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Randomized Cross-Over Evaluation of Body-Surface Area–Based Dosing Versus Flat-Fixed Dosing of Paclitaxel

From the Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, the Netherlands.

Address reprint requests to Alex Sparreboom, PhD, Medical Oncology Clinical Research Unit, National Cancer Institute, 9000 Rockville Pike, Bldg 10, Rm 5A01, Bethesda, MD 20892; email: sparreba{at}mail.nih.gov.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: Despite dose calculation using body-surface area (BSA), pharmacokinetics of most anticancer drugs show wide interindividual variability. In this study, we evaluated the role of BSA in paclitaxel disposition.

Patients and Methods: Paclitaxel pharmacokinetics were prospectively studied in 12 patients that were treated in a randomized cross-over design with paclitaxel (3-hour infusion at a 3-week interval) at 175 mg/m² in cycle 1 (A) and a flat-fixed dose of 300 mg in cycle 2 (B), or vice versa. Blood samples were collected up to 24 hours after dosing and analyzed for total and unbound paclitaxel.

Results: The area under the curves (AUC) of unbound paclitaxel were similar in both dosing groups, with mean values ± SD (A v B) of 1.34 ± 0.158 versus 1.30 ± 0.329 µM•h, indicating that BSA-based dosing reduced the coefficient of variation by 53.3%. Unbound and total paclitaxel clearance was also significantly related to various body-size measures, including BSA (R 0.617; P .033), weight (R 0.621; P .031), and lean-body mass (r 0.630; P .028). We hypothesize that this is caused by the association of paclitaxel in the circulation with Cremophor EL, the distribution of which is linked to total blood volume, and thus to BSA.

Conclusion: This study indicates that paclitaxel disposition is significantly related to BSA. This provides a pharmacokinetic rationale for BSA-based dosing of this drug.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
IN MEDICINE, most drugs for adult patients are administered at a flat-fixed dose. Only the dosage of some drugs with a small therapeutic index, such as aminoglycosides, cyclosporine, phenytoin, and sympaticomimetics, are based on the body weight of the patient and are adjusted by monitoring either serum drug levels or clinical outcome. In contrast, in oncology, the dosage of nearly all cytotoxic drugs is based on body-surface area (BSA) of the patient.¹ The optimal dose of a cytotoxic drug is expected to result in two important clinical end points—a maximum antitumor effect and a minimum of toxicity. Studies on the appropriate rate of input (ie, dose and schedule) of antitumor agents are difficult because the desired tumor responses cannot be observed immediately and may vary as a result of differences in drug sensitivity; furthermore, possible toxic effects may be severe and life threatening. Therefore, pharmacokinetic variables such as drug clearance, area under the curve (AUC), and volume of distribution may serve as surrogate end points. Gurney¹ has described a positive correlation of several pharmacokinetic parameters, especially AUC, with the toxicity of anticancer drugs, although a correlation with the tumor response is found less often. However, for most cytotoxic agents, no significant correlation has been noticed between BSA and drug clearance or AUC.^1,2 Because normalization of drug dose to BSA seems unlikely to have a relevant effect on tumor response or toxicity of most anticancer drugs, this common method of dose calculation has been questioned.^1–4

The antineoplastic agent paclitaxel is widely used to treat a variety of solid tumors, particularly ovarian and breast cancer.⁵ Dose calculation of paclitaxel is based on BSA, using a dosing schedule of 135 to 225 mg/m² that is usually administered as a 3-hour infusion every 3 weeks. Despite this dose adjustment based on BSA, a wide interpatient variability persists for total paclitaxel clearance.⁶ In the present report, we prospectively studied paclitaxel disposition in 12 patients treated in a randomized cross-over design with BSA-based versus flat-fixed dosing to provide a pharmacokinetic rationale for appropriate dosing strategies for this agent.

	PATIENTS AND METHODS

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Eligibility Criteria
Eligible patients had histologically or cytologically documented solid cancer for which paclitaxel was a therapeutic option or for which no effective therapy was known. To observe any potential influence of BSA-based dosing on the pharmacokinetics and/or toxicity of paclitaxel, the BSA of potential patients was established to be 1.65 or 1.85 m² (based on a mean BSA value with a ± SD percentage of 1.73 mg/m² ± 5%). This procedure was chosen because it would provide information on the need for potential dosage adjustments at extreme BSA values and it would avoid inclusion of patients receiving similar total doses according to the fixed- or BSA-based dosing regimen. Patients were required to have a World Health Organization performance status 2, an age 18 years, an adequate bone marrow function (absolute neutrophil count [ANC] 1.5 x 10⁹/L, platelets 100 x 10⁹/L, and hemoglobin 6.0 mmol/L), an adequate liver function (bilirubin < 1.5 times the upper limit of institutional normal values and AST and ALT < 2.5 times the upper limit of normal), a normal renal function (creatinine clearance 60 mL/min), and no previous chemotherapy or radiotherapy during the 4 weeks before treatment. All patients gave written informed consent before study entry. The study was approved by the ethical committee of the Erasmus MC–Daniel den Hoed Cancer Center (Rotterdam, the Netherlands).

Treatment Plan
Paclitaxel formulated in a mixture of Cremophor EL and ethanol USP (Taxol; Bristol-Myers Squibb, Woerden, the Netherlands) was administered as a 3-hour intravenous infusion diluted in 500 mL of isotonic sodium chloride solution on the first day of a 3-week cycle. Standard intravenous premedication consisted of dexamethasone (8 mg), clemastine (2 mg), and ranitidine (50 mg), all given 30 minutes before start of the paclitaxel infusion. At study entry, patients were randomly allocated, using a random-number generator, to receive either one cycle of paclitaxel at a flat-fixed dose of 300 mg followed by a second cycle of paclitaxel at a BSA-based dose of 175 mg/m² or vice versa, with each patient serving as his or her own control. No dose reductions were allowed. Patients who could not receive the two cycles of paclitaxel went off study and were replaced. In the case of absence of progressive disease, patients were offered the option of continuing treatment outside this study with paclitaxel at the standard BSA-based dose in consecutive 3-week cycles.

Pretreatment and Follow-Up Evaluation
At study entry and before each chemotherapy cycle, a history and physical examination were performed, and weight, height, complete blood cell count with differential (including hemoglobin, platelets, WBC, and ANC), and a clinical chemistry analysis (including sodium, potassium, calcium, albumin, total serum proteins, creatinine, bilirubin, -glutamyltransferase, alkaline phosphatase, AST, and ALT) were measured. Various measures of body size, including BSA (in meters squared), lean body mass (in kilograms), ideal body weight (in kilograms), adjusted ideal body weight (in kilograms), and body mass index were calculated as described elsewhere.⁷ Blood cell counts and a chemistry analysis were also obtained weekly while on study. Tumor measurements were performed every two cycles, and responses and toxicity were evaluated according to the World Health Organization criteria and the National Cancer Institute common toxicity criteria (March 1998 version), respectively.

Sampling Procedure
Venous blood samples of approximately 5 mL were collected in both cycles at the following time points: before infusion, at 1 and 2 hours during infusion, at 5 minutes before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, 4, 8, 10, and 21 hours after the end of infusion. Blood samples were taken from a vein in the arm opposite the one used for drug infusion and collected in tubes containing lithium heparin as an anticoagulant. Plasma was separated by centrifugation at 3,000 x g for 10 minutes at 4°C and stored frozen at -80°C until analysis.

Analytic Assays
Concentrations of total paclitaxel (the total of bound and unbound fractions) in plasma samples were determined by reversed-phase high-performance liquid chromatography with detection at 230 nm as described earlier.⁸ Measurement of unbound paclitaxel was performed by equilibrium dialysis using a [G-³H]paclitaxel tracer.⁹ Coinciding levels of Cremophor EL were measured by a colorimetric dye-binding microassay.¹⁰

Pharmacologic Calculations
Concentration-time profiles of unbound paclitaxel and total paclitaxel were analyzed by compartmental methods using the Siphar v4.0 software package (InnaPhase, Philadelphia, PA) as described previously.^11–13 The AUC was extrapolated to infinity and determined based on the best-fitted curve and used for calculation of the absolute clearance (L/h), defined as the ratio of dose delivered (in milligrams) and AUC. The apparent clearance (L/h/m²) was calculated by dividing the absolute clearance of paclitaxel by a patient’s individual BSA value. All paclitaxel concentration-time curves were best described by a three-compartment model, without any demonstration of saturable behavior (R² ± SD = 0.989 ± 0.006, range, 0.967 to 0.997; root mean squared error ± SD = 18.5% ± 5.52%, range, 10.1% to 31.6%; n = 48). Noncompartmental analysis was used for calculation of Cremophor EL parameters.¹⁴

Statistical Evaluation
All pharmacologic parameters are reported as mean values ± SD. Least-squares linear-regression analysis was performed to evaluate relationships between paclitaxel clearance and each of the studied body-size measures. Interindividual variability in parameters was evaluated by the coefficient of variation, defined as the ratio of SD and the observed mean value. For all tests, a P < .05 was considered statistically significant, and all analyses were carried out using NCSS v2001 Statistical Analysis System (NCSS Statistical Software, Kaysville, UT).

The sample size calculation was based on the detection of clinically relevant differences in AUC variability between patients. The coefficient of variation in AUC, expressed as the ratio of the SD and the mean of unbound paclitaxel AUC values (multiplied by 100), was estimated from a group of 26 cancer patients treated with paclitaxel to be 25%.¹¹ Because we intended to conduct a cross-over trial with paired continuous data, the SD of the differences of the two measurements was required (denoted _d), with the sample size calculation using the standardized effect size (defined as d = /_d, where is the effect size). The value for _d was calculated as _w x 2, where _w denotes the intrasubject SD.¹⁵ The _w was estimated from a residual error model using the NONMEM software package (Beal SL and Sheiner LB, University of California, San Francisco, CA), assuming log-normal parameter distribution (_w = 5.73 and _d = 5.73 x 2 = 8.10). In the planned trial, we assumed that the 3-week interval between treatments would be an adequate washout period, so that there was no carryover and no period effect. The trial was designed to detect an effect size of approximately 30% ( = 25 x 30/100 = 7.50), providing the standardized effect (d = 7.50/8.10 = 0.93). In a pair-wise (two-sided) analysis, this results in a sample size of 12 for the prospective evaluation, with a significance level () of 0.05 and a statistical power (1-ß) of 0.80 (80%). This analysis was performed in the SISA-Binomial program (D.G. Uitenbroek, Hilversum, the Netherlands, 1997; available at http://home.clara.net/sisa/samsize.htm [accessed August 15, 2002]), with the values of 7.50 and 8.10 plugged into the boxes labeled "Expected Average 1" and "Std Dev 1," respectively. The calculation can also be performed using a sample size table, such as that provided in the online statistics textbook StatPrimer v5.1 (B.B. Gerstman, San Jose, CA, 2001; available at http://www.sjsu.edu/faculty/gerstman/StatPrimer/[accessed August 15, 2002]).

Differences in pharmacokinetic and pharmacodynamic parameters between cycles were evaluated using a two-tailed, paired Student’s t test after testing for normality. The significance of the relationship between the absolute clearance of paclitaxel (unbound and total drug) and the various measures of body size was evaluated by analyzing the cycles in which patients received fixed doses.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Twelve patients were studied in a randomized cross-over design with two treatment cycles of paclitaxel based on BSA-corrected dose or flat-fixed dose regimens. Seven patients started with a flat-fixed dose followed by a BSA-based dose, and five patients were randomly assigned to receive the reverse sequence. Baseline demographic data and the various body-size measures were similar between patients randomly assigned to a flat-fixed dose or a BSA-based dose in cycle 1 (Tables 1 and 2). The most prominent tumor types were breast (n = 4) and lung cancer (n = 3), and half of the patients had received two or more prior chemotherapy regimens.

View larger version (20K): [in this window] [in a new window]   Fig 1. Relationships between absolute clearance (CL) of unbound paclitaxel and height, weight, body-surface area (BSA), and body-mass index (BMI). Data were obtained from the flat-fixed dose cycles (open circles and solid line) or the BSA-based dose cycles (filled circles and dashed line) from 12 patients.

View larger version (19K): [in this window] [in a new window]   Fig 2. Relationships between absolute clearance (CL) of total paclitaxel and height, weight, body-surface area (BSA), and body-mass index (BMI). Data were obtained from the flat-fixed dose cycles (open circles and solid line) or the BSA-based dose cycles (filled circles and dashed line) from 12 patients.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
In this study, we have investigated paclitaxel disposition as a function of body-size measures by a comparative randomized cross-over study using the conventional method for dose calculation based on BSA (175 mg/m²) and a flat-fixed dosing regimen (300 mg). Interestingly, we observed that the interindividual variability in exposure to unbound and total paclitaxel after administration as a 3-hour infusion in a 3-week regimen is approximately 50% reduced by BSA-based dosing compared with flat-fixed dosing.

To achieve a therapeutic response with a predictable and acceptable degree of toxicity, one would have to obtain a certain level of drug exposure. To minimize any variation in this level, the dose of most anticancer agents is currently based on the BSA of individual patients. However, the contribution of other patient-related factors to variability in drug exposure is usually much larger than that of body-size measures alone, so that the additional value of BSA in dose calculations may be questioned.^1,2 Indeed, a review of the available literature reveals that the clearance of most drugs in clinical oncology, including anticancer agents that have been available for many years (eg, cisplatin,¹⁶ epirubicin,¹⁷ irinotecan,⁷ and topotecan¹⁸), as well as investigational agents (eg, ET-743¹⁹ and ZD9331²⁰; reviewed by Felici et al²¹) is not related to BSA.

Previously, Grochow et al³ correlated pharmacokinetic variables of total paclitaxel (dosed on the basis of BSA in milligrams per meter squared) with the body-size measures, including height, weight, and BSA. In a total of 16 patients treated in a phase I trial with paclitaxel administered in a 3-week regimen, only height was significantly associated with the clearance of paclitaxel. Unfortunately, the data generated in this trial were based on measurement of the total plasma concentration of paclitaxel using different dose groups. This is of particular importance in view of the profound nonlinear paclitaxel disposition in humans,^6,22 which suggests that correlation analyses based on total plasma levels alone are not appropriate when different dose groups are included. Because the AUC of unbound paclitaxel is a linear function of the paclitaxel dose administered,^11,12 we focused here on the unbound paclitaxel fraction.

The level of drug exposure varies with individual rates of absorption, distribution, metabolism, and excretion. The disposition of paclitaxel in patients depends on the duration of infusion and the dose- and time-varying concentrations of its vehicle Cremophor EL because of a preferential affinity of paclitaxel for Cremophor EL in blood.²³ It has been demonstrated that Cremophor EL has an extremely small volume of distribution (mean ± SE, 2.53 ± 0.124 L/m²; n = 67),¹⁴ approximating the volume of the blood compartment.²⁴ In this study, Cremophor EL clearance was not significantly related to BSA, which is most likely caused by the profound interindividual kinetic variability that is larger than normal for most drugs. However, others have recently found in a larger group of patients that BSA is a significant covariate on clearance in a population model for Cremophor EL pharmacokinetics.²⁵ Because total blood volume is related to BSA,²⁶ we hypothesize that the effect of BSA on variability in paclitaxel pharmacokinetics is caused by the association of paclitaxel in the circulation with Cremophor EL micelles, of which the distribution is linked to total blood volume, and thus to BSA. To lend further support to this hypothesis, we are currently evaluating the relationship between BSA and clearance of other chemotherapeutic agents formulated for clinical use in a Cremophor EL–containing vehicle (eg, teniposide).

Paclitaxel is eliminated mainly by hepatic metabolism through CYP3A4 and CYP2C8 activity,²⁷ as well as by MDR1 P-glycoprotein–mediated intestinal secretion.²⁸ The metabolic capacity of the liver has not been associated with body-size measures,⁴ indicating that interindividual differences in enzyme activity contribute to pharmacokinetic variability independent of a patient’s BSA. Furthermore, genetic polymorphism in the population results in a large variability in CYP3A4,²⁹ CYP2C8,³⁰ and P-glycoprotein activity³¹ and is, therefore, likely to have a major role in paclitaxel pharmacokinetics. In fact, altered liver functions in the elderly might explain the previously observed change in clearance of unbound paclitaxel in this age group compared with adult patients.³² Ongoing trials currently explore the role of metabolic capacity in paclitaxel disposition and treatment outcome using genotyping and phenotyping approaches for CYP3A4, CYP2C8, and P-glycoprotein as a potential measure for dose calculation of paclitaxel in addition to BSA.

In conclusion, this study shows that paclitaxel disposition has a unique feature in that the interindividual variability in exposure is greatly reduced by adjusting the dose to BSA. Because hepatic metabolism is the principal elimination route for paclitaxel, it is of particular interest to investigate any correlation between metabolic capacity and variability in paclitaxel pharmacokinetics. At present, arguments to abandon the current way of dose calculation based on BSA are lacking in the case of paclitaxel.

	ACKNOWLEDGMENTS

 
We thank Desiree M. van Zomeren for her expert technical assistance.

	REFERENCES

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Submitted January 14, 2002; accepted October 4, 2002.

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