creatinine (4350 – 34 ´ Age + 522 ´ Ln(CK)) ´ BSA ´ (1 – 0.217 ´ Sex) GFR = (1) With CK: SCr (6230 – 32.8 ´ Age) ´ BSA ´ (1 – 0.23 ´ Sex) GFR = (2) Without CK: SCr Using Jaffe Serum Creatinine (4520 – 40 ´ Age + 570 ´ Ln(CK)) ´ BSA ´ (1 – 0.15 ´ Sex) GFR = (3) With CK: SCr (6580 – 38.8 ´ Age) ´ BSA ´ (1 – 0.168 ´ Sex) GFR = (4) Without SCr –1 CrCl = Creatinine clearance; GFR = Glomerular filtration rate ml min ; Age = Age in years;Ln(CK) = natural logarithm of creatine –1 0.425 0.725 kinase in units l ; Sex = 1 if female; 0 if male, BSA = Dubois body surface area = 0.007184 ´ Weight ´ Height ; SCr = Serum –1 Creatinine in mmol l ; Wt = Weight in kg. Table 3 Percentage prediction errors on the validation dataset. Formula Assay MAPE MPE Min 10th percentile 90th percentile Max C & G Enzymatic 16 –8 –46 –26 16 42 Jelliffe Enzymatic 19 –15 –33 –30 5 30 CK (1) Enzymatic 12 –3 –20 –17 15 33 NonCK (2) Enzymatic 13 –5 –24 –20 8 36 C & G Jaffe 19 –12 –62 –35 11 40 Jelliffe Jaffe 22 –19 –50 –37 4 16 CK (3) Jaffe 16 –1 –41 –24 22 50 NonCK (4) Jaffe 15 –5 –39 –26 17 39 Numbers in parentheses refer to equations in Table 2. MAPE is mean absolute percentage error, a measure of precision, and MPE is mean percentage error, a measure of bias. The effect of gender on GFR was relatively small (typical Comparison of new and existing formulae female GFR 77–85% that of typical male). This is similar to the Measures of performance calculated from the separate validation arbitrary correction factor introduced by Cockcroft and Gault. set for each formula are shown in Table 3. The derived formulae With the enzymatic assay using equation (1), GFR changes by were more precise and less biased than the Cockcroft and Gault approximately 8% for 10 years of age difference from the median formula and it would appear that, in general, enzymatic serum (57 years). Changes of BSA of 0.1 m produce GFR changes of creatinines gave more accurate estimates of GFR. Statistical 5%. The relationship with SCr is a reciprocal one, but around the comparisons of the estimates of GFR from each formula are shown median value, an increase in GFR of 20% is associated with a –1 in Table 4. As shown in Figure 2, the formulae derived here, for decrease in SCr of 14 micromoles l , while a 20% decrease corres- –1 both methods of serum creatinine assay, are significantly less ponds to a SCr increase of 20 micromoles l . Variation of CK from –1 biased than the C&G or Jelliffe formulae. Figure 3 shows a 22 to 114 (median 50) units l is associated with a 10% variation comparison of the Cr-EDTA clearance in the validation dataset, of GFR around the median value. © 2001 Cancer Research Campaign British Journal of Cancer (2001) 84(4), 452–459 456 JG Wright et al Table 4 Statistical significance of differences in mean percentage error (MPE) by paired two-sided t-test and mean absolute percentage error (MAPE) by nonparametric two-sided Wilcoxon ranked sum test on the validation set. Values significant at the 5% level are shown in bold Null Hypothesis: There is no predictive difference P-value of evidence against, for MPE P-value of evidence against, for MAPE between first and second formulae (equation numbers in parentheses, see Table 2) With enzymatic serum creatinine CK (Eq 1) vs C&G 0.01 (–3 vs –8) 0.02 (12 vs 16) NonCK (Eq 2) vs C&G 0.15 (–5 vs –8) 0.03 (15 vs 19) CK (Eq 1) vs NonCK (Eq 2) 0.04 (–3 vs –5) 0.39 (12 vs 13) With Jaffe serum creatinine CK (Eq 3) vs C&G <0.01 (–1 vs –12) 0.17 (16 vs 19) NonCK (Eq 4) vs CG <0.01 (–5 vs –12) 0.01 (15 vs 19) CK (Eq 3) vs NonCK (Eq 4) 0.01 (–1 vs –5) 0.40 (16 vs 15) Comparing formulae for each assay CK enzymatic (Eq 1) vs CK Jaffe (Eq 3) 0.87 (–3 vs –1) <0.01 (12 vs 16) NonCK enzymatic (Eq 2) vs NonCK Jaffe (Eq 4) 0.98 (–5 vs –5) 0.05 (13 vs 15) exposure to active drug. The optimum method for GFR estimation, and that used to derive the Calvert equation, is clearance of Cr- Jaffe Enzymatic EDTA. Substitution of other methods for estimation of GFR has been employed, with varying degrees of success. Unfortunately, the most commonly used method, the Cockcroft and Gault equation with a measure of serum creatinine, results in significant 200 Female Male line of equality 20% error . {]. -~-- -· .. CG Jel CK NCK CG Jel CK NCK -· .. Formula and Cr assa y 4-.-.-~~-- • -~--·--·· a.····· .. ··· ..... ·· Figure 2 Comparison of Cockroft and Gault (CG), Jelliffe (Jel) and novel formulae for the estimation of GFR, with both Jaffe and enzymatic methods of SCr measurement. CK is the formula using creatine kinase (Equations 1 20 and 3), NCK is without creatine kinase (Equations 2 and 4). MPE is mean 0 20 40 60 80 100 120 140 160 180 200 prediction error (solid columns), with the extreme range of prediction errors 51 –1 CrEDTA clearance (ml min ) shown as error bars with estimates obtained either by equation 1, or using the C&G formula. The performance of the formula developed here is super- ior to that of C&G, with almost all of the patients estimated GFR within 20% of the observed value. While no effect of was observed 200 in the model development group, 4 of the 5 patients (one had no enzyme creatinine measure) in the validation group who had previ- ously been treated with cisplatin seemed to show a small but systematic bias in the estimation of GFR (Figure 3). In 2 of these 100 patients EDTA clearance was overestimated by greater than 20%. .. This phenomenon should be investigated further and care should be taken in applying the proposed formula in cisplatin-pretreated patients. 0 0 20 40 60 80 100 120 140 160 180 200 51 –1 CrEDTA clearance (ml min ) DISCUSSION Figure 3 Performance of A: best predictive equation (1) and B: Cockcroft A measure of glomerular function provides a practical, easily and Gault equation, using enzymatic method of serum creatinine assay. Estimates of GFR are compared to measured Cr-EDTA clearance, plotted obtainable method to estimate overall renal function. In the treat- with line of identity and 20% error boundaries. Data for males (l l) and ment of patients with carboplatin, a good measure of renal function females (l) plotted separately. Triangles indicate patients with prior cisplatin is essential to obtain predictable and uniform pharmacological treatment British Journal of Cancer (2001) 84(4), 452–459 © 2001 Cancer Research Campaign MPE (%) –1 –1 ) CK formula estimate (ml min ) Cockcroft and Gault estimate (ml min Renal function in cancer patients 457 deviation from the target AUC. The use of the C&G model to esti- The estimates of GFR from the Jelliffe formula were extremely mate GFR is not appropriate for dosing of carboplatin because it downward biased in the validation set, perhaps because this was derived in an inappropriate patient population, takes no formula was originally based on 15 patients who had undergone account of non-GFR elimination of creatinine and is highly depen- renal transplantation. Using the population pharmacokinetic dent on the method used to measure creatinine in serum. approach, the formulae arrived at have the same structural form In this study the relationship between Cr-EDTA pharmacokin- as that of Jelliffe, although the coefficients estimated from the etics and patient covariates has been explored in order to develop a current study are substantially different. Jelliffe assumed that the more robust, flexible and reliable equation for the calculation of percentage reduction in GFR for female patients, all other covari- renal function from serum creatinine. The population pharmaco- ates being equal, was 10%; compared to the 17% estimated in this kinetic approach has been applied to a number of drugs used in study. C&G assumed 15% in their weight-based formula, but chemotherapy, and its use to estimate GFR from the pharmaco- Martin et al estimated the value to be somewhat higher at 25%. A kinetics of EDTA represents the use of contemporary analysis similar coefficient for the negative effect of age was found by methods to a persistent clinically-relevant problem. Jelliffe (–41) and in the current study (–39). The consistently A potential source of variability in the results previously lower predictions of the former formula are due to the difference in reported for GFR estimation arises from the serum creatinine the constant term in the first bracket. assay since different methods give systematically different results Recently, Levey et al derived several formulae for the estima- (Figure 1). Creatinine is partially eliminated by tubular secretion, tion of renal function from 1628 patients with renal disease (Levey in addition to glomerular filtration. The commonly used alkaline et al, 1999). This population is fundamentally different from that picrate colourimetric reaction (Jaffé reaction) over-estimates the studied here and using their formula, also derived from readily serum level of creatinine by a similar proportion, thus partly available patient covariates, on the validation set provided predic- compensating for the error. Thus, when a 24-hour creatinine clear- tions comparable to that of the Jelliffe formula (MAPE 20%, MPE ance measurement is made, the potential over-estimation of GFR –15%, range –50% to 31%, with the Jaffe creatinine assay; MAPE is compensated by the over-estimation of the serum (but not the 17%, MPE-11%, range –52% to 53% with the enzymatic assay). urinary) level of creatinine. However, if one of the more accurate, Interestingly, their formula was derived using a kinetic alkaline enzymatic methods for creatinine measurement is used, then GFR picrate assay for serum creatinine. This comparison illustrates the will be overestimated. In all the formulae for GFR developed to dangers of applying formulae in populations different from that in date, the reciprocal of serum creatinine is used, thus even small which they were derived – not only are there difficulties in extrapo- discrepancies between assays can compromise GFR prediction. It lating into regions with little data, but the relationship between would appear from this study that the enzymatic creatinine assay covariates and renal function need not be the same in different gave more informative serum creatinine values for the prediction populations. Indeed, Levey et al found both serum urea nitrogen of renal function, especially in conjunction with the adjustment for and albumin to be useful independent predictors, whereas these creatine kinase (CK). covariates did not appear to be predictive in the current study As in previous studies, the C&G formula was found to underes- population. timate GFR (or carboplatin clearance) on average and produced Although Martin et al used weight rather than BSA as a measure widely scattered predictions (Van Warmerdam et al, 1996; of body size (Martin et al, 1998), the effect of age (–0.50% GFR Okamoto et al, 1998; Ando et al, 1997). Another study has shown per year) is similar to the enzymatic formula derived here (equa- that C&G overpredicts GFR in renally impaired patients (Levey tion 2, –0.53% per year). The use of weight was investigated, but et al, 1999). The poor performance of C&G may be a consequence could not be justified in this study. It is important that Dubois BSA 0.425 0.725 of differences between the populations under study, or of varia- (0.007184 ´ weight ´ height ) (Dubois and Dubois, 1916) is tions in the assay method for serum creatinine. Cockcroft and used, as the Gehan and George estimate of BSA (0.02350 ´ 0.51456 0.42246 Gault based their formula on 249 patients, of whom only 4% were weight ´ height ) (Gehan and George, 1970) places more female, and excluded patients whose serum creatinine was not emphasis on weight and failed to improve predictive performance. deemed to be at steady state. The validation set in this study indi- The use of creatine kinase (CK) in the prediction of GFR is cates that the use of the C&G formula will systematically under- novel. CK is released into the bloodstream by cardiovascular and estimate GFR in patients with normal or mildly impaired renal skeletal muscle turnover and gross elevation of serum CK is a function. When C&G is used as the basis for carboplatin dosing it symptom of myocardial infarction. A source of interindividual has been common for target AUCs to be set higher than when an variation in serum creatinine, other than renal function, is its rate isotope method is used (Ando et al, 1997). Nevertheless, pharma- of endogenous production. Creatine kinase was investigated as a cokinetically based dosing of carboplatin using C&G, although covariate because it mediates the interconversion of creatinine and greatly superior to surface-area based dosing, will still lead to a creatine intracellularly, and so may directly influence serum cre- wide scatter of AUC values, with patients potentially receiving atinine levels, as well as reflecting the rate of muscle turnover. either toxic or sub-therapeutic doses. Cachexia in cancer patients may cause reduced muscle mass and An improved formula recently proposed by Martin et al (1998) hence reduced creatinine production in some patients. Even in the was derived in cancer patients using similar methodology to the absence of cachexia, there is likely to be interindividual variation current investigation. In that study, the statistical comparison with in the rate of endogenous creatinine production, for which CK may C&G was limited to failing to reject the null hypothesis that their act as a surrogate. The inclusion of CK in the formula led to signifi- formula was unbiased, a hypothesis successfully rejected for cantly less bias, particularly when used in conjunction with the C&G. However, on the validation set in this study, the formula enzymatic creatinine assay (equation 1). Any adverse effect on suggested by those authors showed no improvement in precision GFR estimation due to artefactually elevated values of CK is over C&G, due to a skewed distribution of prediction errors (data minimised by the use of a logarithmic transformation. CK may not shown). prove to be a useful surrogate in other populations, however care © 2001 Cancer Research Campaign British Journal of Cancer (2001) 84(4), 452–459 458 JG Wright et al must be taken in employing this covariate when it takes very high (Huitema et al, 2000) has confirmed the accuracy and precision of values. the model. They should also be applicable to the individualised Given that a primary aim of estimating GFR is its use in carbo- dosing of other drugs, such as aminoglycoside antibiotics, and the platin dosing, Chatelut et al (1995) used a population pharmacokin- routine monitoring of renal function before and after potentially etic approach with NONMEM to derive a formula for the dosing nephrotoxic chemotherapy. of carboplatin based directly on weight, age and serum creatinine. The latter was determined by the Ektachem enzymatic assay. The ACKNOWLEDGEMENTS Chatelut formula for carboplatin clearance: This work was supported by the Cancer Research Campaign and Bristol Myers Squibb. Cl (carboplatin) = 0.134 × Wt (218 × Wt × (1 – 0.00457 × Age) × (1 – 0.217 × Sex) REFERENCES Scr Ando Y, Saka HMA, Sakai S and Shimokata K (1997) Adjustment of creatinine clearance improves accuracy of Calvert’s formula for carboplatin dosing. Br J Cancer 76: 1067–1071 gives different results to doses predicted using the Calvert formula 51 Boeckmann A, Beal SL and Sheiner LB (1997) Technical report of the Division of with Cr-EDTA clearance. Compared to estimates derived from Clinical Pharmacology. In: NONMEM users manual V5 the latter method, the Chatelut formula has an MPE of 4%, an Calvert AH (1997) A review of the pharmacokinetics and pharmacodynamics of MAPE of 17% and a range of –34% to +45%. Substituting the combination carboplatin/paclitaxel. Semin Oncol 24: S85–S90 enzymatic formulae with CK (equation 1) into the Calvert formula Calvert AH Newell DR, Gumbrell LA, O’Reilly S, Burnell M, Boxall FE, Siddik ZH, Judson IR, Gore ME and Wiltshaw E (1989) Carboplatin dosage: gives a MPE 2%, a MAPE of 9% and a range of –17% to +26%. prospective evaluation of a simple formula based on renal function. J Clin Studies comparing the performance of the Chatelut formula Oncol 7: 1748–1756 with carboplatin pharmacokinetics have shown conflicting results. Chantler C, Garnett ES, Parsons V and Veall N (1969) Glomerular filtration rate Okamoto et al (1998), studied 52 patients who had received carbo- measurement in man by the single injection method using CrEDTA. Clinical Science, 37: 169–190 platin. Using an enzymatic assay for SCr, the Chatelut formula was Chatelut E, Canal P, Brunner V, Chevreau C, Pujol A, Boneu A, Roche H, Ilouin G inferior to dosing using C&G in the Calvert formula, especially and Bugat R (1995). Prediction of carboplatin clearance from standard with low doses of carboplatin. It was proposed that differences morphological and biological patient characteristics. J Natl Cancer Inst 87: between the SCr assay or demographic differences between the 573–580 patients studied may have been responsible. van Warmerdam et al Childs W, Nicholls J and Horwich A (1992) The optimisation of carboplatin dose in carboplatin, etoposide and bleomycin combination chemotherapy for good (1996) studied carboplatin pharmacokinetics in 14 non-small cell prognosis metastatic nonseminomatous germ cell tumours of the testis. Ann lung cancer patients with metastatic or unresectable disease, who Oncol 3: 291–296 were also receiving etoposide, ifosfamide and mesna. They found Cockcroft D and Gault M (1976) Prediction of creatinine clearance from serum similar root mean square errors for the prediction of AUC using creatinine. Nephron 16: 31–41 Dubois D and Dubois EF (1916) A formula to estimate the approximate surface area the Chatelut formula (14%), or the Calvert formula with C&G if height and weight be known. Archives of Internal Medicine, 17: 863–871 (17%) or 24-hour creatinine clearance (15%). It was concluded Efroymson MA (1962) In Mathematical Methods for Digital Computers, Ralston A that the Chatelut formula was superior, as the null hypothesis that and Wilf HS (eds). Wiley: New York it was unbiased (MPE = –5%) could not be rejected on this small Egorin MJ, van Echo DA, Tipping SJ, Olman EA, Whitacre MY, Thompson BW and dataset, which was not the case for 24-hour creatinine clearance Aisner J (1984) Pharmacokinetics and dosage reduction of cis-diammine (1, 1-cyclobutanedicarboxylato)platinum in patients with impaired renal function. (MPE = –9%) and C&G (MPE = 11%). A recent study of the Cancer Res 44: 5432–5438 combination of carboplatin, dosed according to Chatelut, in combi- Fukuda M, Oka M, Soda H, Terashi K, Kawabata S, Nakatomi K, Takatani H, nation with irinotecan in 11 patients also found a good correlation Tsurutani J, Tsukamoto K, Noguchi Y, Fukuda M, Kinoshita A and Kohno S between predicted and observed clearance (Fukuda et al, 1999). (1999). Phase I study of irinotecan combined with carboplatin in previously untreated solid cancers. Clinical Cancer Research, 5: 3963–3969 The study presented here extends and refines those previously Gehan EA and George SL (1970) Estimation of human body surface area from performed in this area. The effects of different assay methods for height and weight. Cancer Chemother Rep 54: 225–235 serum creatinine, particularly the more common Jaffe assay, on Gietema JA, Veldhuis GJ, Guchelaar HJ, Willemse PHB, Uges DRA, Cats A, renal function prediction have been evaluated and creatine kinase Boonstra H, van der Graaf WTA, Sleijfer DT, de Vries EGE and Mulder NH has been identified as a novel predictive factor for GFR estimation. (1995) Phase II and pharmacokinetic study of lobaplatin in patients with relapsed ovarian cancer. Br J Cancer 71: 1302–1307 Evaluation of the models developed in the independent validation Hartman AE (1985) Accuracy of creatinine results reported by participants in the dataset suggests that the formulae described here represent an CAP Chemistry Survey Program. Archives of Pathology and Laboratory improvement on those currently available. These formulae are not Medicine 109: 1068–1071 recommended for use in paediatric patients, where the dosing of Huitema ADR, Mathot RAA, Tibben MM, Schellens JHM, Rodenhuis S and Beijnen JH (2000) Validation of techniques for the prediction of carboplatin exposure: carboplatin should be estimated from weight and Cr-EDTA half- Application of Bayesian methods. Clinical Pharmacology and Therapeutics 67: life (Newell et al, 1993) or from direct determination of carbo- 621–630 platin pharmacokinetics (Peng et al, 1995). Nor should these Jelliffe R (1973) Creatinine clearance: bedside estimate. Ann Intern Med 79: formulae be used in patients with acute renal failure, as they 604–605 constitute an entirely different population to that studied. Jelliffe R, Iglesias T, Hurst A, Foo K and Rodriguez J (1991) Individualising gentamicin dosage regimens: A comparative review of selected models, data The formulae derived here provide accurate and assay-specific fitting methods and monitoring strategies. Clin Pharmacokin 21: 461–478 predictions and will permit more accurate dosing of carboplatin, Jodrell DI, Egorin MJ, Canetta RM, Langenberg P, Goldbloom EP, Burroughs JN, via the Calvert formula, and more precise estimation of renal func- Goodlow JL, Tan S and Wiltshaw E (1992) Relationships between carboplatin tion in clinical investigations. Following publication of this method exposure and tumor response and toxicity in patients with ovarian cancer. J Clin Oncol 10: 520–528 in abstract form (Wright et al, 1999), a prospective evaluation British Journal of Cancer (2001) 84(4), 452–459 © 2001 Cancer Research Campaign Renal function in cancer patients 459 125 169 99 Levey, AS, Bosch JP, Lewis JB, Greene T, Rogers N and Roth D (1999) A more insufficiency: Simultaneous comparison of I-iothalamate, Yb-DTPA, accurate method to estimate glomerular filtration rate from serum creatinine: Tc-DTPA and inulin. Am J Kid Dis 16: 224–235 A new prediction equation. Ann Intern Med 130: 461–470 Perrone RD, Madias NE & Levey AS (1992) Serum creatinine as an index of Martin L, Chatelut E, Boneu A, Rostaing L, Roussilhes C and Caselles O (1998) renal function: New insights into old concepts. Clin Chem 38: Improvement of the Cockcroft and Gault equation for predicting glomerular 1933–1953 filtration in cancer patients. Bulletin du Cancer 85: 631–636 Pflüger, K-H, Hahn M, Holz J-B, Schmidt L, Köhl P, Fritsch H-W, Jungclas H and Millward MJ, Webster LK, Toner GC, Bishop JF, Rischin D, Stokes KH, Johnston Havemann K (1993) Pharmacokinetics of etoposide: correlation of VK and Hicks R (1996) Carboplatin dosing based on measurement of renal pharmacokinetic parameters with clinical conditions. Cancer Chemother function – experience at the Peter MacCallum Cancer Institute. Australian and Pharmacol 31: 350–356 New Zealand Journal of Medicine 26: 372–379 Reece PA, Stafford I, Russell J, Khan M and Gill PG (1987) Creatinine clearance as Newell DR, Pearson ADJ, Balmanno K, Price L, Wyllie RA, Kier M, Calvert AH, a predictor of ultrafilterable platinum disposition in cancer patients treated with Lewis IJ, Pinkerton CR and Stevens MCG (1993) Carboplatin cisplatin: relationship between peak ultrafilterable platinum plasma levels and pharmacokinetics in children: the development of a pediatric dosing formula. nephrotoxicity. J Clin Oncol 5: 304–309 J Clin Oncol 11: 2314–2323 Salazar DE and Corcoran GB (1988) Predicting creatinine clearance and renal drug Okamoto H, Nagatomo A, Kunitoh H, Kunikane and Watanabe K (1998) Prediction clearance in obese patients from estimated fat-free body mass. Am J Med 84: of carboplatin clearance: comparison of the performance of three formulae. 1053–1060 Cancer Chemother Pharmacol 42: 307–312 Stoller R, Jacobs S, Drake J, Lutz R and Chabner B (1975) Pharmacokinetics of O’Reilly S, Rowinsky EK, Slichenmeyer W, Donehower RC, Forastiere AA, high-dose methotrexate (NSC-740). Cancer Chemother Rep 6: Ettinger DS, Chen TL, Sartorius S and Grochow LB (1996) Phase I and 19–24 pharmacologic study of topotecan in patients with impaired renal function. Van Warmerdam LJC, Rodenhuis S, ten Bokkel Huinink WW, Maes RAA and J Clin Oncol 14: 3062–3073 Beijnen JH (1996) Evaluation of formulas using the serum creatinine level to Peng B, Boddy A, Cole M, Pearson A, Chatelut E, Rubie H and Newell D (1995) calculate the optimal dose of carboplatin. Cancer Chemother Pharmacol 37: A comparison of methods used in the estimation of carboplatin 266–270 pharmacokinetics in paediatric cancer patients. Eur J Cancer 31a: 1804–1810 Wright JG, Calvert AH, Highley MS, Roberts JT, MacGill A, Fenwick J and Boddy Perrone RD, Steinman TI, Beck GJ, Skibinski CI, Royal HD, Lawlor M and AV (1999) Accurate prediction of renal function for carboplatin dosing. Proc Hunsicker LG (1990) Utility of radioisotopic filtration markers in chronic renal Amer Assoc Cancer Res, Philadelphia, PA, 40: Abs 2542 © 2001 Cancer Research Campaign British Journal of Cancer (2001) 84(4), 452–459 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Cancer Springer Journals

Estimation of glomerular filtration rate in cancer patients

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Springer Journals
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Copyright © 2001 by The Author(s)
Subject
Biomedicine; Biomedicine, general; Cancer Research; Epidemiology; Molecular Medicine; Oncology; Drug Resistance
ISSN
0007-0920
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1532-1827
DOI
10.1054/bjoc.2000.1643
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Abstract

British Journal of Cancer (2001) 84(4), 452–459 © 2001 Cancer Research Campaign http://www.bjcancer.com doi: 10.1054/ bjoc.2000.1643, available online at http://www.idealibrary.com on Estimation of glomerular filtration rate in cancer patients 1 1 1 2 3 1 JG Wright , AV Boddy , M Highley , J Fenwick , A McGill and AH Calvert 1 2 3 Departments of Oncology, Medical Physics and Clinical Biochemistry, University of Newcastle, NE2 4HH, UK Summary 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 Cr-EDTA clearance were analysed to determine the most appropriate formula relating this method of measuring GFR to patient characteristics. The population pharmacokinetics of Cr-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. Cr-EDTA clearance (GFR) was positively related to Dubois surface area, negatively related to age, and inversely related to serum creatinine (SCr). Females had lower Cr-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. © 2001 Cancer Research Campaign http://www.bjcancer.com Keywords: glomerular filtration; renal function; EDTA; population pharmacokinetics It is frequently necessary to estimate the renal function of cancer monitoring for the toxicities of these agents is undertaken. patients. Many of the drugs used in treating cancer are, at least in Assessing renal function in such studies is additionally important part, excreted via the kidneys, so that renal impairment will lead to because impaired renal clearance of a drug can lead to toxicities in impaired drug elimination and potentially lethal toxicity. For most organs other than the kidney that are related to pre-treatment renal practical purposes, glomerular filtration rate (GFR) may be taken function (Gietema et al, 1995). as an indicator of overall kidney function and can be used to In the case of GFR-based dosing of carboplatin, a clear relation- modify drug dosing. The best-known example of this is carbo- ship has been demonstrated between the rate of drug elimination platin, which is eliminated almost entirely by glomerular filtration. (clearance – Cl) and overall systemic drug exposure, as quantified Dosing of carboplatin based on GFR has become the standard by the area under the plasma concentration time curve (AUC). practice and is indeed included on the data sheet for the product This is implemented in the Calvert formula (Calvert et al, 1989): sold in the USA (Egorin et al, 1984; Calvert et al, 1989). In addi- –1 –1 –1 Dose (mg) = AUC (mg ml min ) ´ (GFR (ml min ) + 25). tion, methotrexate is predominantly excreted by the kidneys and In using this equation, dose adjustment is important in avoiding an estimate of renal function is essential before the use of high- toxicity, which has been shown to be closely related to AUC dose therapy (Stoller et al, 1975). Many other drugs, such as (Egorin et al, 1984; Jodrell et al, 1992). Using GFR to achieve a etoposide (Pflüger et al, 1993), topotecan (O’Reilly et al, 1996) target AUC also ensures appropriate dosing for patients with and aminoglycoside antibiotics (Jelliffe et al, 1991), also have a higher-than-average GFR, who may otherwise receive inadequate large element of renal clearance. treatment. Retrospective studies have shown that response rate in Measurements of GFR are also essential in monitoring patients ovarian cancer (Jodrell et al, 1992) and relapse rate in testicular on treatment. The use of nephrotoxic drugs such as cisplatin cancer (Childs et al, 1992) are related to the area under the curve to requires that an index of renal function be obtained repeatedly which patients are exposed. during treatment (Reece et al, 1987). Chemotherapy may increase Despite the importance of measuring GFR, good methods of renal function in certain patients if there is a response in pelvic doing so are not readily available to many physicians treating disease, leading to relief of ureteric obstruction and this, in turn, cancer. The Cr-EDTA clearance method (Chantler et al, 1969) is may require an increase in the dose of a renally cleared agent such widely accepted as being accurate and reproducible and was used as carboplatin (Calvert et al, 1989). The evaluation of new anti- in many of the initial studies used to derive carboplatin dosing cancer agents in Phase I and II studies requires that careful formulae in Europe. Other isotope-based methods, such as those using iodothalamate or DTPA have been shown to be equivalent Received 17 May 2000 (Perrone et al, 1990; Millward et al, 1996). However, these Revised 11 October 2000 methods are relatively costly and are not available in many parts of Accepted 21 November 2000 the world ( Cr-EDTA is not licensed for this use in the USA). Correspondence to: A Boddy Alternative, more convenient, methods of estimating GFR have 452 Renal function in cancer patients 453 been in use for many years, usually based on a measure of serum a nonlinear hierarchical model in the computer program creatinine (SCr), the age, size and sex of the patient (Cockcroft- NONMEM. Two commonly used creatinine assays (kinetic Jaffe Gault (C&G) (Cockcroft and Gault, 1976) or Jelliffe (Jelliffe, and enzymatic) were investigated to determine the consequences 1973)). Although approximately 20% of creatinine elimination is for GFR prediction. The formulae derived here provide better, by tubular secretion (Perrone et al, 1992), use of these methods to assay-specific estimates for GFR, which are sufficiently precise predict GFR is based on the assumption that creatinine is elimin- and unbiased to be employed for carboplatin dose-optimization. ated entirely by glomerular filtration. Also, variations in the assay methods for creatinine introduce another source of variability PATIENTS AND METHODS (Hartman, 1985). These formulae were derived over 20 years ago using a 24-hour A total of 102 patients, all performance status 0 or 1, undergoing urinary creatinine clearance as the reference. Recent data on the treatment for cancer at the Northern Centre for Cancer Treatment, plasma pharmacokinetics of carboplatin when the doses were Newcastle General Hospital, UK were assessed. All patients gave calculated using the C&G formula as the estimate of GFR have informed consent and the study was approved by the local ethics shown that the AUCs obtained were significantly lower than those committee. Prior to analysis, one patient was excluded because of intended (Van Warmerdam et al, 1996; Ando et al, 1997). A direct acute renal failure, and another because of extremely high creatine 51 –1 comparison with Cr-EDTA clearance has shown that the C&G kinase (2048 units l ), secondary to chest wall invasion by method overestimates GFR in patients with normal renal function tumour. 38 patients were randomly assigned to the validation set, (Calvert, 1997). The use of weight as the index of body size can which played no part in the development of the models. The also lead to an overestimate of GFR in obese patients (Salazar and remaining 62 patients were used to develop formulae for predic- Corcoran, 1988). tion of GFR. The following covariates were recorded: age, weight, The measurement of creatinine clearance using a 24-hour urine height, sex, tumour type, weight change in the past month, pres- collection has given satisfactory results for carboplatin dosing in ence of nephrectomy, presence of pelvic disease (defined as the some trials (Egorin et al, 1984). However complete 24-hour urine presence of disease below the level of the renal pedicles), collections are notoriously difficult to achieve and the accuracy of chemotherapy and concomitant medication, previous chemo- the result also depends on the method used for creatinine estima- therapy, liver function tests (bilirubin, alanine transaminase, alka- tion (Perrone et al, 1992). line phosphatase and albumin), other blood chemistry (urea, We have developed a method to estimate GFR. In order to be sodium, chlorine, potassium, creatinine and creatine kinase) and widely applicable, it is based on the serum creatinine level and Cr-EDTA pharmacokinetics. Blood samples for biochemistry 51 51 other readily obtainable covariates. The pharmacokinetics of Cr- were taken at the same time as the first baseline sample in the Cr- EDTA and its relationship to patient covariates were studied using EDTA estimation of renal function. Table 1 Characteristics of all patients studied Population characteristics Model development Prospective validation No. of patients 62 38 Age (years) 58 (23–81) 56 (18–80) Weight (kg) 71 (41–113) 69 (36–93) Height (m) 1.64 (1.48–1.9) 1.64 (1.47–1.96) BSA Dubois (m ) 1.8 (1.34–2.37) 1.76 (1.31–2.18) 51 –1 CrEDTA clearance (ml min ) 73 (30–148) 91 (42–176) Serum creatinine (mmol) Enzymatic method 84 (50–190) 79 (45–195) Jaffe method 90 (60–167) 84 (56–174) –1 Creatine kinase (units l ) 44 (6–209) 56 (18–188) Sex (male/female) 20/42 13/25 Prior cisplatin therapy 10 5 Nephrectomies 2 1 Presence of pelvic disease 17 8 –1 Albumin (g l ) 40 (25–51) 41 (33–50) Diagnosis Ovarian 24 12 Urinary tract 11 4 Breast 5 2 Testicular 6 3 Colorectal 4 3 Mesothelioma 3 6 Melanoma 2 1 Lung 1 1 Sarcoma 4 1 Cervical 1 Brain 1 2 Adrenocortical 1 Unknown primary 2 Values given as median (range). © 2001 Cancer Research Campaign British Journal of Cancer (2001) 84(4), 452–459 454 JG Wright et al A Hitachi 717 auto-analyser was used for the analysis of creatine where y is the estimate and x is the observed value. In comparing kinase (CK-NAC activated kit, Boehringer-Mannheim) and serum the derived and existing formulae for GFR, the statistical signific- creatinine by kinetic Jaffe (HiCo creatinine, Boehringer-Mannheim) ance of differences in MPE and MAPE was assessed using the and enzymatic (Creatinine PAP, Boehringer-Mannheim) methods. paired t-test and the Wilcoxon signed rank test, respectively. Table 1 summarizes the characteristics of the patients studied. RESULTS Procedure for Cr-EDTA clearance assessment Comparison of serum creatinine assays Cr-EDTA was administered as an intravenous bolus and plasma samples were withdrawn from the opposite arm at approximately Systematic differences were found between the kinetic Jaffe and 2, 3, 4 and 5 hours. Linear regression on the logarithmically trans- enzymatic serum creatinine assays (Figure 1). The Jaffe method formed counts against time was used to estimate the elimination gave higher results than the enzymatic at lower concentrations –1 rate constant K, with volume of distribution V calculated by back (<100 micromoles l ). This is consistent with endogenous inter- extrapolation of this log-transformed data. Individual estimates of fering substances resulting in a higher value with the former assay. Cr-EDTA clearance were calculated from the product KxV. This At higher concentrations, the enzymatic assay produced larger is the routine practice of the Medical Physics department and is a values than the kinetic Jaffe. As serum creatinine measures are method widely employed for this purpose (Chantler et al, 1969). reciprocally related to renal function, the discrepancies at the These estimates of Cr-EDTA clearance were used for the evalua- lower end of the range (high GFR) would have a large impact on tion of the formula on the validation set and were consistent with GFR estimation. those calculated by nonlinear regression. The Cr-EDTA concen- –1 trations (cpm ml ) versus time data were used directly in the Development of formulae population analyses. Given these differences between assays, independent predictive formulae were derived for each assay. The formulae derived from Population pharmacokinetic analysis the initial 62 patients are shown in Table 2, together with those for Model development the most commonly used current methods, the Cockcroft and The pharmacokinetics of Cr-EDTA were analysed in the model Gault and Jelliffe formulae. The functional form of the newly development dataset (n = 62) using the first-order conditional es- derived formulae is identical to that of the Jelliffe formula, but the timation method in the computer program NONMEM V5 coefficients differ substantially. This format for the equation was (Boeckmann et al, 1997). The data were described accurately by a found to provide the best estimates of Cr-EDTA clearance, one compartment model with first-order elimination. This model although numerous other combinations of additive and multiplica- was parameterized in terms of clearance and volume of distribu- tive models were explored. Dubois Body surface area (Dubois and 0.425 0.725 tion, with an interindividual random effect on each parameter. A Dubois, 1916) (0.007184 ´ weight ´ height ) proved to be proportional error model best described interindividual and the most predictive body size variable. Weight, height, Gehan residual error. For interindividual error, this model is consistent and George surface area (Gehan and George, 1970) (0.02350 0.51456 0.42246 with the implied loss function, as percentage errors in dose are ´ weight ´ height ) or ideal body weight as body size closely related to percentage errors in AUC obtained. Although measures were inferior in the model development set. supported by the fit of the model without covariates, these assump- The covariate creatine kinase (CK) was also found to be import- tions were re-evaluated as the explanatory covariate model for ant in the model. Since accurate and reproducible measures of CK clearance was adjusted. As over 20 covariates were available, it activity may not be universally available, formulae without this was necessary to take a pragmatic approach to the selection of covariate were also derived. There was no detectable independent important covariates and their relationship to each other in the influence on EDTA clearance of prior cisplatin therapy, nephrec- formula. The inclusion of a covariate in the formula, and the tomy or presence of pelvic disease in the patients studied. appropriateness of the functional form chosen, were determined primarily by changes in residual plots, estimates of interindividual variability and the NONMEM objective function, although no statistical significance was attached to changes in the latter measure. Initial investigations were based on Efroymson’s algo- rithm (Efroymson, 1962), a subset selection procedure that altern- Y=0.76X + 24.4 ates between forward selection and backward elimination, commencing from covariate models selected randomly and also those suggested from prior considerations. Comparisons on the validation set Bias was assessed by the mean percentage error (MPE) and preci- sion by mean absolute percentage error (MAPE). Respectively, 0 50 100 150 200 these are calculated for n patients as: –1 Enzymatic (micromolesl ) Figure 1 Plot of serum creatinine estimates obtained by the enzymatic or 1 1 Jaffe methods. Both model development and validation data sets are yx yx MPE = () and MAPE = included. Solid line represents the regression of Jaffe on enzymatic S S1 n x n x 1 1 - 1 determinations. Dotted line is the line of identity British Journal of Cancer (2001) 84(4), 452–459 © 2001 Cancer Research Campaign –1 l ) Jaffe (micromoles Renal function in cancer patients 455 Table 2 Formulae for the estimation of GFR. Comparison of equations developed here and those routinely used Formulae for the prediction of creatinine clearance (140 – Age) ´ Wt ´ (1 – 0.15 ´ Sex) CrCl = Cockcroft and Gault (1976): 72 ´ SCr ´ 0.0113 (98 – 0.8 ´ (Age – 20)) ´ (1 – 0.1 ´ Sex) ´ (BSA/1.73) CrCl = Jelliffe and Jelliffe (1973): SCr ´ 0.0113 Formulae derived for GFR in a cancer population Using enzymatic serum creatinine (4350 – 34 ´ Age + 522 ´ Ln(CK)) ´ BSA ´ (1 – 0.217 ´ Sex) GFR = (1) With CK: SCr (6230 – 32.8 ´ Age) ´ BSA ´ (1 – 0.23 ´ Sex) GFR = (2) Without CK: SCr Using Jaffe Serum Creatinine (4520 – 40 ´ Age + 570 ´ Ln(CK)) ´ BSA ´ (1 – 0.15 ´ Sex) GFR = (3) With CK: SCr (6580 – 38.8 ´ Age) ´ BSA ´ (1 – 0.168 ´ Sex) GFR = (4) Without SCr –1 CrCl = Creatinine clearance; GFR = Glomerular filtration rate ml min ; Age = Age in years;Ln(CK) = natural logarithm of creatine –1 0.425 0.725 kinase in units l ; Sex = 1 if female; 0 if male, BSA = Dubois body surface area = 0.007184 ´ Weight ´ Height ; SCr = Serum –1 Creatinine in mmol l ; Wt = Weight in kg. Table 3 Percentage prediction errors on the validation dataset. Formula Assay MAPE MPE Min 10th percentile 90th percentile Max C & G Enzymatic 16 –8 –46 –26 16 42 Jelliffe Enzymatic 19 –15 –33 –30 5 30 CK (1) Enzymatic 12 –3 –20 –17 15 33 NonCK (2) Enzymatic 13 –5 –24 –20 8 36 C & G Jaffe 19 –12 –62 –35 11 40 Jelliffe Jaffe 22 –19 –50 –37 4 16 CK (3) Jaffe 16 –1 –41 –24 22 50 NonCK (4) Jaffe 15 –5 –39 –26 17 39 Numbers in parentheses refer to equations in Table 2. MAPE is mean absolute percentage error, a measure of precision, and MPE is mean percentage error, a measure of bias. The effect of gender on GFR was relatively small (typical Comparison of new and existing formulae female GFR 77–85% that of typical male). This is similar to the Measures of performance calculated from the separate validation arbitrary correction factor introduced by Cockcroft and Gault. set for each formula are shown in Table 3. The derived formulae With the enzymatic assay using equation (1), GFR changes by were more precise and less biased than the Cockcroft and Gault approximately 8% for 10 years of age difference from the median formula and it would appear that, in general, enzymatic serum (57 years). Changes of BSA of 0.1 m produce GFR changes of creatinines gave more accurate estimates of GFR. Statistical 5%. The relationship with SCr is a reciprocal one, but around the comparisons of the estimates of GFR from each formula are shown median value, an increase in GFR of 20% is associated with a –1 in Table 4. As shown in Figure 2, the formulae derived here, for decrease in SCr of 14 micromoles l , while a 20% decrease corres- –1 both methods of serum creatinine assay, are significantly less ponds to a SCr increase of 20 micromoles l . Variation of CK from –1 biased than the C&G or Jelliffe formulae. Figure 3 shows a 22 to 114 (median 50) units l is associated with a 10% variation comparison of the Cr-EDTA clearance in the validation dataset, of GFR around the median value. © 2001 Cancer Research Campaign British Journal of Cancer (2001) 84(4), 452–459 456 JG Wright et al Table 4 Statistical significance of differences in mean percentage error (MPE) by paired two-sided t-test and mean absolute percentage error (MAPE) by nonparametric two-sided Wilcoxon ranked sum test on the validation set. Values significant at the 5% level are shown in bold Null Hypothesis: There is no predictive difference P-value of evidence against, for MPE P-value of evidence against, for MAPE between first and second formulae (equation numbers in parentheses, see Table 2) With enzymatic serum creatinine CK (Eq 1) vs C&G 0.01 (–3 vs –8) 0.02 (12 vs 16) NonCK (Eq 2) vs C&G 0.15 (–5 vs –8) 0.03 (15 vs 19) CK (Eq 1) vs NonCK (Eq 2) 0.04 (–3 vs –5) 0.39 (12 vs 13) With Jaffe serum creatinine CK (Eq 3) vs C&G <0.01 (–1 vs –12) 0.17 (16 vs 19) NonCK (Eq 4) vs CG <0.01 (–5 vs –12) 0.01 (15 vs 19) CK (Eq 3) vs NonCK (Eq 4) 0.01 (–1 vs –5) 0.40 (16 vs 15) Comparing formulae for each assay CK enzymatic (Eq 1) vs CK Jaffe (Eq 3) 0.87 (–3 vs –1) <0.01 (12 vs 16) NonCK enzymatic (Eq 2) vs NonCK Jaffe (Eq 4) 0.98 (–5 vs –5) 0.05 (13 vs 15) exposure to active drug. The optimum method for GFR estimation, and that used to derive the Calvert equation, is clearance of Cr- Jaffe Enzymatic EDTA. Substitution of other methods for estimation of GFR has been employed, with varying degrees of success. Unfortunately, the most commonly used method, the Cockcroft and Gault equation with a measure of serum creatinine, results in significant 200 Female Male line of equality 20% error . {]. -~-- -· .. CG Jel CK NCK CG Jel CK NCK -· .. Formula and Cr assa y 4-.-.-~~-- • -~--·--·· a.····· .. ··· ..... ·· Figure 2 Comparison of Cockroft and Gault (CG), Jelliffe (Jel) and novel formulae for the estimation of GFR, with both Jaffe and enzymatic methods of SCr measurement. CK is the formula using creatine kinase (Equations 1 20 and 3), NCK is without creatine kinase (Equations 2 and 4). MPE is mean 0 20 40 60 80 100 120 140 160 180 200 prediction error (solid columns), with the extreme range of prediction errors 51 –1 CrEDTA clearance (ml min ) shown as error bars with estimates obtained either by equation 1, or using the C&G formula. The performance of the formula developed here is super- ior to that of C&G, with almost all of the patients estimated GFR within 20% of the observed value. While no effect of was observed 200 in the model development group, 4 of the 5 patients (one had no enzyme creatinine measure) in the validation group who had previ- ously been treated with cisplatin seemed to show a small but systematic bias in the estimation of GFR (Figure 3). In 2 of these 100 patients EDTA clearance was overestimated by greater than 20%. .. This phenomenon should be investigated further and care should be taken in applying the proposed formula in cisplatin-pretreated patients. 0 0 20 40 60 80 100 120 140 160 180 200 51 –1 CrEDTA clearance (ml min ) DISCUSSION Figure 3 Performance of A: best predictive equation (1) and B: Cockcroft A measure of glomerular function provides a practical, easily and Gault equation, using enzymatic method of serum creatinine assay. Estimates of GFR are compared to measured Cr-EDTA clearance, plotted obtainable method to estimate overall renal function. In the treat- with line of identity and 20% error boundaries. Data for males (l l) and ment of patients with carboplatin, a good measure of renal function females (l) plotted separately. Triangles indicate patients with prior cisplatin is essential to obtain predictable and uniform pharmacological treatment British Journal of Cancer (2001) 84(4), 452–459 © 2001 Cancer Research Campaign MPE (%) –1 –1 ) CK formula estimate (ml min ) Cockcroft and Gault estimate (ml min Renal function in cancer patients 457 deviation from the target AUC. The use of the C&G model to esti- The estimates of GFR from the Jelliffe formula were extremely mate GFR is not appropriate for dosing of carboplatin because it downward biased in the validation set, perhaps because this was derived in an inappropriate patient population, takes no formula was originally based on 15 patients who had undergone account of non-GFR elimination of creatinine and is highly depen- renal transplantation. Using the population pharmacokinetic dent on the method used to measure creatinine in serum. approach, the formulae arrived at have the same structural form In this study the relationship between Cr-EDTA pharmacokin- as that of Jelliffe, although the coefficients estimated from the etics and patient covariates has been explored in order to develop a current study are substantially different. Jelliffe assumed that the more robust, flexible and reliable equation for the calculation of percentage reduction in GFR for female patients, all other covari- renal function from serum creatinine. The population pharmaco- ates being equal, was 10%; compared to the 17% estimated in this kinetic approach has been applied to a number of drugs used in study. C&G assumed 15% in their weight-based formula, but chemotherapy, and its use to estimate GFR from the pharmaco- Martin et al estimated the value to be somewhat higher at 25%. A kinetics of EDTA represents the use of contemporary analysis similar coefficient for the negative effect of age was found by methods to a persistent clinically-relevant problem. Jelliffe (–41) and in the current study (–39). The consistently A potential source of variability in the results previously lower predictions of the former formula are due to the difference in reported for GFR estimation arises from the serum creatinine the constant term in the first bracket. assay since different methods give systematically different results Recently, Levey et al derived several formulae for the estima- (Figure 1). Creatinine is partially eliminated by tubular secretion, tion of renal function from 1628 patients with renal disease (Levey in addition to glomerular filtration. The commonly used alkaline et al, 1999). This population is fundamentally different from that picrate colourimetric reaction (Jaffé reaction) over-estimates the studied here and using their formula, also derived from readily serum level of creatinine by a similar proportion, thus partly available patient covariates, on the validation set provided predic- compensating for the error. Thus, when a 24-hour creatinine clear- tions comparable to that of the Jelliffe formula (MAPE 20%, MPE ance measurement is made, the potential over-estimation of GFR –15%, range –50% to 31%, with the Jaffe creatinine assay; MAPE is compensated by the over-estimation of the serum (but not the 17%, MPE-11%, range –52% to 53% with the enzymatic assay). urinary) level of creatinine. However, if one of the more accurate, Interestingly, their formula was derived using a kinetic alkaline enzymatic methods for creatinine measurement is used, then GFR picrate assay for serum creatinine. This comparison illustrates the will be overestimated. In all the formulae for GFR developed to dangers of applying formulae in populations different from that in date, the reciprocal of serum creatinine is used, thus even small which they were derived – not only are there difficulties in extrapo- discrepancies between assays can compromise GFR prediction. It lating into regions with little data, but the relationship between would appear from this study that the enzymatic creatinine assay covariates and renal function need not be the same in different gave more informative serum creatinine values for the prediction populations. Indeed, Levey et al found both serum urea nitrogen of renal function, especially in conjunction with the adjustment for and albumin to be useful independent predictors, whereas these creatine kinase (CK). covariates did not appear to be predictive in the current study As in previous studies, the C&G formula was found to underes- population. timate GFR (or carboplatin clearance) on average and produced Although Martin et al used weight rather than BSA as a measure widely scattered predictions (Van Warmerdam et al, 1996; of body size (Martin et al, 1998), the effect of age (–0.50% GFR Okamoto et al, 1998; Ando et al, 1997). Another study has shown per year) is similar to the enzymatic formula derived here (equa- that C&G overpredicts GFR in renally impaired patients (Levey tion 2, –0.53% per year). The use of weight was investigated, but et al, 1999). The poor performance of C&G may be a consequence could not be justified in this study. It is important that Dubois BSA 0.425 0.725 of differences between the populations under study, or of varia- (0.007184 ´ weight ´ height ) (Dubois and Dubois, 1916) is tions in the assay method for serum creatinine. Cockcroft and used, as the Gehan and George estimate of BSA (0.02350 ´ 0.51456 0.42246 Gault based their formula on 249 patients, of whom only 4% were weight ´ height ) (Gehan and George, 1970) places more female, and excluded patients whose serum creatinine was not emphasis on weight and failed to improve predictive performance. deemed to be at steady state. The validation set in this study indi- The use of creatine kinase (CK) in the prediction of GFR is cates that the use of the C&G formula will systematically under- novel. CK is released into the bloodstream by cardiovascular and estimate GFR in patients with normal or mildly impaired renal skeletal muscle turnover and gross elevation of serum CK is a function. When C&G is used as the basis for carboplatin dosing it symptom of myocardial infarction. A source of interindividual has been common for target AUCs to be set higher than when an variation in serum creatinine, other than renal function, is its rate isotope method is used (Ando et al, 1997). Nevertheless, pharma- of endogenous production. Creatine kinase was investigated as a cokinetically based dosing of carboplatin using C&G, although covariate because it mediates the interconversion of creatinine and greatly superior to surface-area based dosing, will still lead to a creatine intracellularly, and so may directly influence serum cre- wide scatter of AUC values, with patients potentially receiving atinine levels, as well as reflecting the rate of muscle turnover. either toxic or sub-therapeutic doses. Cachexia in cancer patients may cause reduced muscle mass and An improved formula recently proposed by Martin et al (1998) hence reduced creatinine production in some patients. Even in the was derived in cancer patients using similar methodology to the absence of cachexia, there is likely to be interindividual variation current investigation. In that study, the statistical comparison with in the rate of endogenous creatinine production, for which CK may C&G was limited to failing to reject the null hypothesis that their act as a surrogate. The inclusion of CK in the formula led to signifi- formula was unbiased, a hypothesis successfully rejected for cantly less bias, particularly when used in conjunction with the C&G. However, on the validation set in this study, the formula enzymatic creatinine assay (equation 1). Any adverse effect on suggested by those authors showed no improvement in precision GFR estimation due to artefactually elevated values of CK is over C&G, due to a skewed distribution of prediction errors (data minimised by the use of a logarithmic transformation. CK may not shown). prove to be a useful surrogate in other populations, however care © 2001 Cancer Research Campaign British Journal of Cancer (2001) 84(4), 452–459 458 JG Wright et al must be taken in employing this covariate when it takes very high (Huitema et al, 2000) has confirmed the accuracy and precision of values. the model. They should also be applicable to the individualised Given that a primary aim of estimating GFR is its use in carbo- dosing of other drugs, such as aminoglycoside antibiotics, and the platin dosing, Chatelut et al (1995) used a population pharmacokin- routine monitoring of renal function before and after potentially etic approach with NONMEM to derive a formula for the dosing nephrotoxic chemotherapy. of carboplatin based directly on weight, age and serum creatinine. The latter was determined by the Ektachem enzymatic assay. The ACKNOWLEDGEMENTS Chatelut formula for carboplatin clearance: This work was supported by the Cancer Research Campaign and Bristol Myers Squibb. Cl (carboplatin) = 0.134 × Wt (218 × Wt × (1 – 0.00457 × Age) × (1 – 0.217 × Sex) REFERENCES Scr Ando Y, Saka HMA, Sakai S and Shimokata K (1997) Adjustment of creatinine clearance improves accuracy of Calvert’s formula for carboplatin dosing. Br J Cancer 76: 1067–1071 gives different results to doses predicted using the Calvert formula 51 Boeckmann A, Beal SL and Sheiner LB (1997) Technical report of the Division of with Cr-EDTA clearance. Compared to estimates derived from Clinical Pharmacology. In: NONMEM users manual V5 the latter method, the Chatelut formula has an MPE of 4%, an Calvert AH (1997) A review of the pharmacokinetics and pharmacodynamics of MAPE of 17% and a range of –34% to +45%. Substituting the combination carboplatin/paclitaxel. 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British Journal of CancerSpringer Journals

Published: Feb 13, 2001

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