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Originally published as JCO Early Release 10.1200/JCO.2005.11.036 on January 18 2005 © 2005 American Society of Clinical Oncology. Randomized Pharmacokinetic and Pharmacodynamic Study of Docetaxel: Dosing Based on Body-Surface Area Compared With Individualized Dosing Based on Cytochrome P450 Activity Estimated Using a Urinary Metabolite of Exogenous CortisolFrom the Division of Internal Medicine, National Cancer Center Hospital; Pharmacology Division and Cancer Information and Epidemiology Division, National Cancer Center Research Institute, Tokyo, Japan Address reprint requests to Tomohide Tamura, MD, Division of Internal Medicine, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan; e-mail: ttamura{at}ncc.go.jp
PURPOSE: Docetaxel is metabolized by cytochrome P450 (CYP3A4) enzyme, and the area under the concentration-time curve (AUC) is correlated with neutropenia. We developed a novel method for estimating the interpatient variability of CYP3A4 activity by the urinary metabolite of exogenous cortisol (6-beta-hydroxycortisol [6-ß-OHF]). This study was designed to assess whether the application of our method to individualized dosing could decrease pharmacokinetic (PK) and pharmacodynamic (PD) variability compared with body-surface area (BSA) –based dosing. PATIENTS AND METHODS: Fifty-nine patients with advanced non–small-cell lung cancer were randomly assigned to either the BSA-based arm or individualized arm. In the BSA-based arm, 60 mg/m2 of docetaxel was administered. In the individualized arm, individualized doses of docetaxel were calculated from the estimated clearance (estimated clearance = 31.177 + [7.655 x 10–4 x total 6-ß-OHF] – [4.02 x alpha-1 acid glycoprotein] – [0.172 x AST] – [0.125 x age]) and the target AUC of 2.66 mg/L · h. RESULTS: In the individualized arm, individualized doses of docetaxel ranged from 37.4 to 76.4 mg/m2 (mean, 58.1 mg/m2). The mean AUC and standard deviation (SD) were 2.71 (range, 2.02 to 3.40 mg/L · h) and 0.40 mg/L · h in the BSA-based arm, and 2.64 (range, 2.15 to 3.07 mg/L · h) and 0.22 mg/L · h in the individualized arm, respectively. The SD of the AUC was significantly smaller in the individualized arm than in the BSA-based arm (P < .01). The percentage decrease in absolute neutrophil count (ANC) averaged 87.1% (range, 59.0 to 97.7%; SD, 8.7) in the BSA-based arm, and 87.4% (range, 78.0 to 97.2%; SD, 6.1) in the individualized arm, suggesting that the interpatient variability in percent decrease in ANC was slightly smaller in the individualized arm. CONCLUSION: The individualized dosing method based on the total amount of urinary 6-ß-OHF after cortisol administration can decrease PK variability of docetaxel.
Many cytotoxic drugs have narrow therapeutic windows despite having a large interpatient pharmacokinetic (PK) variability. The doses of these cytotoxic drugs are usually calculated on the basis of body-surface area (BSA). Although several physiologic functions are proportional to BSA, systemic exposure to a drug is only partially related to this parameter.1–3 Consequently, a large interpatient PK variability is seen when doses are based on BSA. This large interpatient PK variability can result in undertreatment with inappropriate therapeutic effects in some patients, or in overtreatment with unacceptable severe toxicities in others. Understanding interpatient PK variability is important for optimizing anticancer treatments. Factors that affect PK variability include drug absorption, metabolism, and excretion. Among these factors, drug metabolism is regarded as a major factor causing PK variability. Unfortunately, however, no simple and practical method for estimating the interpatient variability of drug metabolism is available. If drug metabolism in each patient could be predicted, individualized dosing could be performed to optimize drug exposure while minimizing unacceptable toxicity. Docetaxel is a cytotoxic agent that promotes microtubule assembly and inhibits depolymerization to free tubulin, resulting in the blockage of the M phase of the cell cycle.4 Docetaxel has shown promising activity against several malignancies, including non–small-cell lung cancer, and is metabolized by hepatic CYP3A4 enzyme.5–15 Human CYP3A4 is a major cytochrome P450 enzyme that is present abundantly in human liver microsomes and is involved in the metabolism of a large number of drugs, including anticancer drugs.16–18 This enzyme exhibits a remarkable interpatient variation in activity as high as 20-fold, which accounts for the large interpatient differences in the disposition of drugs that are metabolized by this enzyme.19–22 Several noninvasive in vivo probes for estimating the interpatient variability of CYP3A4 activity have been reported and include the erythromycin breath test, the urinary dapsone recovery test, measurement of midazolam clearance (CL), and measurement of the ratio of endogenous urinary 6-beta-hydroxycortisol (6-ß-OHF) to free-cortisol (FC).23–27 The erythromycin breath test and the measurement of midazolam CL are the best validated, and both have been shown to predict docetaxel CL in patients.28,29 However, neither probe has been used in a prospective study to validate the correlations observed, or to test their utility in guiding individualized dosing. We developed a novel method for estimating the interpatient variability of CYP3A4 activity by urinary metabolite of exogenous cortisol. The total amount of 24-hour urinary 6-ß-OHF after cortisol administration (total 6-ß-OHF) is significantly correlated with docetaxel CL, which is metabolized by the CYP3A4 enzyme. We also illustrate the possibility that individualized dosing to optimize drug exposure and decrease interpatient PK variability could be performed using this method.30 We conducted a prospective, randomized PK and pharmacodynamic (PD) study of docetaxel comparing BSA-based dosing and individualized dosing based on the interpatient variability of CYP3A4 activity, as estimated by a urinary metabolite of exogenous cortisol. The objective of this study was to assess whether the application of our method to individualized dosing could decrease PK and PD variability of docetaxel compared with BSA-based dosing.
Patient Selection Patients with histologically or cytologically documented advanced or metastatic non–small-cell lung cancer were eligible for this study. Other eligibility criteria included the following: age  20 years; Eastern Cooperative Oncology Group performance status of 0, 1, or 2; 4 weeks of rest since any previous anticancer therapy; and adequate bone marrow (absolute neutrophil count [ANC] 2,000/µL and platelet count 100,000/µL), renal (serum creatinine level  1.5 mg/dL), and hepatic (serum total bilirubin level 1.5 mg/dL, AST level 150 U/L, and ALT level 150 U/L) function. Written informed consent was obtained from all patients before enrollment onto the study. The exclusion criteria included the following: pregnancy or lactation; concomitant radiotherapy for primary or metastatic sites; concomitant chemotherapy with any other anticancer agents; treatment with steroids or any other drugs known to induce or inhibit CYP3A4 enzyme17; serious pre-existing medical conditions, such as uncontrolled infections, severe heart disease, diabetes, or pleural or pericardial effusions requiring drainage; and a known history of hypersensitivity to polysorbate 80. This study was approved by the institutional review board of the National Cancer Center.
Pretreatment and Follow-Up Evaluation
Study Design Patients were randomly assigned to either the BSA-based arm or individualized arm (Fig 1). In the BSA-based arm, each patient received a dose of 60 mg/m2 of docetaxel. In the individualized arm, individualized doses of docetaxel were calculated from the estimated docetaxel CL after cortisol administration and the target AUC (described in the Docetaxel Administration section).
Cortisol Administration and Urine Collection In the individualized arm, 300 mg of hydrocortisone (Banyu Pharmaceuticals Co, Tokyo, Japan) was diluted in 100 mL of 0.9% saline and administered intravenously for 30 minutes at 9 AM on day 1 in all patients to estimate the interpatient variability of CYP3A4 activity. After cortisol administration, the urine was collected for 24 hours. The total volume of the 24-hour collection was recorded, and a 5-mL aliquot was analyzed immediately.
Docetaxel Administration
In the individualized arm, individualized dose of docetaxel was calculated from the estimated CL and the target AUC of 2.66 mg/L · h using the following equations:
PK Study PK parameters were estimated by the nonlinear least squares regression analysis method (WinNonlin, Version 1.5; Bellkey Science Inc, Chiba, Japan) with a weighting factor of 1 per year.2 Individual plasma concentration-time data were fitted to two- and three-compartment PK models using a zero-order infusion input and first-order elimination. The model was chosen on the basis of Akaike's information criteria.31 The peak plasma concentration (Cmax) was generated directly from the experimental data. AUC was extrapolated to infinity and determined based on the best-fitted curve; this measurement was then used to calculate the absolute CL (L/h), defined as the ratio of the delivered dosage (in milligrams) and AUC. To assess PD effect of docetaxel, the percentage decrease in ANC was calculated according to the following formula: % decrease in ANC = (pretreatment ANC – nadir ANC)/(pretreatment ANC) x 100.
Measurements Docetaxel concentrations in plasma were also measured by solid-phase extraction and reversed phase high-performance liquid chromatography with UV detection according to the previously published method.30,34 The detection limit corresponded to a concentration of 10 ng/mL.
Statistical Analysis
A two-sided P value of
Patient Characteristics Between October 1999 and May 2001, 59 patients were enrolled onto the study and randomly assigned to either the BSA-based arm (n = 30) or the individualized arm (n = 29). All 59 patients were assessable for PK and PD analyses. The pretreatment characteristics of the 59 patients are listed in Table 1. The baseline characteristics were well balanced between the arms except for three laboratory parameters: ALB, AAG, and ALP. These three parameters were not included in the eligibility criteria. The majority of patients (95%) had a performance status of 0 or 1. Twenty (67%) and 16 (55%) patients had been treated with platinum-based chemotherapy in the BSA-based arm and individualized arm, respectively. Only two patients in the individualized arm had liver metastasis, and most of the patients had good hepatic functions.
Individualized Dosing of Docetaxel In the individualized arm, the total amount of 24-hour urinary 6-ß-OHF after cortisol administration (total 6-ß-OHF) was 9,179.6 ± 3,057.7 µg/d (mean ± SD), which was similar to the result of our previous study.30 The estimated docetaxel CL was 21.9 ± 3.5 L/h/m2 (mean ± SD), and individualized dose of docetaxel ranged from 37.4 to 76.4 mg/m2 (mean, 58.1 mg/m2; Fig 1).
PK
In the BSA-based arm, docetaxel CL was 22.6 ± 3.4 L/h/m2 (mean ± SD), and AUC averaged 2.71 mg/L · h (range, 2.02 to 3.40 mg/L · h). In the individualized arm, docetaxel CL was 22.1 ± 3.4 L/h/m2, and AUC averaged 2.64 mg/L · h (range, 2.15 to 3.07 mg/L · h). The least squares linear regression analysis showed that the observed docetaxel CL was well estimated in the individualized arm (r2 = 0.821; Fig 2).
The SDs of AUC in the BSA-based arm and in the individualized arm were 0.40 and 0.22, respectively, and the ratio of SD in the individualized arm to that in the BSA-based arm was 0.538 (95% CI, 0.369 to 0.782). The biases from the target AUC in the BSA-based arm and in the individualized arm were 0.047 (95% CI, –0.104 to 0.198) and –0.019 (95% CI, –0.102 to 0.064), respectively, with no significant difference. The interpatient variability of AUC was significantly smaller in the individualized arm than in the BSA-based arm (P < .01; Fig 3).
PD In both arms, neutropenia was the predominant toxicity related to docetaxel treatment, and 28 of 30 (93%) patients in the BSA-based arm and 25 of 29 (86%) patients in the individualized arm had grade 3 or 4 neutropenia. Nonhematologic toxicities, such as gastrointestinal and hepatic toxicities (ie, hyperbilirubinemia, aminotransferase elevations), were mild in both arms. PD effects shown as the percentage decrease in ANC are listed in Table 3. The percentage decrease in ANC for the BSA-based arm and individualized arm were 87.1% (range, 59.0 to 97.7%; SD, 8.7) and 87.5% (range, 78.0 to 97.2%; SD, 6.1), respectively, suggesting that the interpatient variability in the percentage decrease in ANC was slightly smaller in the individualized arm than in the BSA-based arm (Fig 4). The response rates between the two arms were similar; five of 30 (16.7%) and four of 29 (13.8%) patients achieved a partial response in the BSA-based arm and individualized arm, respectively.
In oncology practice, the prescribed dose of most anticancer drugs is currently calculated from BSA of individual patients to reduce the interpatient variability of drug exposure. However, PK parameters, such as CL of many anticancer drugs, are not related to BSA.2,39–43 Although PK parameters of docetaxel are correlated with BSA, individualized dosing based on individual metabolic capacities could further decrease the interpatient variability.43 CYP3A4 plays an important role in the metabolism of many drugs, including anticancer agents such as docetaxel, paclitaxel, vinorelbine, and gefitinib. This enzyme exhibits a large interpatient variability in metabolic activity, accounting for the large interpatient PK and PD variability. We have developed a novel method of estimating the interpatient variability of CYP3A4 activity by urinary metabolite of exogenous cortisol. That is, the total amount of 24-hour urinary 6-ß-OHF after cortisol administration was highly correlated with docetaxel CL. We conducted a prospective randomized PK and PD study of docetaxel to evaluate whether the application of our method to individualized dosing could decrease PK and PD variability compared with BSA-based dosing. The study by Hirth et al28 showed a good correlation between the result of the erythromycin breath test and docetaxel CL, and the study by Goh et al29 showed a good correlation between the midazolam CL and docetaxel CL. In our study, we prospectively validated the correlation between docetaxel CL and our previously published method using the total amount of urinary 6-ß-OHF after cortisol administration in the individualized arm. As shown in Fig 2, the observed docetaxel CL was well estimated, and the equation for the estimation of docetaxel CL developed in our previous study was found to be reliable and reproducible. The target AUC in the individualized arm was set at 2.66 mg/L · h. This value was the mean value from our previous study, in which 29 patients were treated with 60 mg/m2 of docetaxel. Individualized doses of docetaxel ranged from 37.4 to 76.4 mg/m2 and were lower than expected. The SD of AUC in the individualized arm was about 46.2% smaller than that in the BSA-based arm, a significant difference; this result seems to indicate that the application of our method to individualized dosing can reduce the interpatient PK variability. Assuming that the variability of AUC could be decreased 46.2% by individualized dosing applying our method, overtreatment could be avoided in 14.5% of BSA-dosed patients by using individualized dosing (Fig 5, area A), and undertreatment could be avoided in another 14.5% of these patients (Fig 5, area B). We considered that neutropenia could be decreased with patients in area A by individualized dosing. However, it is unknown whether the therapeutic effect of docetaxel could be improved in the patients in area B by individualized dosing because no significant positive correlation has been found between docetaxel AUC and antitumor response in patients with non–small-cell lung cancer.43 In this study, seven of 30 (23.3%) and two of 30 (6.7%) patients in the BSA-based arm were included in area A and B, respectively (Figs 3 and 5).
As shown in Figure 4, the percentage decrease in ANC was well correlated with AUC in both arms, which was similar to previous reports.37,43 It was also indicated that the interpatient variability in the percentage decrease in ANC was slightly smaller in the individualized arm than in the BSA-based arm; however, this difference was not significant. The response rates between the two arms were similar. Although the interpatient PK variability could be decreased by individualized dosing in accordance with our method, the interpatient PD variability such as toxicity and the antitumor response could not be decreased. Several reasons could be considered. With regard to toxicity, the pretreatment characteristics of the patients in this study were highly variable. More than half of the patients in each arm had previously received platinum-based chemotherapy, and more than 30% had received radiotherapy. The laboratory parameters (ie, ALB, AAG, and ALP) were not balanced across the arms, although they were not included in the eligibility criteria (Table 1). These variable pretreatment characteristics and unbalanced laboratory parameters may have influenced the frequency and severity of the hematologic toxicity as well as the pharmacokinetic profiles. The antitumor effect may have been influenced by the intrinsic sensitivity of tumors, the variable pretreatment characteristics, and the imbalance in laboratory parameters. Non–small-cell lung cancer is a chemotherapy-resistant tumor. The response rate for docetaxel ranges from 18% to 38%,5 and no significant positive correlation between docetaxel AUC and antitumor response has been found. We considered it quite difficult to control the interpatient PD variability by controlling the interpatient PK variability alone. Although we did not observe any outliers in either arm, such as the two outliers with severe toxicity observed in the study by Hirth et al,28 our method may be more useful for identifying such outliers. If we had not excluded patients with more abnormal liver function or a history of liver disease by the strict eligibility criteria, the results with the two dosing regimens may have been more different, and the interpatient PD variability, such as the percentage decrease in ANC, may have been smaller in the individualized arm than in the BSA-based arm. Furthermore, the primary end point of this study was PK variability, evaluated by the SD of AUC in both arms, and the sample size was significantly underpowered to evaluate whether the application of our method to individualized dosing could decrease PD variability compared with BSA-based dosing. For the genotypes of CYP3A4, several genetic polymorphisms have been reported (http://www.imm.ki.se/CYPalleles/); however, a clear relationship between genetic polymorphisms and the enzyme activity of CYP3A4 has not been reported. Our phenotype-based individualized dosing using the total amount of urinary 6-ß-OHF after cortisol administration produced good results. However, this method is somewhat complicated, and a simpler method would be of great use. We analyzed the expression of CYP3A4 mRNA in the peripheral-blood mononuclear cells of the 29 patients in the individualized arm. No correlation was observed between the expression level of CYP3A4 mRNA and docetaxel CL or the total amount of urinary 6-ß-OHF after cortisol administration (data not shown). In conclusion, the individualized dosing of docetaxel using the total amount of urinary 6-ß-OHF after cortisol administration is useful for decreasing the interpatient PK variability compared with the conventional BSA-based method of dosing. This method may be useful for individualized chemotherapy.
The authors indicated no potential conflicts of interest.
Supported in part by a Grant-in-Aid for Cancer Research (9–25) from the Ministry of Health, Labor, and Welfare, Tokyo, Japan. Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, May 18–21, 2002, Orlando, FL. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
= .05 and a power of 0.914. 
2 test was used to compare categoric data, and Student's t test was used for continuous variables. The strength of the relationship between the estimated docetaxel CL and the observed docetaxel CL was assessed by least squares linear regression analysis. The interpatient variability of AUC for each arm was evaluated by determining the SD and was compared by F test. Biases, or the mean AUC value in each arm minus the target AUC (2.66 mg/L · h), were also compared between the arms by Student's t test. 
