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Adjustment of creatinine clearance improves accuracy of Calvert's formula for carboplatin dosing.

Carboplatin clearance depends on the glomerular filtration rate (GFR), and Calvert's formula is frequently used to achieve a target area under the time vs concentration curve (mg ml(-1) min). Creatinine clearance is a substitute for GFR when creatinine values are determined by the JaffÃ© method, which is being replaced by the enzymatic method. When the enzymatic method is used, the corresponding creatinine clearance theoretically exceeds GFR, and the use of creatinine clearance as GFR in Calvert's formula results, accordingly, in overdosing of carboplatin. In this study, we have established a model for adjusting the creatinine clearance to offset this bias based on a relationship between creatinine values measured by the JaffÃ© method and by the enzymatic method: adjusted creatinine clearance (ml min(-1)) = creatinine clearance (ml min(-1)) x [serum creatinine (mg dl(-1))]/[serum creatinine (mg dl(-1)) + 0.2]. Subsequently, we validated this model using the data from 35 lung cancer patients. Estimated clearances of carboplatin with the original equation [creatinine clearance + 25] were systematically higher than observed clearances [mean prediction error (MPE) +/- standard error (s.e.) = 26 +/- 5%]. This positive bias was corrected by the adjustment (MPE +/- s.e. = 5 +/- 4%). When the enzymatic method is used, the adjusted creatinine clearance should be used in Calvert's formula.

of the dosing: dose (mg) = target AUC x [GFR (ml min-1) + 25], where AUC denotes the area under the time vs concentration curve (mg ml-' min) (Harland et al, 1984;Calvert et al, 1989). In developing this formula, the GFR has been measured using the [5'Cr]EDTA clearance method. However, many oncologists have used creatinine clearance as a measure of GFR in the clinical use of this formula (Green and Smith, 1990;Sessa et al, 1991;Jodrell et al, 1992;Reyno et al, 1993;Langer et al, 1995), because obtaining the creatinine clearance is more convenient than measuring GFR directly. However, creatinine is both filtered by glomeruli and secreted by renal tubules, so the creatinine clearance theoretically exceeds GFR, thereby causing carboplatin overdosing (Doolan et al, 1962;Kassirer, 1971;Shemesh et al, 1985;Levey et al, 1991). We have reported more than 20% overdosing by replacing GFR with the creatinine clearance in this formula (Ando et al, 1997).
At present, two methods are available for measuring creatinine levels, the Jaffe method and the enzymatic method (Doolan et al, 1962;Fabiny and Ertingshausen, 1971;Kassirer, 1971;Larsen, 1972;Lustgarten and Wenk, 1972;Guder and Hoffmann, 1986;Accepted 4 April 1997 Correspondence to: Y Ando, Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060, Japan Crocker et al, 1988). The Jaffe method is based on a picrate reaction with creatinine under alkaline conditions and has been widely used for a long time with several modifications to the detailed procedure (Doolan et al, 1962;Fabiny and Ertingshausen, 1971;Larsen, 1972;Lustgarten and Wenk, 1972). This method is known to overestimate the serum level of creatinine by 5-15% because of a reaction with non-creatinine chromogens in serum but not in urine (Doolan et al, 1962;Kassirer, 1971). As a result of this bias, the true creatinine clearance is underestimated and can be accepted as a useful measure of GFR in clinical practice as this error coincidentally offsets the excess of creatinine clearance over GFR (Levey et al, 1991). On the other hand, the new enzymatic method is more specific and ensures better interlaboratory agreement than the traditional Jaffe method (Guder and Hoffmann, 1986;Crocker et al, 1988). Because the enzymatic method is not influenced by chromogens, the serum creatinine level is lower than when using the Jaffe method, and the corresponding creatinine clearance would be higher than GFR (Guder and Hoffmann, 1986;Crocker et al, 1988;Weber and van Zanten, 1991;Sokoll et al, 1994). Hence, the replacement of GFR with creatinine clearance in Calvert's formula causes carboplatin overdosing when the enzymatic method is used. This would explain the overestimation of carboplatin clearance in our previous study in which the enzymatic method was used.
We have attempted to evaluate the relationship between the creatinine levels determined using the Jaffe method and those determined using the enzymatic method. We have thus established a model to adjust the creatinine clearance by the enzymatic method to be used as GFR in Calvert's formula for the accurate prediction of the carboplatin clearance.

METHODS
Relationship between the Jaffe method and the enzymatic method We measured creatinine levels in serum and urine of the patients admitted to Shinshiro Municipal Hospital from November 1995 to March 1996. Diseases of these patients included various cancers, chronic obstructive pulmonary disease, ischaemic heart diseases, stable diabetes and chronic renal failure. Haemolysed samples or those from patients receiving any kind of antibiotics or vitamins were excluded (Lustgarten and Wenk, 1972;Guder and Hoffmann, 1986;Crocker et al, 1988;Weber and van Zanten, 1991). A urine sample from 24-h urine collection was obtained in the morning when the patient's serum sample was taken. The samples were stored at -20°C until analysis. The serum and urine creatinine levels were determined using both the Jaff6 method and the enzymatic method. The kinetic Jaff6 method without deproteinization was performed with creatinine-HR (Wako Pure Chemical Industries, Osaka) using the autoanalyser Hitachi 747-400. The intraand inter-day coefficient variation (CV) of the assay was under 3% and 6% respectively. The enzymatic method was carried out with Determiner-L CRE (Kyowa Medex, Tokyo) using Hitachi 717. The intraand interday CV was less than 2% and 3% respectively. We developed equations using linear regression to convert creatinine values by the enzymatic method to those by the Jaffe method. Based on these equations, a model was developed to adjust creatinine clearance so as to be similar to GFR.

Carboplatin pharmacokinetics
The pharmacokinetic data were available from 35 lung cancer patients (Table 1). They were treated with three different regimens including carboplatin (Table 2). Carboplatin was infused as monotherapy with the target AUC (mg ml-1 min) of seven for untreated or five for previously treated patients in regimens A or B (Calvert et al, 1989). No antineoplastic treatment was allowed during the 4 weeks before entry for previously treated patients (3 months for cisplatin-containing regimen) (Daugaard et al, 1988). In regimen C, previously untreated patients received irinotecan at a dose ranging from 40 to 60 mg m-2 followed by carboplatin. Creatinine clearance from 24-h urine collection was measured three times in regimens A and B or two times in regimen C, and Blood samples were taken in a tube coated with a coagulation accelerant (Insepack, Sekisui Medical, Osaka) for pharmacokinetic analysis of carboplatin in regimens A and B, and the serum was immediately separated by centrifugation. Ultrafiltered serum was obtained using a Millipore Ultrafree-C3 filter unit (UFC3LGC0O, Japan Millipore, Tokyo). In regimen C, plasma was obtained in heparinized tubes and was ultrafiltered with Amicon MPS micropartition system with YMT membranes (Grace Japan KK, Amicon, Tokyo). According to our data, the absolute difference in free platinum levels between the two procedures was 3.5 ± 0.8% (mean ± standard error, n = 13). The ultrafiltered samples were stored at -20°C until analysis. All studies were approved by each institutional ethics committee, and written informed consent was obtained from all patients.
The ultrafiltered platinum level was measured by flameless atomic absorption spectrometry (LeRoy et al, 1977). The lower limit of detection was 25 ng ml'. The intraand interassay CV was 2.6% and 4.1% respectively. The carboplatin level was calculated based on the molar ratio of platinum-carboplatin. Observed AUC was calculated by the trapezoidal method with extrapolation to infinity using PCNONLIN (version 4.0, Scientific Consulting, Apex, NC, USA). Estimated and observed clearances were calculated as follows: Estimated clearance (ml min-1) = creatinine clearance (ml min-') + 25 Observed clearance (ml min-') = dose (mg) observed AUC (mg ml-1 min) All creatinine values had been determined by the enzymatic method. We recalculated the corresponding creatinine clearance in individual patients using the developed model. The accuracy of the clearance estimation was evaluated with the mean prediction error, its standard error (MPE ± s.e.) and the root mean squared error (RMSE) (Sheiner and Beal, 1981).

RESULTS
The linear regression analysis for serum creatinine levels between the Jaffe and enzymatic methods showed a slope of 0.99 and an intercept of 0.18, which was significantly different from zero (Table 3 and Figure 1). This implied that the values determined by the Jaffe method consistently exceeded those obtained by the enzymatic method for all creatinine levels investigated. To confirm that this relationship can be applied for the relevant levels to each dosing, we examined samples containing < 1.7 mg dl-1 as measured by the enzymatic method. The results were essentially the same (Table 3). Thus, when the enzymatic method was used to measure creatinine levels, serum creatinine in the denominator of the equation for creatinine clearance (eqn 1) should be replaced by serum creatinine + 0.2. On the other hand, good agreement was found in the urine creatinine levels by the two methods, and no modification was needed in the equation (Table 3 and Figure 1). Therefore, when creatinine levels were measured by the enzymatic method, GFR was estimated by adjusting the clearance as follows: Adjusted creatinine clearance (ml min-') = [urine volume (ml min-1)] x urine creatinine (mg dl-[) serum creatinine (mg dl-') + 0.2 = creatinine clearance (ml min-') x serum creatinine (mg dl-1) serum creatinine (mg dl -') + 0.2 When the creatinine clearance was calculated with the values analysed by the enzymatic method and used in Calvert's formula, the estimated carboplatin clearance was positively biased and imprecise. After adjustment using the above model, this bias was significantly decreased (P < 0.001 by paired t-test; Table 4 Figure 2). The precision expressed as RMSE was also improved (Table 4).

DISCUSSION
The bias and precision of the carboplatin clearance estimation were improved by adjusting the creatinine clearance calculated with the values measured by the enzymatic method. This result confirmed our hypothesis that the use of the enzymatic method for serum creatinine determination overestimates carboplatin clearance when creatinine clearance is used as a substitute for GFR in Calvert's formula. Recently, Chatelut et al (1995) proposed an alternative formula to calculate carboplatin clearance using the non-linear mixedeffect model (NONMEM), which included variables such as age, gender, weight and serum creatinine measured with an enzymatic   (Chatelut et at, 1997). This model is beneficial when accurate measurement of GFR or creatinine clearance is difficult. However, in our study population, the Chatelut formula overestimated carboplatin clearance by 37±+5 ml min-1 (42±5%SS, MPE ± s.e.). There might be an ethnic difference in the utility of the Chatelut formula or a further as yet unestablished difference in the method of creatinine measurement. This report recommends discontinuation of the Jaffe method for creatinine measurement, as it is readily influenced by non-creatinine chromogens and shows more interlaboratory variation (Doolan et al, 1962;Kassirer, 1971;Guder and Hoffmann, 1986). Instead, we suggest that creatinine levels should be measured by the enzymatic method while adjusting the creatinine clearance. This adjustment would lead to safer individualized dosing of carboplatin using Calvert's formula.