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Body-Surface Area–Based Dosing Does Not Increase Accuracy of Predicting Cisplatin Exposure

From the Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, Rotterdam, the Netherlands.

Address reprint requests to Alex Sparreboom, PhD, Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands; email: sparreboom{at}onch.azr.nl

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Most anticancer drugs are dosed based on body-surface area (BSA) to reduce interindividual variability of drug effects. We evaluated the relevance of this concept for cisplatin by analyzing cisplatin pharmacokinetics obtained in prospective studies in a large patient population.

PATIENTS AND METHODS: Data were obtained from 268 adult patients (163 males/105 females; median age, 54 years [range, 21 to 74 years]) with advanced solid tumors treated in phase I/II trials with cisplatin monotherapy or combination chemotherapy with etoposide, irinotecan, topotecan, or docetaxel. Cisplatin was administered either weekly (n = 93) or once every 3 weeks (n = 175) at dose levels of 50 to 100 mg/m² (3-hour infusion). Analysis of 485 complete courses was based on measurement of total and non–protein-bound cisplatin in plasma by atomic absorption spectrometry.

RESULTS: No pharmacokinetic interaction was found between cisplatin and the anticancer drugs used in combination therapies. A linear correlation was observed between area under the curves of unbound and total cisplatin (r = 0.63). The mean plasma clearance of unbound cisplatin (CL_free) was 57.1 ± 14.7 L/h (range, 31.0 to 116 L/h), with an interpatient variability of 25.6%. BSA varied between 1.43 and 2.40 m² (mean, 1.86 ± 0.19 m²), with an interpatient variability of 10.4%. When CL_free was corrected for BSA, interindividual variability remained in the same order (23.6 v 25.6%). Only a weak correlation was found between CL_free and BSA (r = 0.42). Intrapatient variability in CL_free, calculated from 90 patients was 12.1% ± 7.8% (range, 0.30% to 32.7%).

CONCLUSION: In view of the high interpatient variability in CL_free relative to variation in observed BSA, no rationale for continuing BSA-based dosing was found. We recommend fixed-dosing regimens for cisplatin.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
IN CLINICAL ONCOLOGY, dose calculations for cytotoxic drugs based on body-surface area (BSA) have become standard practice. The use of BSA has largely resulted from its use in the extrapolation of drug doses used in experimental animals to those considered safe as starting doses for phase I clinical trials in human cancer patients. However, a proper scientific rationale for BSA-based dosing of anticancer drugs in adults is lacking.^1,2 One exception is docetaxel, for which BSA was reported to be a good predictor of drug clearance (CL) in a population pharmacokinetic model.³ For many other drugs, including epirubicin⁴ and oral topotecan,⁵ the pharmacokinetic and pharmacodynamic behavior cannot be predicted reliably by BSA, because several other factors, like intestinal absorption, kidney function, and activity of key enzymes in metabolic pathways, are more important denominators. For example, the finding that carboplatin CL is closely related to glomerular filtration rate has resulted in dosing of this agent according to creatinine CL by the use of an alternative dosing algorithm to achieve a target measure of systemic exposure.⁶ However, for most agents, including cisplatin, there still is no better method of dose individualization than the non–evidence-based (though accepted) use of BSA-adjusted dosing. The aim of the present study was to investigate the utility of BSA in dosing of the anticancer drug cisplatin.

Cisplatin (cis-diaminedichloroplatinum) is a frequently applied agent with a broad spectrum of activity against solid tumors, including testicular, ovarian, bladder, lung, and head and neck cancers. With the use of optimal hydration measures, including supplementation of potassium and magnesium, the dose-limiting toxicity of cisplatin has changed from nephrotoxicity toward neurotoxicity and ototoxicity. Myelosuppression is generally moderate. Because of this toxicity profile, there is no useful short-term clinical marker for dose-limiting toxicity and dose adjustment. Earlier studies have shown that the area under the plasma concentration–time curve (AUC) of unbound cisplatin was significantly related to important pharmacodynamic end points.^7-11 For example, the AUC of free cisplatin and the platinum-DNA adduct formation measured in leukocytes were strongly correlated. The same applies to the grade of thrombocytopenia (which proved to be a dose-limiting side effect of weekly administration of cisplatin at a dose of 80 mg/m²), as well as to the tumor response.¹²

Here, we have analyzed pharmacokinetic data of 268 adult cancer patients who were treated with either cisplatin monotherapy or cisplatin-based combination therapy in several prospective studies. Intra- and interpatient variability in CL of total and free cisplatin was determined. In addition, the interpatient variability in BSA was calculated and compared with the interindividual variability in pharmacokinetic behavior of cisplatin.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Selection
All patients studied had a confirmed diagnosis of malignant solid tumor and were treated with cisplatin monotherapy or cisplatin-based combination therapy (with either oral etoposide,¹³ intravenous [IV] irinotecan,^14,15 oral topotecan,^16,17 or IV docetaxel¹⁸) in clinical trials that included pharmacokinetic analysis of cisplatin. Detailed clinical and pharmacologic profiles have been documented previously.^13-19 According to the inclusion criteria of these trials, all patients were 18 to 75 years of age with an Eastern Cooperative Oncology Group performance status 2, had no previous anticancer therapy for at least 4 weeks, and had adequate hematopoietic (absolute neutrophil count 1.5 x10⁹/L and platelet count 100 x10⁹/L), hepatic (total serum bilirubin 1.25 times the upper limit of normal and AST and ALT levels 2.5 times the upper limit of normal or 5.0 times in case of liver metastases), and renal function (creatinine CL, 60 mL/min) at the time of study entry.

Drug Administration
In all treatment schedules, cisplatin powder (Platosin; Pharmachemie, Haarlem, the Netherlands) was dissolved in 250 mL of 3% (weight-to-volume ratio [w/v]) hypertonic saline and administered as a 3-hour continuous IV infusion. The drug was administered at doses ranging from 50 to 100 mg/m², with treatment cycles repeated every week or every 3 weeks. For prevention of cisplatin-induced renal damage, a standard prehydration infusion with 1 L of 0.9% (w/v) isotonic saline or a mixture of 5% (w/v) dextrose and isotonic saline was used, as well as posthydration with at least 3 L of saline or dextrose saline supplemented with potassium chloride (20 mmol/L) and magnesium sulfate (2 g/L). Antiemetic prophylaxis consisted of a 5HT₃-antagonist in combination with dexamethasone. Diuretics were not administered routinely.

Clinical Samples
Blood samples for pharmacokinetic analysis were drawn from the arm opposite to the infusion site during the first and (if required by protocol) during the second and third treatment course on the day of drug administration and were collected in 4.5-mL glass tubes containing lithium heparin as anticoagulant. Samples were collected immediately before the infusion, during (ie, 1 and 2 hours after the start of the infusion), at the end of infusion (approximately 3 hours), and 0.5, 1, 2, 3, and 18 hours after the end of cisplatin infusion. Immediately after collection, samples were centrifuged to obtain the plasma fraction (3,000 x g for 10 minutes). Next, 500-µL aliquots of the plasma supernatant were added to 1.0 mL of ice-cold (-20°C) ethanol. After vortex mixing for 10 seconds, samples were stored at -80°C until the day of analysis.

Analytic Methods
Plasma concentrations of unbound and total cisplatin were determined by a validated flameless atomic absorption spectrometric procedure based on measurement of platinum atoms as described elsewhere.¹⁶ For measurement of unbound cisplatin, 500-µL aliquots of plasma were extracted with 1.0 mL of neat, ice-cold ethanol in a 2-mL polypropylene vial (Eppendorf, Hamburg, Germany). The plasma supernatant was collected by centrifugation at 23,000 x g for 5 minutes at 4°C and transferred to a clean tube. A volume of 600 µL was evaporated to dryness under nitrogen at 60°C, and the residue was reconstituted in 200 or 600 µL of water containing 0.2% (volume-to-volume ratio) Triton X-100 and 0.06% (w/v) cesium chloride by vigorous mixing. A volume of 20 µL was eventually injected into the spectrometer. For determination of the total cisplatin concentrations, 100 µL of plasma was added to 900 µL of water containing 0.2% (volume-to-volume ratio) Triton X-100 and 0.06% (w/v) cesium chloride, followed by vortex mixing for 10 seconds. Of this solution, a volume of 20 µL was injected into the spectrometer. Samples were analyzed using a Perkin Elmer 4110 ZL Spectrometer (Perkin Elmer, Überlingen, Germany) with Zeeman-background correction using peak area signal measurements at a wavelength of 265.9 nm and a slid width of 0.7 nm. Drug concentrations were determined by interpolation on linear calibration curves, constructed in blank human plasma, by least-squares regression of response values versus 1/x². The mean percentage deviations from nominal values (accuracy) and precision (within-run and between-run variability) were always less than 15%.

Data Analysis
Individual plasma concentrations of unbound and total cisplatin were fit to a one-compartment linear model with extended least-squares analysis with a weighting factor of 1/y using the software package Siphar 4.0 (InnaPhase, Philadelphia, PA). The AUC of cisplatin was calculated to the last sampling time point (C_last) using the linear trapezoid method and extended to infinity by addition of C_last/k_term, where k_term is the slope obtained by log-linear regression of the final plasma concentration values. The apparent CL of unbound (CL_free) and total cisplatin (CL_tot) were calculated by dividing the dose per squared meter of BSA by the observed AUC values, expressed in L/h/m². The absolute CL values, expressed in L/h, were calculated by dividing the absolute dose (in milligrams) by the respective AUC values. After studying the entire patient population, patients were also divided into several groups. First, sex was studied separately; second, patients were classified into three different BSA groups: BSA less than 1.7 m², BSA between 1.7 and 2.0 m², and BSA more than 2.0 m², respectively.

Statistical Evaluation
All pharmacokinetic parameters are reported as mean values ± SD, unless reported otherwise. Potential relationships between evaluated parameters were assessed by univariable or multivariate linear-regression analysis and Pearson’s correlation coefficient (r) using the NCSS package (Version 5.X; J.L. Hintze, East Kaysville, UT, 1992). Interpatient differences in pharmacokinetic parameters were calculated by defining the coefficient of variation, expressed as the ratio of the SD and the observed mean value. Similarly, values for intrapatient variability in cisplatin CL were obtained from patients who had received three pharmacokinetically assessable treatment courses. Variability in kinetic parameters between treatment courses or between the various cotreatment regimens was evaluated by the Wilcoxon signed-rank test or one-way analysis of variance (ANOVA) after testing for normality. ANOVA was also used to compare differences in body-size normalized CL among the different BSA categories with the Bonferroni correction for multiple comparisons. The Kruskal-Wallis statistic followed by a Dunn’s multiple comparison test was applied for comparison of kinetic variables between cisplatin dose levels. Probability values of less than .05 were considered statistically significant.

	RESULTS

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Patient Population
A total of 268 patients (163 males and 105 females; median age, 54 years [range, 21 to 74 years]) were studied in the present analysis (Table 1). The predominant disease types were non–small-lung cancer (n = 80 patients), colorectal cancer (n = 55), head and neck cancer (n = 42), and carcinoma of unknown primary (n = 35). The patients received single-agent cisplatin (n = 17) or cisplatin in combination with either docetaxel (n = 61), etoposide (n = 76), irinotecan (n = 57), or topotecan (n = 57). In total, 485 cycles were available for pharmacokinetic analysis.

View larger version (11K): [in this window] [in a new window]   Fig 1. Plasma concentration-time profiles of unbound cisplatin () and total cisplatin (•) in 76 patients receiving cisplatin at a dose of 70 mg/m2.

View larger version (13K): [in this window] [in a new window]   Fig 2. Relationship between the AUCs of unbound and total cisplatin in data obtained from first treatment courses of 268 patients.

View larger version (15K): [in this window] [in a new window]   Fig 3. (A) Relationship between the absolute cisplatin dose (milligrams) and the absolute clearance of unbound cisplatin (expressed in liters per hour), and (B) the relationship between the cisplatin dose (milligrams per square meter) and the apparent clearance of unbound cisplatin (expressed in liters per hour per square meter). Data were obtained from 268 pharmacokinetically assessable patients.

View larger version (13K): [in this window] [in a new window]   Fig 4. BSA versus absolute clearance of unbound cisplatin (expressed in liters per hour). Data were obtained from 268 pharmacokinetically assessable patients.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The current clinical practice for dosing of the anticancer agent cisplatin is based on BSA of the individual patient. This use, in turn, is explained by the assumption of a narrow relationship between the CL of the drug and BSA. However, no data in the literature exist to support this assumption for cisplatin. In the present report, we have studied the relationship between cisplatin CL and BSA in a group of 268 patients who were treated with cisplatin in phase I/II clinical studies.

In line with previous findings, the concentration-time curves of unbound cisplatin and total cisplatin (ie, bound to plasma proteins [mainly albumin] plus unbound) did not run parallel, suggesting that protein-binding is essentially irreversible.^20,21 It has been shown that the drug is primarily eliminated by the kidneys, although within 24 hours of treatment cisplatin exhibits relatively low recovery in urine (approximately 11% to 32%).²² This observation probably reflects the extensive binding of reactive platinum metabolites to plasma proteins and tissues and implies that renal CL is relatively unimportant, at least during the initial phases of drug CL. In view of this restrictive CL of cisplatin, it has been recommended to use unbound cisplatin-concentration data for representative calculation of pharmacokinetic parameters (AUC values and CL). Indeed, as mentioned previously, it has been shown that correlations exist between clinical effects and kinetic parameters of unbound cisplatin.^7-12 Thus the interindividual variability in CL of the pharmacologically active unbound cisplatin is an important determinant of treatment outcome. Furthermore, it has been demonstrated in several studies (in which patients received a constant dose in milligrams per square meter) that inappropriate cisplatin AUC was the single most important determinant of toxicity or relapse.¹² Here, we found that the coefficient of variation for cisplatin CL expressed in absolute measures or relative to BSA were both in the same order (23.6% v 25.6%) and that BSA was poorly related to unbound cisplatin CL. Thus, given the frequency with which cisplatin AUC will exceed thresholds associated with undesired outcomes even when dose is adjusted for BSA, unbound cisplatin monitoring and/or the need to adjust cisplatin dose based on AUC measured in the individual patient may be required regardless of body-size measures. On the other hand, it is noteworthy that the interindividual variability in BSA of the patients was only 10.4%, indicating that an effect of BSA on cisplatin CL was measurable but not highly contributory. This strongly suggests that other (unknown) factors than BSA could be considered more important predictors of CL and AUC.

Using univariable and multivariate regression analysis, we found that various demographic variables or other covariates, including comedication, disease type, and drug dose, were not related to unbound cisplatin CL, which is in agreement with previous population models for cisplatin pharmacokinetics.^23,24 Interestingly, it was observed in these models that only BSA and infusion duration impacted on CL, although interindividual variability as well as residual variability remained large (approximately 23% to 36%, respectively). The finding that age is not a covariate on CL is at odds with at least one recent observation of a significant negative correlation between age and CL for both total cisplatin and unbound drug.²⁵ Using a general linear model, these authors found that age was independent of sex and tumor type as a predictor of cisplatin kinetics and suggested that with increasing age (a known determinant of renal function), cisplatin elimination by the kidneys might be reduced, leading to a reduction in overall CL. The basis for these discrepant findings is currently unknown, although they may relate, for example, to patient-specific differences in the studied populations.

Interestingly, we observed that male patients had approximately 15% faster CL of unbound cisplatin compared with female patients, whose CL values were 9.0% lower than the mean of all patients. The reason for a lower CL of unbound cisplatin in females is not clear, although it does not seem to be related to differences in prior chemotherapy. Previous studies have revealed similar differences for several other anticancer agents, including irinotecan and topotecan,²⁶ and that major factors responsible for sex-dependent pharmacokinetics are related to differences in body composition, renal elimination, and hepatic function.²⁷ Indeed, we found a significant difference in BSA between males and females, although most importantly, the apparent CL of unbound cisplatin remained significantly different even when expressed relative to BSA. As studies have identified kinetic thresholds for severe toxicity and antitumor activity, the current data suggest that an apparent decrease in cisplatin CL in females could result in enhanced toxicity after fixed-dosing regimens (in milligrams per square meter) as compared with males. However, the relatively small difference found in this analysis indicates that it might not be of clinical relevance and suggests that this issue should be investigated further.

The variability in unbound cisplatin CL in the patients we studied is similar to that reported for cisplatin administered to 26 cancer patients at a dose of 80 mg/m² by infusion over 2, 3.5, or 4 hours (23.6% v 22.9%).²⁴ In general, variability in absolute CL of most anticancer drugs, including docetaxel, etoposide, irinotecan, paclitaxel, and topotecan, is substantially larger (ie, > 30%) than that observed here for cisplatin. One reason for this might be that these agents are primarily eliminated by hepatic P450 oxidative metabolic (phase I) enzymes, the expression of which is highly variable among individuals (up to six-fold) and which is sensitive to induction and inhibition by various other xenobiotics. It is also noteworthy that CL of several other platinum analogs (eg, carboplatin and oxaliplatin) is predominantly driven by glomerular filtration, which may explain increased kinetic variability as compared with cisplatin.²⁸

The intrapatient variability in the AUC and CL of total and unbound cisplatin, measured in a subset of 90 patients sampled during three courses, was also exceptionally low (approximately 12%). Part of this intraindividual variability, particularly for total cisplatin, was caused by a decrease in CL after repeated administration of cisplatin, suggesting that this variation might even be overestimated. The mechanism of decreased cisplatin CL after repeated administration is not completely understood. One explanation is that part of the observed increase in AUC (and hence decrease in CL) may be artificial because drug levels have not fallen to zero at the time of next administration (ie, as a result of carryover effects).

It is concluded that cisplatin CL is related to BSA. The relation, however, is weak and other presently unknown factors are probably more important. The effect of BSA on pharmacokinetics was measurable but had little, if any, predictive ability. In view of the relatively high interindividual variability in the CL of unbound drug and the small range in observed BSA in the entire patient population, cisplatin can be added to the list of anticancer agents where BSA-adjusted dosing does not seem more accurate. A careful study to identify alternative clinical or laboratory parameters with predictive value toward cisplatin CL and AUC by a population approach to pharmacokinetic modeling using NONMEM (S.L. Beal and L.B. Sheiner, San Francisco, CA) is currently in progress. Unless better predictors for unbound drug CL are identified, it is recommended (in the therapeutic dose range of 50 to 100 mg/m²) to apply fixed-dosing regimens for cisplatin in adult cancer patients. Currently, a further randomized clinical study is being conducted to fully explore the advantages of this approach, in which simultaneously the need for potential dosage adjustments at extreme BSA values will be investigated.

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Submitted February 23, 2001; accepted June 5, 2001.

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