|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2003 American Society for Clinical Oncology
Paclitaxel Pharmacokinetics, Threshold Models, and Dosing Strategies
1 National Cancer Institute, Bethesda, MD To the Editor: We read with interest the editorial by Dr Egorin1 that accompanied our recent article,2 which investigated the suitability of using body-surface area (BSA) in dosing of paclitaxel in humans. After careful consideration of our study, the author concluded that it "raises more questions than it answered."
First, Dr Egorin is concerned with the use of the area under the curve (AUC) of (unbound) paclitaxel as the pharmacokinetic parameter to study in the context of our trial, and proposes instead the use of a parameter that describes the duration that concentrations of paclitaxel in plasma are greater than 0.05 µmol/L. Unfortunately, the selection of pharmacokinetic parameter end points and basic model types for exposure-toxicity relationships of paclitaxel is usually based on tradition rather than physiological relevance. Indeed, pharmacokinetic-pharmacodynamic relationships for paclitaxel are still most commonly described with empirically-designed threshold models, which have little or no mechanistic basis and lack usefulness when applied to conditions (eg, schedules, vehicles, or routes of administration) different from those from which they were originally derived. Since the initial reports on threshold models for paclitaxel-induced neutropenia,3,4 knowledge of paclitaxel pharmacokinetics has vastly increased, and alternative models with a foundation in the known properties of the agent’s pharmacological behavior have been proposed.5–10 Several of these have clearly demonstrated the importance of the AUC of unbound paclitaxel as a pharmacokinetic parameter to describe exposure-neutropenia relationships, both with 1-hour and 3-hour infusion regimens.9–11 For the interested reader, we have provided the previously omitted threshold parameters for total paclitaxel in Table 1
The second concern relates to the generalizability of the results in view of the current trend to administer paclitaxel routinely as a 1-hour infusion, or at reduced doses given on a weekly basis. In our manuscript, we hypothesized that the influence of BSA on variability in paclitaxel pharmacokinetics is caused by the association of paclitaxel in the circulation with the formulation vehicle Cremophor EL, the distribution of which is linked to total blood volume, which itself is related to BSA.2 Previously, the clearance of Cremophor EL in patients was found to be time-dependent, resulting in disproportional increases in systemic exposure being associated with shortening of infusion from 3 hours to 1 hour.11 This suggests that similar, if not stronger, effects of BSA on variability in paclitaxel pharmacokinetics are expected with 1-hour infusions as compared with the studied regimen. This hypothesis is supported by a recent retrospective analysis that shows that the relationship between BSA and the clearance of unbound paclitaxel is stronger with 1-hour infusions (R = 0.57; P < .001; n = 34) as compared with 3-hour infusions (R = 0.45; P = .003; n = 40).12 It is also noteworthy in this context that, in contrast to Dr Egorin’s statement, the AUC of the pharmacologically active species (ie, unbound paclitaxel) is substantially reduced following 1-hour infusions of the same total dose as compared with those encountered in our study.11 Our initial assumption of an average BSA of 1.73 m2 came from a European Organization for Research and Treatment of Cancer (EORTC) database including 3,000 patients, both male and female, treated for sarcomas, lymphomas, and rectal cancers during the period from 1990 to 1998 (unpublished data). We agree with the author that more recent estimates for an adult, 21st century patient population may be somewhat higher. Fortunately, the ranges of observed BSA for the 2 tested BSA groups (between 1.462 and 1.539 m2 for the first group and between 1.875 and 2.097 m2 for the second; see Table 2 in our article) also conform to a mean BSA value of 1.8 m2 ± 5% standard deviation.
The final issue relates to the omission of pretreatment neutrophil counts in our original article (Table 1
REFERENCES
1. Egorin MJ: Horseshoes, hand granades, and body-surface area-based dosing: aiming for a target. J Clin Oncol 21:182–183, 2003
2. 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
3. Huizing MT, Keung AC, Rosing H, et al: Pharmacokinetics of paclitaxel and metabolites in a randomized comparative study in platinum-pretreated ovarian cancer patients. J Clin Oncol 11:2127–2135, 1993
4. Gianni L, Kearns CM, Giani, et al: Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol 13:180–190, 1995 5. Karlsson MO, Molnar, Bergh J, et al: A general model for time-dissociated pharmacokinetic-pharmacodynamic relationship exemplified by paclitaxel myelosupp-ression. Clin Pharmacol Ther 63:11–25, 1998[CrossRef][Medline] 6. Minami H, Sasaki Y, Saijo N, et al: Indirect-response model for the time course of leukopenia with anticancer drugs. Clin Pharmacol Ther 64:511–521, 1998[CrossRef][Medline] 7. Minami H, Sasaki Y, Watanabe T, et al: Pharmacodynamic modeling of the entire time course of leukopenia after a 3-hour infusion of paclitaxel. Jpn J Cancer Res 92:231–238, 2001[CrossRef][Medline] 8. Fetterly GJ, Tamburlin JM, Straubinger RM: Paclitaxel pharmacodynamics: application of a mechanism-based neutropenia model. Biopharm Drug Dispos 22:251–261, 2001[CrossRef][Medline] 9. Henningsson A, Karlsson MO, Vigano L, et al: Mechanism-based pharmacokinetic model for paclitaxel. J Clin Oncol 19:2065–2073, 2001
10. Friberg LE, Henningsson A, Maas H, et al: Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol 20:4713–4721, 2002
11. Gelderblom H, Mross K, ten Tije AJ, et al: Comparative pharmacokinetics of unbound paclitaxel during 1- and 3-hour infusions. J Clin Oncol 20:574–581, 2002
12. 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
Related Articles
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
