Randomized Pharmacokinetic and Pharmacodynamic Study of Docetaxel: Dosing Based on Body-Surface Area Compared With Individualized Dosing Bas
http://www.100md.com
▲還散笫雖悝◎
the Division of Internal Medicine, National Cancer Center Hospital
Pharmacology Division and Cancer Information and Epidemiology Division, National Cancer Center Research Institute, Tokyo, Japan
ABSTRACT
PATIENTS AND METHODS: Fifty-nine patients with advanced non每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每4 x total 6--OHF] 每 [4.02 x alpha-1 acid glycoprotein] 每 [0.172 x AST] 每 [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--OHF after cortisol administration can decrease PK variability of docetaxel.
INTRODUCTION
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每small-cell lung cancer, and is metabolized by hepatic CYP3A4 enzyme.5每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每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每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--OHF) to free-cortisol (FC).23每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--OHF after cortisol administration (total 6--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.
PATIENTS AND METHODS
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
On enrollment onto the study, a history and physical examination were performed, and a complete differential blood cell count (including WBC count, ANC, hemoglobin, and platelets), and a clinical chemistry analysis (including serum total protein, albumin [ALB], bilirubin, creatinine, AST, ALT, gamma-glutamyltransferase, alkaline phosphatase [ALP], and alpha-1 acid glycoprotein [AAG]) were performed. Blood cell counts and a chemistry analysis except for AAG were performed at least twice a week throughout the study. Tumor measurements were performed every two cycles, and antitumor response was assessed by WHO standard response criteria. Toxicity was evaluated according to the National Cancer Institute Common Toxicity Criteria (version 2.0).
Study Design
This study was designed to assess whether the application of our method to individualized dosing could decrease PK and PD variability compared with BSA-based dosing. The primary end point was PK variability and the secondary end point was PD variability (ie, toxicity). In our previous study involving 29 patients who received 60 mg/m2 of docetaxel, the area under the concentration-time curve (AUC) was calculated to be 2.66 ㊣ 0.91 (mean ㊣ standard deviation [SD]) mg/L ﹞ h.30 We assumed that the variability of AUC, represented by the SD, could be reduced by 50% in the individualized arm compared with that in the BSA-based arm, and that AUC would be normally distributed. The required sample size was 25 patients per arm to detect this difference with a two-sided F test at {alpha} = .05 and a power of 0.914.
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
Docetaxel (Taxotere; Aventis Pharm Ltd, Tokyo, Japan) was obtained commercially as a concentrated sterile solution containing 80 mg of the drug in 2 mL of polysorbate 80. In the BSA-based arm, a dose of 60 mg/m2 of docetaxel was diluted in 250 mL of 5% glucose or 0.9% saline and administered by 1-hour intravenous infusion at 9 AM to all patients.
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:
30
At least 2 days after cortisol administration, individualized doses of docetaxel were diluted in 250 mL of 5% glucose or 0.9% saline and administered by 1-hour intravenous infusion at 9 AM to each patient. The doses of docetaxel in subsequent cycles of treatment were unchanged, and no prophylactic premedication to protect against docetaxel-related hypersensitivity reactions was administered in either of the treatment arms.
PK Study
Blood samples for PK studies were obtained from all of the patients during the initial treatment cycle. An indwelling cannula was inserted in the arm opposite that used for the drug infusion, and blood samples were collected into heparinized tubes. Blood samples were collected before the infusion; 30 minutes after the start of the infusion; at the end of the infusion; and 15, 30, and 60 minutes and 3, 5, 9, and 24 hours after the end of the infusion. All blood samples were centrifuged immediately at 4,000 rpm for 10 minutes, after which the plasma was removed and the samples were placed in polypropylene tubes, labeled, and stored at 每20∼C or colder until analysis.
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 每 nadir ANC)/(pretreatment ANC) x 100.
Measurements
The concentration of urinary 6--OHF was measured by reversed phase high-performance liquid chromatography with UV absorbance detection according to previously published methods.30,32,33
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
Fisher's exact test or {chi}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.
A two-sided P value of ≒ .05 or less was considered to indicate statistical significance. All statistical analyses were performed using SAS software version 8.02 (SAS Institute, Cary, NC).
RESULTS
Individualized Dosing of Docetaxel
In the individualized arm, the total amount of 24-hour urinary 6--OHF after cortisol administration (total 6--OHF) was 9,179.6 ㊣ 3,057.7 米g/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
Docetaxel PK data were obtained from all 59 patients during the first cycle of therapy, and PK parameters are listed in Table 2. Drug levels declined rapidly after infusion and could be determined to a maximum of 25 hours. The concentration of docetaxel in plasma was fitted to a biexponential equation, which was consistent with previous reports.30,35每38 The mean alpha and beta half-lives were 9.2 minutes and 5.0 hours in the BSA-based arm and 9.2 minutes and 7.4 hours in the individualized arm, respectively.
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, 每0.104 to 0.198) and 每0.019 (95% CI, 每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.
DISCUSSION
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--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--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每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每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--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--OHF after cortisol administration (data not shown).
In conclusion, the individualized dosing of docetaxel using the total amount of urinary 6--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.
Authors' Disclosures of Potential Conflicts of Interest
NOTES
Supported in part by a Grant-in-Aid for Cancer Research (9每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每21, 2002, Orlando, FL.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Pharmacology Division and Cancer Information and Epidemiology Division, National Cancer Center Research Institute, Tokyo, Japan
ABSTRACT
PATIENTS AND METHODS: Fifty-nine patients with advanced non每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每4 x total 6--OHF] 每 [4.02 x alpha-1 acid glycoprotein] 每 [0.172 x AST] 每 [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--OHF after cortisol administration can decrease PK variability of docetaxel.
INTRODUCTION
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每small-cell lung cancer, and is metabolized by hepatic CYP3A4 enzyme.5每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每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每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--OHF) to free-cortisol (FC).23每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--OHF after cortisol administration (total 6--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.
PATIENTS AND METHODS
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
On enrollment onto the study, a history and physical examination were performed, and a complete differential blood cell count (including WBC count, ANC, hemoglobin, and platelets), and a clinical chemistry analysis (including serum total protein, albumin [ALB], bilirubin, creatinine, AST, ALT, gamma-glutamyltransferase, alkaline phosphatase [ALP], and alpha-1 acid glycoprotein [AAG]) were performed. Blood cell counts and a chemistry analysis except for AAG were performed at least twice a week throughout the study. Tumor measurements were performed every two cycles, and antitumor response was assessed by WHO standard response criteria. Toxicity was evaluated according to the National Cancer Institute Common Toxicity Criteria (version 2.0).
Study Design
This study was designed to assess whether the application of our method to individualized dosing could decrease PK and PD variability compared with BSA-based dosing. The primary end point was PK variability and the secondary end point was PD variability (ie, toxicity). In our previous study involving 29 patients who received 60 mg/m2 of docetaxel, the area under the concentration-time curve (AUC) was calculated to be 2.66 ㊣ 0.91 (mean ㊣ standard deviation [SD]) mg/L ﹞ h.30 We assumed that the variability of AUC, represented by the SD, could be reduced by 50% in the individualized arm compared with that in the BSA-based arm, and that AUC would be normally distributed. The required sample size was 25 patients per arm to detect this difference with a two-sided F test at {alpha} = .05 and a power of 0.914.
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
Docetaxel (Taxotere; Aventis Pharm Ltd, Tokyo, Japan) was obtained commercially as a concentrated sterile solution containing 80 mg of the drug in 2 mL of polysorbate 80. In the BSA-based arm, a dose of 60 mg/m2 of docetaxel was diluted in 250 mL of 5% glucose or 0.9% saline and administered by 1-hour intravenous infusion at 9 AM to all patients.
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:
30
At least 2 days after cortisol administration, individualized doses of docetaxel were diluted in 250 mL of 5% glucose or 0.9% saline and administered by 1-hour intravenous infusion at 9 AM to each patient. The doses of docetaxel in subsequent cycles of treatment were unchanged, and no prophylactic premedication to protect against docetaxel-related hypersensitivity reactions was administered in either of the treatment arms.
PK Study
Blood samples for PK studies were obtained from all of the patients during the initial treatment cycle. An indwelling cannula was inserted in the arm opposite that used for the drug infusion, and blood samples were collected into heparinized tubes. Blood samples were collected before the infusion; 30 minutes after the start of the infusion; at the end of the infusion; and 15, 30, and 60 minutes and 3, 5, 9, and 24 hours after the end of the infusion. All blood samples were centrifuged immediately at 4,000 rpm for 10 minutes, after which the plasma was removed and the samples were placed in polypropylene tubes, labeled, and stored at 每20∼C or colder until analysis.
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 每 nadir ANC)/(pretreatment ANC) x 100.
Measurements
The concentration of urinary 6--OHF was measured by reversed phase high-performance liquid chromatography with UV absorbance detection according to previously published methods.30,32,33
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
Fisher's exact test or {chi}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.
A two-sided P value of ≒ .05 or less was considered to indicate statistical significance. All statistical analyses were performed using SAS software version 8.02 (SAS Institute, Cary, NC).
RESULTS
Individualized Dosing of Docetaxel
In the individualized arm, the total amount of 24-hour urinary 6--OHF after cortisol administration (total 6--OHF) was 9,179.6 ㊣ 3,057.7 米g/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
Docetaxel PK data were obtained from all 59 patients during the first cycle of therapy, and PK parameters are listed in Table 2. Drug levels declined rapidly after infusion and could be determined to a maximum of 25 hours. The concentration of docetaxel in plasma was fitted to a biexponential equation, which was consistent with previous reports.30,35每38 The mean alpha and beta half-lives were 9.2 minutes and 5.0 hours in the BSA-based arm and 9.2 minutes and 7.4 hours in the individualized arm, respectively.
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, 每0.104 to 0.198) and 每0.019 (95% CI, 每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.
DISCUSSION
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--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--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每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每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--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--OHF after cortisol administration (data not shown).
In conclusion, the individualized dosing of docetaxel using the total amount of urinary 6--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.
Authors' Disclosures of Potential Conflicts of Interest
NOTES
Supported in part by a Grant-in-Aid for Cancer Research (9每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每21, 2002, Orlando, FL.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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