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© 2002 American Society for Clinical Oncology Impact of Body-Size Measures on Irinotecan Clearance: Alternative Dosing RecommendationsByFrom 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, PO Box 5201, 3008 AE Rotterdam, the Netherlands; email: sparreboom{at}onch.azr.nl
PURPOSE: To evaluate relationships between various body-size measures and irinotecan (CPT-11) clearance and metabolism in cancer patients, and to provide future dosing recommendations for this agent. PATIENTS AND METHODS: Pharmacokinetic data were obtained from 82 adult patients (50 men, 32 women; median age, 54 years) receiving CPT-11 as a 90-minute intravenous infusion (dose range, 175 to 350 mg/m2). In each patient, plasma samples were collected at timed intervals in the first administration of a 3-week schedule, and CPT-11 and its metabolite, SN-38, were measured by a liquid chromatographic assay. RESULTS: The mean (± SD) CPT-11 clearance was 33.6 ± 10.8 L/h, with an interindividual variability (IIV) of 32.1%. When clearance was adjusted for body-surface area (BSA), the IIV was similar (34.0%). In addition, in a multiple linear regression analysis, none of the studied measures (BSA, lean body mass, [adjusted] ideal body weight, and body mass index) was a significant covariate (P > .13; r2 < .014) in our population. Similarly, BSA did not significantly contribute to variability in the relative extent of conversion to SN-38 (P = .26). CONCLUSION: BSA is not a predictor of CPT-11 clearance or SN-38 pharmacokinetics and does not contribute to reducing kinetic variability. These findings provide a rationale for the conduct of a comparative phase III study between BSA-based dosing and flat or fixed dosing of CPT-11.
IRINOTECAN (7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin; CPT-11) belongs to the class of topoisomerase I inhibitors, and it acts as a prodrug of SN-38, which is approximately 100- to 1,000-fold more cytotoxic than the parent drug.1 CPT-11 has shown a broad spectrum of antitumor activity in preclinical models as well as clinically, with responses observed in various disease types, including colorectal, lung, cervical, and ovarian cancer.2 The pharmacokinetics and metabolism of CPT-11 are extremely complex and have been the subject of intensive investigation in recent years. Both CPT-11 and SN-38 are known in an active lactone form and an inactive carboxylate form, between which equilibrium exists that depends on the pH and the presence of binding proteins. In addition, CPT-11 is subject to extensive metabolic conversion by both phase I and phase II enzyme systems, including carboxylesterases to form SN-38,3 uridine diphosphoglucuronate glucuronosyltransferases (UGT1A1) mediating glucuronidation of SN-38,4 as well as cytochrome P-450 isoforms (mainly CYP3A4) which form several pharmacologically inactive oxidation products.5,6 Elimination routes of CPT-11 also depend on the presence of drug-transporting proteins, notably P-glycoprotein7 and a canalicular multispecific organic anion transporter (cMOAT),8 present on the bile canalicular membrane. The various processes that mediate drug elimination, either through metabolic breakdown or excretion, likely have a substantial impact on interindividual variability in drug handling. Strategies are now underway to individualize CPT-11 administration schedules based on patient differences in enzyme or protein expression or by coadministration of specific agents modulating side effects.9 These strategies may ultimately lead to more selective chemotherapeutic use of this agent. In contrast, the prescribed dose of CPT-11 is currently calculated using body-surface area (BSA) as the only independent variable, and it has been shown that this approach still results in large interindividual variability in exposure. Although this has been widely recognized for some agents, until recently its significance has not been fully appreciated and remains unstudied for most anticancer drugs used in today’s clinical practice. The purpose of this report was to assess CPT-11 clearance and metabolism as a function of commonly used body-size measures in adult cancer patients to provide a pharmacokinetic rationale for the appropriate dosing of CPT-11.
Patients Population Records collected as part of clinical CPT-11 monitoring at the Rotterdam Cancer Institute were examined retrospectively; the full clinical profiles have been documented elsewhere.10-13 All patients had malignant solid tumors that stipulated a CPT-11–based regimen and had adequate hematopoietic (absolute neutrophil count  1.5 x109/L; platelet count 100 x109/L), hepatic, and renal function at the time of study entry. Inclusion also required an Eastern Cooperative Oncology Group performance status of 2 or less and age between 18 and 75 years. All patients with complete information (consisting of age, disease, height, weight, and first-dose pharmacokinetic data) were included in the current analysis. No other agents known to interfere with CPT-11 disposition were administered immediately before or concomitantly with CPT-11. All patients provided informed consent for the pharmacologic analysis.
Drug Administration
Pharmacokinetic Analysis Concentration-time data of CPT-11 and SN-38 were fitted to a triexponential equation, using the software package Siphar, version 4.0 (InnaPhase, Philadelphia, PA), on the basis of a previously described model discrimination.17 Inverse square weighting of the measured concentrations was used for all compartmental analyses. The absolute clearance of CPT-11 (in L/h) was calculated by dividing the dose administered (in mg) by the observed area under the curve values. The apparent clearance (in L/h/m2) was also calculated by dividing the absolute clearance of irinotecan by a patient’s individual BSA value. For SN-38, the apparent metabolic clearance and the relative extent of conversion, defined as the area under the curve (in Mxh) ratio of SN-38 and CPT-11, were calculated.
The various body-size measures, including BSA (in m2),18 lean body mass (LBM; in kg),19 ideal body weight (IBW; in kg),20 adjusted ideal body weight (AIBW; in kg),20 and body mass index (BMI),20 were calculated using the following equations, with length expressed in meters and weight in kg:
After studying the whole included population, patients were divided into several groups. First, sex was studied separately. Second, patients were classified into three BSA groups: BSA less than 1.7 m2, BSA between 1.7 and 2.0 m2, and BSA more than 2.0 m2.
Statistical Analysis
Patient Population The entire population studied consisted of 82 patients, of whom 50 were male and 32 were female (Table 1). The median age was 54 years (range, 36 to 71 years), and the majority of patients suffered from colorectal carcinomas. Administered CPT-11 dose levels varied from 175 to 350 mg/m2.
CPT-11 Clearance The mean plasma clearance of CPT-11 was 33.6 ± 10.8 L/h (range, 13.5 to 64.8 L/h), with an interindividual variability of 32.1% (Table 2). After correction of the clearance for BSA, a mean value of 17.9 ± 6.1 L/h/m2 was found, along with a similar degree of variability (ie, 34.0%). Similarly, after adjustments of CPT-11 clearance for LBM, IBW, AIBW, BMI, weight, or length, the interpatient variability was not reduced (Table 2). Using linear regression analysis, we found that CPT-11 was not significantly related to any of the studied body-size estimates (Figs 1 and 2). In a univariate analysis that included weight, length, dose, sex, age, and tumor type as independent variables, no significant covariates were identified (P values between .09 and .58; adjusted r2 between < .0001 and .023) (Table 3). Multiple regression analysis also did not result in any significant correlation with CPT-11 clearance (P = .21, r2 = .032).
The interindividual variability in CPT-11 clearance was similar between men (33.4%) and women (34.6%), whereas variabilities in absolute clearance were 32.0% and 32.3% for these two groups, respectively. No differences in clearance for the three studied BSA groups (ie, < 1.7 m2, between 1.7 and 2.0 m2, and > 2.0 m2) were found (P = .06), with mean values of 33.8, 31.0, and 37.4 L/h, respectively. Neither BSA nor any other body-size estimate could reduce interpatient variability (not shown).
SN-38 Pharmacokinetics
A common practice in clinical oncology is to dose anticancer drugs on the basis of a patient’s BSA with the aim of reducing interindividual pharmacokinetic variability. Despite the lack of evidence of the clinical relevance for this dose selection in adults, the use of BSA for this purpose is widespread.21,22 The most commonly used formula to estimate BSA originates from 1916,18 and during the last decade, several critical notes concerning this BSA-based dosing concept have been published.21-29 With the possible exception of docetaxel,30 it has been demonstrated that the clearance of most agents, including epirubicin,25-27 topotecan,28 cisplatin,29 and busulfan,20 is not related to BSA. Various alternative body-size measures have been proposed in recent years, eg, IBW, AIBW, BMI, and LBM, that might be better predictors of drug clearance, but no clear rationale for their use has yet been found.18,25 In the present study, we evaluated the relationship between CPT-11 clearance and metabolism with BSA and several other body-size measures in a group of 82 cancer patients. The interindividual variability in CPT-11 clearance is large and is an important determinant of toxicity.14 The coefficients of variation for the absolute CPT-11 clearance or that expressed relative to BSA when including all patients in this study were 32.1% and 34.0%, respectively. Thus, we found that, similar to the case with most other chemotherapeutic agents, dose calculations based on BSA did not reduce interpatient variability in CPT-11 clearance. In addition, in a multiple regression analysis with body-size measures as the independent variable, no significant covariate on clearance could be identified. In contrast, some estimates of body size (ie, LBM, IBW, and AIBW) were shown to be even worse predictors of CPT-11 clearance and metabolism than BSA. Interestingly, it was reported by Miya et al31 that BMI was an independent predictor of peak plasma concentrations of CPT-11 in a group of 36 patients who received the drug as a 90-minute intravenous infusion at a dose of 100 mg/m2 (P = .01, r2 = .40). These authors speculated that water-soluble drugs such as CPT-11, with drug doses calculated on the basis of BSA, are poorly distributed to adipose tissue and might produce elevated peak concentrations in plasma as compared with hydrophobic agents in obese patients.31 In our current data set, such a correlation between peak levels and BMI could not be established. The basis for these discrepant findings is presently unknown, although they may relate, for example, to patient-specific (ethnic) differences in the studied patient populations. Much controversy has also arisen with respect to potential sex-dependent differences in the pharmacokinetic behavior of camptothecin anticancer agents. At least one recent observation indicated that whole blood and plasma concentrations of unchanged CPT-11 were generally lower in males as compared to females.32 In addition, sex has been identified recently as an important independent variable for the occurrence of severe CPT-11–induced leukocytopenia (grade 4) and/or diarrhea (grade 3 or worse).33 However, because of substantial interindividual variability and the small sample size, differences in pharmacokinetic parameters or the effects of sex on severe toxicity were not statistically significant. In our patient population, sex was unrelated to (variability in) CPT-11 clearance, which finding is supported by earlier pharmacokinetic data.34 In addition, in a recent population pharmacokinetic model developed using NONMEM (S.L. Beal and L.B. Sheiner, San Francisco, CA), sex was not a significant covariate on CPT-11 clearance and formation ratio of SN-38 (R.H.J.M. and A.S., manuscript in preparation). In contrast, for the related agent topotecan, a sex-dependent difference in clinical pharmacokinetics was noticed recently resulting from physiologic differences in hematocrit between males and females.35 These differences in kinetic behavior as a function of hematocrit between the various camptothecin analogs are not completely understood but may involve a variable degree in binding affinity for plasma proteins mediating erythrocyte partitioning and sequestration. Using univariate and multivariate regression analyses, we also found that various additional demographic variables, including disease type, drug dose, and age, were unrelated to CPT-11 clearance. This is in agreement with previous data,36,37 suggesting that reduced starting doses are not required for elderly patients. The results of this study also suggest that CPT-11 clearance is similar in lean and obese subjects, whereas the metabolic clearance of SN-38 is slightly higher, although not significantly different, in obese patients as compared with lean controls. These findings with CPT-11 and SN-38 are consistent with data indicating that the absolute clearance of xenobiotics eliminated by hepatic P450 oxidase metabolism is similar in obese and lean patients, whereas the absolute clearance of drugs eliminated primarily by phase II enzymes is higher in the obese.20 The only current factor routinely taken into consideration in clinical practice to predict toxicity after CPT-11 administration and to optimize or alter the dosage is a pathologic condition indicating hepatic dysfunction. It has been demonstrated that (elevated) bilirubin and alkaline phosphatase levels in plasma samples taken before treatment correlate positively with CPT-11 clearance, which may (partly) be explained by cMOAT activity.38 Also, correlations between CPT-11 clearance and gamma-glutamyl transferase (negative), gamma-glutamyl transpeptidase (negative), AST (positive), and ALT (positive) were recently observed.39,40 In addition, it has been documented that interindividual variability in cMOAT expression, as for instance in the Dubin-Johnson syndrome,41 can result in hyperbilirubinemia and require dose modifications. Importantly, however, it is increasingly recognized that the bilirubin level is not an appropriate parameter per se to predict severe CPT-11–induced toxicity, and it seems clinically negligible as a tool to predict toxicity,33 unless patients abstain from drug and alcohol and are strictly fasted. Thus, at present, bilirubin measurements have low predictability and are highly impractical. In addition, in view of the multiple enzyme systems and drug transporters involved in CPT-11 elimination, it seems that pharmacogenetic analysis such as that described for UGT1A1,42-46 CYP3A4,47 and P-glycoprotein48,49 polymorphism is unlikely to be the sole factor contributing to interindividual variability in CPT-11 clearance. We believe that this inherent uncertainty, as well as a host of logistic problems associated with its implementation in routine clinical practice for the near future, presents significant limitations of pharmacogenetic analyses to individualization of CPT-11 dosage. In contrast, the concept of fixed rather than BSA-normalized dosing should be an area for fruitful clinical pharmacologic studies with CPT-11. We intend to conduct a study to prospectively evaluate the feasibility of delivering a fixed dose of CPT-11 as a 90-minute intravenous infusion every 3 weeks, based on the known flat-dose (mg) area under the plasma concentration-versus-time curve and systemic exposure-toxicity relationships of the compound,14 rather than following the standard practice of administering the drug on a mg/m2 basis. Clearly, implementation of such concepts would have significant economic implications. The ability to manufacture a unit dose has obvious benefits for the pharmaceutical company involved. Similarly, reconstituting a fixed dose without subsequent individualization for different patients is more efficient and cost-effective than preparing individualized doses, and it would eliminate a significant source of error in attempting to obtain precise dosing.50 In conclusion, we have shown that BSA as well as all other tested body-size measures are unrelated to CPT-11 clearance and metabolism. In view of the significant degree of interindividual variability in systemic exposure to CPT-11 and SN-38 and the small range in observed BSA within the studied population, CPT-11 can be added to the list of anticancer agents where BSA-based dosing does not seem to be more accurate and might suggest a (harmful) false sense of accuracy. Better individual predictors of CPT-11 elimination and pharmacodynamics might be available in the future. However, further research into the exact relationships between these key factors and pharmacologic end points is clearly required before they can be implemented in routine clinical practice. Therefore, the findings of this study provide a rationale for the conduct of a phase III study comparing BSA-based dosing and fixed dosing of CPT-11. In case of fixed dosing, variability in drug clearance will still be approximately five-fold, and many patients will still be over- or underdosed. Since CPT-11 clearance and SN-38 pharmacokinetics correlate with toxicity, adjusting the dose for subsequent cycles based on toxicity induced by the drug is clearly recommended. The economic advantage may not be lost, since a range of fixed doses could be made available. As better methods of dose calculation become available in the future, these same doses could still be used as starting doses.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
