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Journal of Clinical Oncology, Vol 25, No 30 (October 20), 2007: pp. 4707-4713 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.2938 Evaluation of Alternate Size Descriptors for Dose Calculation of Anticancer Drugs in the Obese
From the Department of Medical Oncology, Erasmus MC–Daniel den Hoed Cancer Center, Rotterdam, the Netherlands; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Institut Claudius-Regaud, Toulouse, France; and the Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX Address reprint requests to Alex Sparreboom, PhD, Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 332 North Lauderdale, DTRC, Mail Stop 314, Room D1034B, Memphis, TN 38105; e-mail: alex.sparreboom{at}stjude.org
Purpose Despite the rising prevalence of obesity, there is paucity of information describing how doses of anticancer drugs should be adjusted in clinical practice. Here, we assessed the pharmacokinetics of eight anticancer drugs in adults and evaluated the potential utility of alternative weight descriptors in dose calculation for the obese.
Patients and Methods A total of 1,206 adult cancer patients were studied, of whom 162 (13.4%) were obese (body mass index Results The absolute clearance of cisplatin, paclitaxel, and troxacitabine was significantly increased in the obese (P < .023), but this was not observed for carboplatin, docetaxel, irinotecan, or topotecan (P < .17). For doxorubicin, the systemic clearance was statistically significantly reduced in obese women (P = .013), but not in obese men (P = .52). Evaluation of alternate weight descriptors for dose calculation in the obese, including predicted normal weight, lean body mass, (adjusted) ideal body weight, and the mean of ideal and actual body weight, indicated that, for most of the evaluated drugs, weight scalars used to calculate body-surface area should consider actual body weight regardless of size. Conclusion The results suggest that a number of widely used empiric strategies for dose adjustments in obese patients, including a priori dose reduction or dose capping, should be discouraged.
Drug dosing recommendations in oncology are usually based on results from clinical trials that included patients who are considered typical of those likely to receive the drug in clinical practice. In many cases, however, the obese patient may not be well represented, and therefore extrapolation of dosing recommendations to this group must be performed arbitrarily when the dose is required to be standardized to a particular patient demographic such as body-surface area (BSA).1 Moreover, there is a paucity of information available from early clinical trials on the influence of obesity on the pharmacokinetics and pharmacodynamics of anticancer drugs, which is caused, in part, by empiric eligibility restrictions from the outset and a lack of pharmacokinetic and safety analyses performed and published for this subpopulation.2 With the growing number of obese patients with cancer among adults,3,4 this knowledge deficit may have significant ramifications when interpreting the relationships between dose and outcomes or risk of toxicity.5 In clinical practice, a diverse range of empiric dosing regimens is widely employed to calculate drug doses for the obese, including using the patient's BSA up to an arbitrary cutoff (eg, dose capping at 2 m2),6 or using some alternative estimate of the patient's weight, such as predicted normal weight,7 lean body mass,8 (adjusted) ideal body weight,9 or the mean of ideal and actual body weight.10 Most of these practices, however, have not been evaluated in the context of a controlled clinical trial, and in many cases will likely result in significant undertreatment.6,11,12 Because awareness of the physiologic effects of obesity on drug disposition is essential for ensuring appropriate chemotherapy in obese patients, we assessed the plasma pharmacokinetics of eight anticancer agents in lean and obese patients, defined as those individuals having a body mass index of 25 kg/m2 or lower or 30 kg/m2 or higher, respectively.13 Next, we evaluated the influence of various alternative weight descriptors used in the formula to calculate BSA-normalized dose on the predicted drug exposure to provide a pharmacokinetic rationale for selecting the appropriate dose in the obese.
Data Collection The study drugs included carboplatin (n = 103 patients), cisplatin (n = 283), docetaxel (n = 169), doxorubicin (n = 103), irinotecan (n = 167), paclitaxel (n = 80), topotecan (n = 190), and troxacitabine (n = 111). These agents were considered because of the known differences in their primary pathways of elimination (Table 1). Because the rate and extent of drug absorption after oral administration is not known to be altered by obesity,14 only drugs that are administered intravenously were studied. The administered dose for each drug was normalized to BSA, which was calculated from height and actual body weight. All patients were at least 18 years old and provided written informed consent for enrollment on studies approved by the local review boards. Additional common eligibility criteria included: (a) life expectancy of at least 12 weeks; (b) performance status of 2 or lower; (c) no chemotherapy, hormonal therapy, or radiotherapy for at least 4 weeks before enrollment; (d) adequate contraception and a negative pregnancy test result for women of childbearing potential; and (e) adequate bone marrow function, renal function, and hepatic function. Simultaneous use of any medication, dietary supplements, or other compounds known to inhibit, induce, or otherwise affect the pharmacokinetics of the study drugs was not allowed.
Sample Collection and Pharmacokinetic Analysis Preliminary pharmacokinetic data obtained from (subsets of) the studied patient populations have been published previously for carboplatin,15 cisplatin,16 docetaxel,17 doxorubicin,17 irinotecan,18 paclitaxel,19 topotecan,20 and troxacitabine.21 Carboplatin. Patients received carboplatin as a single agent or in combination with paclitaxel, fluorouracil, etoposide, or gemcitabine. Carboplatin was administered as a 60-minute infusion at doses ranging from 290 to 1,700 mg. Blood samples were taken before administration, 5 minutes before the end of infusion, and at 1 and 4 hours after the end of infusion. Carboplatin concentrations in plasma ultrafiltrate were measured using flameless atomic absorption spectrophotometry (AAS) as described previously.22 Cisplatin. Patients were treated with cisplatin monotherapy or cisplatin-based combination therapy with oral etoposide, irinotecan, oral topotecan, or docetaxel. The drug was administered as a 3-hour infusion at doses ranging from 50 to 100 mg/m2, with treatment cycles repeated every week or every 3 weeks. Blood samples were obtained immediately before infusion, at 1 and 2 hours after the start of the infusion, at the end of infusion, and at 0.5, 1, 2, 3, and 18 hours after the end of infusion. Plasma concentrations of unbound cisplatin were determined by AAS.23 Docetaxel. Patients were treated with docetaxel alone or combined with capecitabine, cisplatin, doxorubicin with or without marimastat, or methotrexate. Docetaxel was administered as a 1-hour infusion at doses ranging from 55 to 100 mg/m2. Blood samples were obtained immediately before docetaxel administration; at 30 minutes after the start of infusion, at the end of infusion, and at 1, 3, 5, 23, and 48 hours after the end of infusion. Determination of docetaxel was performed using high-performance liquid chromatography (HPLC) with UV detection.24 Doxorubicin. Patients were treated with doxorubicin monotherapy or with doxorubicin-based combination therapy with cyclophosphamide, docetaxel, or paclitaxel. Doxorubicin was administered as an intravenous bolus (5 minutes), a short infusion (15 to 20 minutes), or as a 1- to 3-hour infusion at doses ranging from 40 to 75 mg/m2. Blood samples were taken immediately before infusion, directly after infusion, and 30 minutes and 1, 2, 4, 7, 12, 24, and 48 hours postinfusion. Concentrations of doxorubicin in plasma were determined by HPLC with fluorescence detection.25 Irinotecan. Irinotecan was administered either alone or in combination with cisplatin as a 90-minute continuous intravenous infusion at a dose level between 175 and 350 mg/m2 or at a flat dose of 600 mg. Blood samples were collected before infusion, at 0.5 and 1.5 hours during infusion, and 10, 20, and 30 minutes and 1, 2, 3, 3.5, 4, 5, 6.5, 10.5, 24, 30.5, 48, and 54.5 hours after the end of infusion. Concentrations of irinotecan and its active metabolite SN-38 were determined by HPLC with fluorescence detection.26 Paclitaxel. Paclitaxel was supplied as a concentrated solution in cremophor-ethanol. The drug was administered as a single agent or in combination with carboplatin. Paclitaxel was administered intravenously over 1 hour, 3 hours, or 24 hours at doses ranging from 50 to 225 mg/m2. Blood samples were obtained at the following time points: immediately before infusion, and 0.5, 1, 1.5, 2, 2.5, 3, 5, 7, 13, 25, 33, and 49 hours after the start of paclitaxel infusion (1-hour schedule); 1, 2, 3, 3.08, 3.25, 3.5, 4, 4.5, 5, 7, 9, 15, 21, 27, 35, and 51 hours after infusion (3-hour schedule); or at 1, 22, 23, 23.92, 24.08, 24.15, 25, 26, 27, 30, 36, and 45 hours after infusion (24-hour schedule). Determination of total paclitaxel was performed by HPLC with UV detection.27 The fraction of unbound paclitaxel was determined using equilibrium-dialysis.28 Topotecan. Topotecan was administered to patients once daily for 5 consecutive days every 3 weeks (dose, 0.2 to 2.4 mg/m2 or a fixed dose of 4 mg), once daily for 7, 10, 13, or 21 days (dose, 0.20 to 1.00 mg/m2), or twice daily for 5, 10, or 21 days (dose, 0.15 to 2.70 mg/m2). The drug was administered as a single agent or in combination with cisplatin. Sample collection was performed before dosing, at 15 minutes after the start of infusion, immediately before the end of infusion, and at 15 and 30 minutes and 1, 2, 3, 4, 6, 8, and 10 hours after the end of infusion. Determination of topotecan was performed by HPLC with fluorescence detection.29 Troxacitabine. Patients with solid tumors or advanced leukemia were treated with a 30-minute intravenous infusion of troxacitabine at a dose of 0.12 to 12.5 mg/m2. The drug was administered once daily for 5 consecutive days once every 21 to 28 days. Blood samples were obtained at baseline, 5 and 15 minutes, immediately before the end of the infusion, and after infusion at 5, 15, 30, 60, and 90 minutes, and at 2, 4, 6, 8, 24, and 48 hours. HPLC and tandem mass spectrometric detection was used to determine concentrations of troxacitabine.30 Clearance, volume of distribution, and terminal half-life for each drug were derived from individual plasma concentration-time profiles using noncompartmental analysis with the software package WinNonlin (Scientific Consultant, Apex, NC) Professional Version 5.0 (Pharsight Corporation, Mountain View, CA), model 202 (plasma data, constant infusion). For each drug, the observed area under the curve (AUC) in lean controls (AUClean) was calculated as dose (in mg) divided by clearance.
Statistical Considerations
A total of 1,206 adult cancer patients were studied, of whom 162 (13.4%) were defined as obese. In the group of obese patients, 105 (64.8%) had a BSA of more than 2.0 m2, and 69 (65.7%) of these patients were men. The absolute clearance (expressed in L/h) of all study drugs was consistently increased in obese patients, and differences reached statistical significance for cisplatin (13% increased; P = .0070), paclitaxel (20% increased; P = .023), and troxacitabine (19% increased; P = .016; Table 3). When values were normalized to BSA calculated using actual body weight, however, no statistically significant differences in clearance (expressed in L/h/m2) between lean and obese patients were observed.
For docetaxel and doxorubicin, dose calculation in the obese on the basis of BSA that used actual body weight resulted in ratios of AUCobese and AUClean that were 33% and 25% higher, respectively, than unity. This observation was primarily caused by a substantially higher systemic drug exposure in obese women compared with lean controls (Table 4), presumably as a result of altered drug clearance. For example, the geometric mean ratio of doxorubicin clearance in obese and lean patients was 0.69 (95% CI, 0.52 to 0.92; P = .013) for women and 1.11 (95% CI, 0.79 to 1.56; P = .52) for men. In contrast, the use of lean body mass in the formula for BSA resulted in predicted ratios of AUCobese and AUClean for docetaxel and doxorubicin that were not statistically significantly different from unity in both women and men. For the other drugs evaluated, the use of weight descriptors other than actual body weight either did not result in substantial improvement in obtaining the target measure of exposure in the obese (irinotecan), resulted in slight improvement albeit not to a significant extent (carboplatin, topotecan), or was predicted to result in significantly reduced exposure (cisplatin, paclitaxel, troxacitabine; Table 4). The use of dose capping at a BSA of 2.0 m2 or flat dosing regardless of body size resulted in AUC ratios for all drugs that were consistently lower than those observed with dose calculation on the basis of actual body weight (Table 4).
Traditionally, anticancer drug doses have been standardized to BSA with the aim of producing a consistent systemic drug exposure (eg, AUC) to minimize the occurrence of excessive toxicity. As mentioned previously, selecting an appropriate drug dose can be a particularly challenging decision for clinicians when treating obese patients. Despite the potential importance of this decision, few studies have investigated the effects of obesity on anticancer drug disposition, providing a remarkably scant database to use as a basis for individualized dosing. In the current study, we sought to identify which weight descriptors are the most important when describing variability in pharmacokinetic parameters between obese and normal-weighted patients for a series of anticancer drugs. The absolute clearance of cisplatin, paclitaxel, and troxacitabine was found to be significantly increased in the obese (P < .023), but this was not observed for carboplatin, docetaxel, doxorubicin, irinotecan, or topotecan (P < .17). The data on the renally cleared drugs cisplatin and troxacitabine are consistent with the notion that especially tubular secretion, rather than glomerular filtration, is disproportionately increased in obese individuals.31 Although physiologic and pharmacokinetic data on the effect of obesity on the systemic clearance of highly extracted drugs are conflicting, oxidative biotransformation in the liver is typically unchanged in the obese.14 However, it has been reported that the phenotypic activity of certain isoforms of the cytochrome P450 system might be elevated in the obese.32 It is therefore possible that the impact of obesity on the clearance of the hepatically cleared drug paclitaxel originates from changes in activity of one or more cytochrome P450 enzymes. Interestingly, a similar effect of obesity on the absolute clearance was not observed for the structurally related drug docetaxel. This discrepancy might be related, in part, to the finding that, for docetaxel, the volume of distribution and the half-life of the terminal phase were statistically significantly increased in the obese. This has been described previously for other hydrophobic drugs that have a high affinity for adipose tissue.31 Regardless of the exact explanation for this incongruence, this example of the two taxanes clearly weakens the ability to support broad recommendations for dose calculation in the obese for drugs on the basis of physicochemical characteristics alone. To assess the utility of various alternate weight descriptors for dose calculation in the obese, a predicted AUC was calculated and compared for differences with the geometric mean AUC in lean controls, which was used as the reference measure of drug exposure for patients within the general oncology population. This is based on the implicit assumption that the dose recommended in clinical practice is for normal-weighted patients.7 In keeping with earlier conjectures, dose calculation in the obese on the basis of BSA that uses actual body weight was found to be an appropriate strategy for cisplatin,16 paclitaxel,33 and troxacitabine,21 as assessed by values for the AUC ratios. For carboplatin, consideration of either predicted normal weight or the mean of ideal and actual weight (eg, the Bénezét equation) resulted in the best prediction of systemic exposure in both men and women. In line with this finding, a prior analysis performed on data obtained in obese patients receiving carboplatin demonstrated that neither actual body weight nor ideal body weight was a perfect size descriptor, and that the average of actual body weight and ideal body weight, obtained from a nonlinear mixed-effect modeling (NONMEM) analysis, was the best predictor of carboplatin clearance within the formula, integrating body weight and glomerular filtration rate.10 Similar observations were also made for topotecan, although the potential impact of the use of alternative size descriptors was minimal for this agent. For docetaxel and doxorubicin, the use of actual body weight in the formula for BSA to calculate dose resulted in statistically significantly increased exposure in the obese, especially in women. For these two agents, applying lean body mass as a dosing scalar seems to be of particular merit, and this is in line with observations for a number of other agents that are predominantly eliminated by the liver.34 However, previous studies have suggested that full weight–based dosing of anthracyclines in obese patients is important in achieving optimal outcomes,35 and also that the practice of any dose reduction for anthracycline-based therapy is not indicated, because obese women did not experience increased toxic effects when dosed according to actual body weight.6,35 This is despite the current demonstration that the clearance of doxorubicin is significantly reduced in obese women, as reported previously.36 It is possible that the finding that obese women who did receive full weight–based doxorubicin doses did not experience excessive neutropenia reflects on influence of body size that is unrelated to drug disposition. For example, Wong et al37 recently demonstrated that BSA was the only pretreatment indicator of vinorelbine-induced myelosuppression independent of drug clearance in a multivariable analysis, and these authors suggested that this relationship can possibly be explained by BSA indirectly reflecting a patient's bone marrow reserve. As previously predicted,38 the use of weight descriptors other than actual body weight was shown to lead to even worse prediction of irinotecan pharmacokinetics in the obese. Because of the highly complex disposition profile of irinotecan, it is possible that any potential clinical importance of body-size consideration in drug dosage may be completely dwarfed by interindividual variations in other important pharmacokinetic factors. In conclusion, the data generated in the current study indicate that the disposition of some, but not all drugs, is significantly altered in the obese; the selection of alternate size descriptors for dose calculation in the obese is drug specific and sex dependent, and seems unrelated to intrinsic physicochemical properties or route of elimination; obesity may affect, possibly in a drug-specific manner, treatment outcome through currently unknown mechanisms that are unrelated to pharmacokinetics; empiric decreases in drug dose for obese patients (eg, dose capping) should be discouraged because these may compromise efficacy; and additional prospective studies are required to further refine dosing strategies in the obese for each individual agent.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: Eric K. Rowinsky, ImClone Systems Leadership: N/A Consultant: N/A Stock: N/A Honoraria: N/A Research Funds: Antonio C. Wolff, Roche, GSK, BMS Testimony: N/A Other: N/A
Conception and design: Alex Sparreboom, Sharyn D. Baker Provision of study materials or patients: Antonio C. Wolff, Etienne Chatelut, Eric K. Rowinsky, Jaap Verweij Collection and assembly of data: Alex Sparreboom, Ron H.J. Mathijssen, Etienne Chatelut, Eric K. Rowinsky, Sharyn D. Baker Data analysis and interpretation: Alex Sparreboom, Ron H.J. Mathijssen, Jaap Verweij, Sharyn D. Baker Manuscript writing: Alex Sparreboom, Antonio C. Wolff, Sharyn D. Baker Final approval of manuscript: Alex Sparreboom, Antonio C. Wolff, Ron H.J. Mathijssen, Etienne Chatelut, Eric K. Rowinsky, Jaap Verweij, Sharyn D. Baker
We thank Susan Buchowsky, Baltimore, MD, for performing preliminary analyses on the database.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Baker SD, Verweij J, Rowinsky EK, et al: Role of body surface area in dosing of investigational anticancer agents in adults, 1991-2001. J Natl Cancer Inst 94:1883-1888, 2002 2. Baker SD, Grochow LB, Donehower RC: Should anticancer drug doses be adjusted in the obese patient? J Natl Cancer Inst 87:333-334, 1995 3. Polednak AP: Trends in incidence rates for obesity-associated cancers in the US. Cancer Detect Prev 27:415-421, 2003[CrossRef][Medline] 4. Sturm R: Increases in clinically severe obesity in the United States, 1986-2000. Arch Intern Med 163:2146-2148, 2003 5. Green B, Duffull SB: What is the best size descriptor to use for pharmacokinetic studies in the obese? Br J Clin Pharmacol 58:119-133, 2004[CrossRef][Medline] 6. Griggs JJ, Sorbero ME, Lyman GH: Undertreatment of obese women receiving breast cancer chemotherapy. Arch Intern Med 165:1267-1273, 2005 7. Duffull SB, Dooley MJ, Green B, et al: A standard weight descriptor for dose adjustment in the obese patient. Clin Pharmacokinet 43:1167-1178, 2004[CrossRef][Medline] 8. Janmahasatian S, Duffull SB, Ash S, et al: Quantification of lean bodyweight. Clin Pharmacokinet 44:1051-1065, 2005[CrossRef][Medline] 9. Bauer LA, Edwards WA, Dellinger EP, et al: Influence of weight on aminoglycoside pharmacokinetics in normal weight and morbidly obese patients. Eur J Clin Pharmacol 24:643-647, 1983[CrossRef][Medline] 10. Bénezét S, Guimbaud R, Chatelut E, et al: How to predict carboplatin clearance from standard morphological and biological characteristics in obese patients. Ann Oncol 8:607-609, 1997 11. Griggs JJ, Culakova E, Sorbero ME, et al: Effect of patient socioeconomic status and body mass index on the quality of breast cancer adjuvant chemotherapy. J Clin Oncol 25:277-284, 2007 12. Jenkins P, Elyan S, Freeman S: Obesity is not associated with increased myelosuppression in patients receiving chemotherapy for breast cancer. Eur J Cancer 43:544-548, 2007[CrossRef][Medline] 13. World Health Organization: Report of a WHO Consultation on Obesity: Preventing and Managing the Global Epidemic. Geneva, Switzerland, WHO, 1998 14. Abernethy DR, Greenblatt DJ: Drug disposition in obese humans: An update. Clin Pharmacokinet 11:199-213, 1986[Medline] 15. Thomas F, Seronie-Vivien S, Gladieff L, et al: Cystatin C as a new covariate to predict renal elimination of drugs: Application to carboplatin. Clin Pharmacokinet 44:1305-1316, 2005[CrossRef][Medline] 16. de Jongh FE, Verweij J, Loos WJ, et al: Body-surface area-based dosing does not increase accuracy of predicting cisplatin exposure. J Clin Oncol 19:3733-3739, 2001 17. Rudek MA, Sparreboom A, Garrett-Mayer ES, et al: Factors affecting pharmacokinetic variability following doxorubicin and docetaxel-based therapy. Eur J Cancer 40:1170-1178, 2004[CrossRef][Medline] 18. de Jong FA, Scott-Horton TJ, Kroetz DL, et al: Irinotecan-induced diarrhea: Functional significance of the polymorphic ABCC2 transporter protein. Clin Pharmacol Ther 81:42-49, 2007[CrossRef][Medline] 19. Henningsson A, Marsh S, Loos WJ, et al: Association of CYP2C8, CYP3A4, CYP3A5, and ABCB1 polymorphisms with the pharmacokinetics of paclitaxel. Clin Cancer Res 11:8097-8104, 2005 20. Léger F, Loos WJ, Bugat R, et al: Mechanism-based models for topotecan-induced neutropenia. Clin Pharmacol Ther 76:567-578, 2004[CrossRef][Medline] 21. Lee CK, Rowinsky EK, Li J, et al: Population pharmacokinetics of troxacitabine, a novel dioxolane nucleoside analogue. Clin Cancer Res 12:2158-2165, 2006 22. LeRoy AF, Wehling ML, Sponseller HL, et al: Analysis of platinum in biological materials by flameless atomic absorption spectrophotometry. Biochem Med 18:184-191, 1977[CrossRef][Medline] 23. de Jonge MJ, Loos WJ, Gelderblom H, et al: Phase I pharmacologic study of oral topotecan and intravenous cisplatin: Sequence-dependent hematologic side effects. J Clin Oncol 18:2104-2115, 2000 24. Loos WJ, Verweij J, Nooter K, et al: Sensitive determination of docetaxel in human plasma by liquid-liquid extraction and reversed-phase high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 693:437-441, 1997[CrossRef][Medline] 25. de Bruijn P, Verweij J, Loos WJ, et al: Determination of doxorubicin and doxorubicinol in plasma of cancer patients by high-performance liquid chromatography. Anal Biochem 266:216-221, 1999[CrossRef][Medline] 26. Sparreboom A, de Bruijn P, de Jonge MJ, et al: Liquid chromatographic determination of irinotecan and three major metabolites in human plasma, urine and feces. J Chromatogr B Biomed Sci Appl 712:225-235, 1998[CrossRef][Medline] 27. Sparreboom A, de Bruijn P, Nooter K, et al: Determination of paclitaxel in human plasma using single solvent extraction prior to isocratic reversed-phase high-performance liquid chromatography with ultraviolet detection. J Chromatogr B Biomed Sci Appl 705:159-164, 1998[CrossRef][Medline] 28. Brouwer E, Verweij J, de Bruijn P, et al: Measurement of fraction unbound paclitaxel in human plasma. Drug Metab Dispos 28:1141-1145, 2000 29. Loos WJ, Stoter G, Verweij J, et al: Sensitive high-performance liquid chromatographic fluorescence assay for the quantitation of topotecan (SKF 104864-A) and its lactone ring-opened product (hydroxy acid) in human plasma and urine. J Chromatogr B Biomed Appl 678:309-315, 1996[CrossRef][Medline] 30. Giles FJ, Cortes JE, Baker SD, et al: Troxacitabine, a novel dioxolane nucleoside analog, has activity in patients with advanced leukemia. J Clin Oncol 19:762-771, 2001 31. Blouin RA, Kolpek JH, Mann HJ: Influence of obesity on drug disposition. Clin Pharm 6:706-714, 1987[Medline] 32. Baker SD, van Schaik RH, Rivory LP, et al: Factors affecting cytochrome P-450 3A activity in cancer patients. Clin Cancer Res 10:8341-8350, 2004 33. Smorenburg CH, Sparreboom A, Bontenbal M, et al: Randomized cross-over evaluation of body-surface area-based dosing versus flat-fixed dosing of paclitaxel. J Clin Oncol 21:197-202, 2003 34. Morgan DJ, Bray KM: Lean body mass as a predictor of drug dosage: Implications for drug therapy. Clin Pharmacokinet 26:292-307, 1994[Medline] 35. Rosner GL, Hargis JB, Hollis DR, et al: Relationship between toxicity and obesity in women receiving adjuvant chemotherapy for breast cancer: Results from cancer and leukemia group B study 8541. J Clin Oncol 14:3000-3008, 1996[Abstract] 36. Rodvold KA, Rushing DA, Tewksbury DA: Doxorubicin clearance in the obese. J Clin Oncol 6:1321-1327, 1988 37. Wong M, Balleine RL, Blair EY, et al: Predictors of vinorelbine pharmacokinetics and pharmacodynamics in patients with cancer. J Clin Oncol 24:2448-2455, 2006 38. Mathijssen RH, Verweij J, de Jonge MJ, et al: Impact of body-size measures on irinotecan clearance: Alternative dosing recommendations. J Clin Oncol 20:81-87, 2002 Submitted February 13, 2007; accepted June 27, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
30). Pharmacokinetic parameters were calculated using noncompartmental analysis, and compared between lean (body mass index 
25) and obese patients. 
