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© 2002 American Society for Clinical Oncology
Dear Doctor: We Really Are Not Sure What Dose of Capecitabine You Should Prescribe for Your PatientUniversity of Chicago, Chicago, IL THE PRODUCT LABEL for capecitabine first became of interest to me during the conduct of a phase I combination study that incorporated capecitabine. To develop a dosing regimen using full-dose capecitabine, the eligibility criteria excluded patients who, according to the manufacturer, required dose modification, which were those patients with creatinine clearance less than 51 mL/min. After a disproportionate number of women and older patients were found to be ineligible, I examined the capecitabine product label in detail, with particular attention to the dosing recommendations for renal impairment. Capecitabine, an oral prodrug of fluorouracil (5-FU), is an unlikely candidate for precise dosing guidelines. As noted in the product label, the interpatient coefficient of variability in 5-FU maximal concentration and area under the curve exceeds 85%, which is much higher than that of parenteral 5-FU.1,2 Capecitabine is commercially available in only two strengths, 150 mg and 500 mg, greatly limiting the available dosages. In fact, the daily dosages recommended in the product label are generally in 300 mg increments. To further complicate the situation, capecitabine must undergo three metabolic reactions to form the active metabolite, 5-FU.3 There are no data to guide the clinician or investigator in regard to optimal concentrations of the parent drug or its metabolites, either in regard to response or toxicity. Not that this is any different than most other oncology drugs, but most manufacturers do not attempt to provide such a sense of precision (as based on a complex dosing algorithm) in the absence of data. In November 2000, the manufacturer issued a "Dear Doctor" letter (authored by Ted P. Szatrowski, MD, Medical Director), informing the oncology community "of important safety-related changes to the prescribing information regarding the use of Xeloda in patients with renal impairment at baseline"4 (Xeloda; Hoffmann-La Roche Inc, Nutley, NJ). How was renal impairment defined? The manufacturer recommended that the starting dose be reduced by 25% in patients whose creatinine clearance was 31 to 50 mL/min, as estimated by the Cockroft-Gault formula, which has been criticized for its lack of accuracy and precision.5-9 Because creatinine clearance (a surrogate for glomerular filtration rate) was not directly measured, the recommended dosage reduction is actually for individuals with increased serum creatinine or increased age or low weight, the variables used to calculate the clearance. Women are also at greater risk for renal impairment, since the Cockroft-Gault formula reduces the creatinine clearance by 15% in women after the calculation based on age, weight, and serum creatinine. However, it is important to note that the manufacturer has not adjusted their definition of renal impairment for body-surface area (BSA), which is the norm in nephrology. A more appropriate recommendation might be to reduce the dose in patients whose calculated creatinine clearance falls below 51 mL/min/1.73 m2 (if supported by a reanalysis of the manufacturer’s unpublished data), because the recommended dosing for capecitabine already incorporates BSA. If one followed the package insert, a small woman (BSA 1.5 m2) with a calculated creatinine clearance of 48 mL/min (55 mL/min/1.73 m2) would be dose-reduced to 2,700 mg/d (1,800 mg/m2), whereas a large man (BSA 2.2 m2) with a calculated creatinine clearance of 70 mL/min (55 mL/min/1.73 m2) would be given the full dose of 5,600 mg/d (2,545 mg/m2). Thus, smaller females are underdosed relative to larger males in the presence of the same normalized renal function. The same implications apply to ethnic groups with a tendency towards a smaller body habitus. (It should also be noted that protocol definitions of acceptable renal function that include creatinine clearance without normalization to size will disproportionately exclude women, as well as ethnic groups of smaller body habitus.) Also, is dose reduction the right solution to the manufacturer’s unpublished findings of increased toxicity in patients with renal impairment? As noted above, it is unclear what pharmacokinetic parameter(s) correlate with toxicity or response. How do we know that patients with renal impairment treated at a reduced dose will benefit? Maybe these patients should not receive capecitabine at all? Furthermore, the manufacturer’s only published pharmacokinetic data relevant to the manufacturer’s dosing recommendations concluded that, "The variables investigated (age, sex, body-surface area, and creatinine clearance) had no clinically significant effect on the pharmacokinetics of capecitabine or its metabolites."10 A close review of the capecitabine package insert revealed other surprising findings. A variety of dosages were used in clinical trials. However, many of these dosages incorporated four significant digits plus BSA (eg, 1,657 mg/m2), which results in calculated dosages of six significant digits (if one estimates BSA to two significant digits), but only two dosage strengths 150 mg and 500 mg. This cannot be considered an appropriate use of precision, and one can question how these trials were even allowed to proceed with this detail unresolved. Another issue is the recommended dose modifications for toxicity. A 25% dose modification is recommended for grade 3 toxicity. Given that grade 3 (or higher) toxicity occurred in the majority of patients enrolled onto the phase III colorectal trials (see Table 8 of package insert),1 is this the correct starting dose? And what is the basis for an empirical dose reduction of 25%, after such precise calculation of the starting dose?
It is important to note that capecitabine is not the only example of unsupported labeling for renal impairment. The topotecan product label also recommends dose reduction for patients with creatinine clearance of 20 to 39 mL/min (not mL/min/1.73 m2).11 Also, a recent National Cancer Institute–sponsored phase I study of oxaliplatin in renal dysfunction incorporated definitions of renal dysfunction that did not adjust for BSA.12 However, this problem may be limited to oncology, as the product label for acyclovir (dosed as mg/kg) clearly recommends dose modification for creatinine clearance Moving forward, what do we need to do? As a first step, the Food and Drug Administration (FDA) should correct the labels for both capecitabine and topotecan. The FDA (and sponsors) should aim towards simple rather than complex dosing recommendations in both protocols and labels, unless clearly supported by data. BSA-based dosing (for adults) should be considered the exception rather than the rule, which could reduce prescribing and pharmacy errors and potentially save both time and money.13,14 Dosing strategies based on well-designed clinical pharmacology studies should be encouraged and possibly incentivized, particularly with the dawning of the age of pharmacogenomics and predictive medicine.15 Although completion of such studies is not always feasible before approval, these studies are of critical importance to the practicing oncologist, who is often faced with the challenge of treating patients who would have been excluded from the pivotal trials on the basis of organ dysfunction, age, body size, or other medical issues. Because some clinicians may have concerns about dosing recommendations in product labels, it will also be important that data from such studies be made publicly available for reanalysis by those who choose to prescribe these relatively toxic drugs.
NOTES M.J.R. consults for a number of companies, some of which are developing drugs that maybe construed as potential competitors of capecitabine. REFERENCES 1. Xeloda [package insert]. Nutley, NJ, Hoffmann-La Roche Inc; 2001. www.rocheusa.com/products/xeloda/pi.html 2. Jodrell DI, Stewart M, Aird R, et al: 5-fluorouracil steady state pharmacokinetics and outcome in patients receiving protracted venous infusion for advanced colorectal cancer. Br J Cancer 84: 600-603, 2001[CrossRef][Medline] 3. Miwa M, Ura M, Nishida M, et al: Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 34: 1274-1281, 1998 4. Food and Drug Administration Safety Information on Xeloda. Available at Http://www.fda.gov/medwatch/safety/2000/xeloda.pdf 5. Millward MJ, Webster LK, Toner GC, et al: Carboplatin dosing based on measurement of renal function: Experience at the Peter MacCallum Cancer Institute. Aust N Z J Med 26: 372-379, 1996[Medline] 6. Baracskay D, Jarjoura D, Cugino A, et al: Geriatric renal function: Estimating glomerular filtration in an ambulatory elderly population. Clin Nephrol 47: 222-228, 1997[Medline] 7. Martin L, Chatelut E, Boneu A, et al: Improvement of the Cockcroft-Gault equation for predicting glomerular filtration in cancer patients. Bull Cancer 85: 631-636, 1998[Medline]
8.
Levey AS, Bosch JP, Lewis JB, et al: A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation–Modification of diet in renal disease study group. Ann Intern Med 130: 461-470, 1999 9. Wright JG, Boddy AV, Highley M, et al: Estimation of glomerular filtration rate in cancer patients. Br J Cancer 84: 452-459, 2001[CrossRef][Medline] 10. Cassidy J, Twelves C, Cameron D, et al: Bioequivalence of two tablet formulations of capecitabine and exploration of age, gender, body surface area, and creatinine clearance as factors influencing systemic exposure in cancer patients. Cancer Chemother Pharmacol 44: 453-460, 1999[CrossRef][Medline] 11. Hycamtin [package insert]. Philadelphia, PA, SmithKline Beecham, 2001 12. Graham MA, Takomoto CH, Remick S, et al: A phase I study of oxaliplatin in cancer patients with impaired renal function. Proc Am Soc Clin Oncol 20: 68a, 2001 (abstr 267) 13. Ratain MJ: Body-surface area as a basis for dosing of anticancer agents: Science, myth, or habit? J Clin Oncol 16: 2297-2298, 1998[Medline] 14. Sawyer M, Ratain MJ: Body surface area as a determinant of pharmacokinetics and drug dosing. Invest New Drugs 19: 171-177, 2001[CrossRef][Medline] 15. Ratain MJ, Relling MV: Gazing into a crystal ball: Cancer therapy in the post-genomic era. Nat Med 7: 283-285, 2001[CrossRef][Medline]
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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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50 mL/min/1.73 m2. And for drugs that are not dosed based on BSA or weight (ie, most drugs), it is appropriate to make dosing recommendations based on creatinine clearance in mL/min. 
