CORRESPONDENCE

Re: Role of Body Surface Area in Dosing of Investigational Anticancer Agents in Adults, 1991-2001

Yuichi Ando, Tomoko Ohtsu, Masahiko Ando, Fumiyoshi Ohyanagi, Fumio Nagashima, Masaru Narabayashi, Nagahiro Saijo, Yasutsuna Sasaki

Affiliations of authors: Saitama Medical School, Saitama, Japan (YA, FO, FN, MN, YS); National Cancer Center Hospital East, Chiba, Japan (TO); Kyoto University, Kyoto, Japan (MA); National Cancer Center Hospital, Tokyo, Japan (NS).

Correspondence to: Yuichi Ando, MD, PhD, Department of Clinical Oncology, Saitama Medical School, 38 Morohongo, Moroyama, Iruma-gun, Saitama 350-0495, Japan (e-mail: yando{at}saitama-med.ac.jp).

In a recent article in the Journal, Baker et al. (1) reported that body surface area (BSA)-based dosing was not associated with a decrease in interpatient variability in the pharmacokinetics of most anticancer agents. Interestingly, a BSA-based dosing strategy was associated with a decrease in interpatient variability in paclitaxel clearance, a finding that has been recently validated in a prospective study (2). Because the pharmacokinetic variability among patients reflects complex interactions between genes and environmental factors, it is possible that the role of BSA in paclitaxel dosing may differ for different ethnic groups. Therefore, we examined the role of BSA in paclitaxel dosing using data from a previous phase I study (3) conducted in Japan.

According to results of simple linear regression analysis, variability in the paclitaxel area under the concentration versus time curve (AUC) was related more to the BSA-based doses than to the actual doses per individual (Fig. 1). Thus, the traditional use of BSA in paclitaxel dosing is also supported by results in Japanese patients, suggesting that the role of BSA is similar in Japanese and non-Japanese patients. We note that approximately 80% of the variability in AUC could be accounted for by the actual doses per individual.



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Fig. 1. Scatter plots showing relationships between log-transformed area under the concentration versus time curve (AUC, µM x h) values and doses of paclitaxel. Twenty-seven patients (18 males, nine females; BSA range = 1.35-1.82 m2; BSA median = 1.65 m2) received paclitaxel over 3 hours in 500 mL of 5% glucose at doses of 105, 135, 180, 210, 240, or 270 mg/m2, and pharmacokinetic evaluations were carried out. Detailed information on the study was provided elsewhere (3). As a surrogate for systemic exposure to paclitaxel, AUC was obtained by a non-compartmental moment method and trapezoidal integration with extrapolation to infinite time. Although Baker et al. (1) originally compared drug clearances with and without BSA-based normalization, their method is not appropriate for the case of paclitaxel because it has nonlinear pharmacokinetics (i.e., the drug clearances are lower at higher doses) (4). Thus, coefficient of determination (r2) of simple linear regression analysis was used to test whether variability in log-transformed AUC values was related to the paclitaxel doses with (A) or without (B) incorporating BSA. Based on these coefficients of determination, the BSA-based doses could explain 84% of the variation in AUC, whereas the actual doses could explain 78% of the variation in AUC. Lines indicate the regression lines. Statistical analyses were performed using SPSS II software (SPSS Japan, Tokyo, Japan).

 
BSA simply mirrors essential biologic factors that would regulate the pharmacokinetics of paclitaxel. Because paclitaxel has a strong affinity for its vehicle, Cremophor EL, in blood circulation, the distribution of paclitaxel depends on that of the vehicle (5). Cremophor EL has a very small distribution volume that approximates the total blood volume, and the statistically significant relationship between body size and blood volume is known. It has been suggested that the effect of BSA on paclitaxel pharmacokinetics is associated with its affinity for its vehicle, the distribution of which is linked to total blood volume and thus to BSA (1,2). By contrast, paclitaxel is metabolized mainly by CYP2C8 in the liver (6), and thus the total amount of this enzyme should be one of the determinants for the metabolic ability of paclitaxel. The amount of this enzyme is related to the total liver volume, and there is a statistically significant correlation between liver volume and BSA (7). With this in mind, it is not surprising that paclitaxel pharmacokinetics may be associated with BSA. It is likely that ethnic differences exist in the activities of drug-metabolizing enzymes and transporters that could influence the metabolism and disposition of the relevant drugs in the body. Sequence variations in genes encoding drug-metabolizing enzymes and transporters may be more common in some ethnic groups than in others. Different diets and lifestyles may modify the functions of those proteins. Thus, the relative contributions of these factors may not be consistent between different ethnic groups, and the appropriate dosing method to reduce interpatient pharmacokinetic variability could differ among different populations. We need to keep this issue in mind in global efforts to develop drugs and in bridging studies that seek to extrapolate the effects of drugs to other populations.

REFERENCES

1 Baker SD, Verweij J, Rowinsky EK, Donehower RC, Schellens JH, Grochow LB, et al. Role of body surface area in dosing of investigational anticancer agents in adults, 1991-2001. J Natl Cancer Inst 2002;94:1883-8.[Abstract/Free Full Text]

2 Smorenburg CH, Sparreboom A, Bontenbal M, Stoter G, Nooter K, Verweij J. Randomized cross-over evaluation of body-surface area-based dosing versus flat-fixed dosing of paclitaxel. J Clin Oncol 2003;21:197-202.[Abstract/Free Full Text]

3 Ohtsu T, Sasaki Y, Tamura T, Miyata Y, Nakanomyo H, Nishiwaki Y, et al. Clinical pharmacokinetics and pharmacodynamics of paclitaxel: a 3-hour infusion versus a 24-hour infusion. Clin Cancer Res 1995;1:599-606.[Abstract]

4 Gianni L, Kearns CM, Giani A, Capri G, Vigano L, Lacatelli A, et al. Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol 1995;13:180-90.[Abstract]

5 Sparreboom A, van Zuylen L, Brouwer E, Loos WJ, de Bruijn P, Gelderblom H, et al. Cremophor EL-mediated alteration of paclitaxel distribution in human blood: clinical pharmacokinetic implications. Cancer Res 1999;59:1454-7.[Abstract/Free Full Text]

6 Rahman A, Korzekwa KR, Grogan J, Gonzalez FJ, Harris JW. Selective biotransformation of taxol to 6 alpha-hydroxytaxol by human cytochrome P450 2C8. Cancer Res 1994;54:5543-6.[Abstract]

7 Urata K, Kawasaki S, Matsunami H, Hashikura Y, Ikegami T, Ishizone S, et al. Calculation of child and adult standard liver volume for liver transplantation. Hepatology 1995;21:1317-21.[ISI][Medline]



             
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