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Correlation Between Docetaxel Clearance and Estimated Cytochrome P450 Activity by Urinary Metabolite of Exogenous Cortisol

From the Division of Internal Medicine, National Cancer Center Hospital, Tokyo, Japan.

Address reprint requests to Tomohide Tamura, MD, Division of Internal Medicine, National Cancer Center Hospital, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo, 104-0045, Japan; email ttamura{at}gan2.ncc go.jp.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: There is no simple and practical method for the estimation of the interpatient variability of cytochrome P450 (CYP3A4) enzyme activity. Cortisol is metabolized by this enzyme and excreted as 6-beta-hydroxycortisol (6ß-OHF) and free-cortisol (FC) in urine, and docetaxel is also metabolized by hepatic CYP3A4 enzyme. We developed a new method for the estimation of CYP3A4 activity by measuring urinary cortisol metabolite after administration of exogenous cortisol. This study was aimed at assessing the predictability of the individual activity of CYP3A4 estimated by this method.

PATIENTS AND METHODS: Thirty patients with advanced non–small-cell lung cancer were entered onto this study. Hydrocortisone 300 mg was administered intravenously, and urinary 6ß-OHF and FC were measured. More than 2 days later, 60 mg/m² of docetaxel was administered intravenously with pharmacokinetic sampling. The correlation between docetaxel pharmacokinetics and estimated interpatient variability of CYP3A4 activity with the application of our method was assessed.

RESULTS: After cortisol administration, the total amount of 24-hour urinary 6ß-OHF (T6ß-OHF) increased about 60-fold compared with pretreatment levels, averaging 12,273 ± 4,076 µg/d (mean ± SD). Docetaxel clearance (CL) and area under the concentration-time curve averaged 24.5 ± 6.4 L/h/m² and 2.66 ± 0.91 mg/L 8729· h, respectively. An excellent correlation between docetaxel CL and T6ß-OHF was observed (r = .867). In multivariate analysis, T6ß-OHF (P < .001), alpha-1-acid glycoprotein (P < .004), AST (P = .007), and age (P = .022) significantly correlated with docetaxel CL.

CONCLUSION: The interpatient variability of CYP3A4 activity and docetaxel CL could be predicted by measuring T6ß-OHF after cortisol administration.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
IT IS WIDELY recognized that many anticancer drugs have a narrow therapeutic index, despite having large interpatient pharmacokinetic (PK) variability. The dosages of these anticancer drugs are usually calculated on the basis of body-surface area (BSA). Although many physiologic functions are proportionate to BSA, systemic exposure to the drug is only partially related to this parameter. Consequently, after the administration of dosages based on BSA, a wide interpatient PK variability can be found, which results in undertreatment with inappropriate therapeutic effect in some patients and overtreatment with unacceptably severe toxicity in others. Understanding the interpatient PK variability is potentially of great importance for optimizing anticancer treatment. Factors that affect PK variability include drug absorption, metabolism, and excretion. Among these, drug metabolism has been regarded as one of the major factors that cause PK variability. Unfortunately, there is no simple and practical method for estimating the interpatient variability of drug metabolism. If drug metabolism could be predicted in each patient, individualized dosing could be performed to optimize drug exposure while minimizing unacceptable toxicity.

Cytochrome P450 (CYP3A4) is an enzyme responsible for the metabolism of a wide variety of chemicals, including drugs. A number of isozymes of P450 are known to exist, and these are classified into families and subfamilies.¹ Of the various P450 isozymes, CYP3A4 is present in abundance in human liver microsomes and plays an important role in the metabolism of a large number of drugs, including anticancer drugs.^2,3 This enzyme has at least a five- to 10-fold interindividual variability in the disposition of these drugs, which suggests that the method predictive of such metabolism has considerable potential for practical application.^4-6

So far, three major noninvasive in vivo probes for the estimation of the interpatient variability of CYP3A4 activity have been reported: the erythromycin breath test, the urinary dapsone recovery test, and the measurement of the ratio of endogenous urinary 6-beta-hydroxycortisol (6ß-OHF) to free-cortisol (FC) (6ß-OHF/FC). However, these three probes do not provide satisfactory estimations.^7-9 The measurement of endogenous 6ß-OHF/FC is considered the simplest and most practical method among these probes. This method is reported to be able to assess intrapatient variability, such as enzyme induction and inhibition. However, it is thought that the estimation of interpatient variability is impossible.^10-13 The reason for this impossibility has not been completely elucidated. One possible reason is that the small amount of endogenous substrate does not reflect the actual activity of CYP3A4. We hypothesized that if we administered a considerable amount of exogenous cortisol, we could estimate the interpatient variability of CYP3A4 activity more precisely. Thus, we developed a new method that measures urinary metabolites of cortisol after the administration of exogenous cortisol.

Docetaxel is a new anticancer agent with a novel mechanism of action that has shown promising activity against metastatic breast cancer and non–small-cell lung cancer.^14-20 This new drug promotes microtubule assembly and inhibits depolymerization to free tubulin, which results in the blockage of the cells in the M phase of the cell cycle.²¹ Docetaxel is currently approved for the treatment of these two malignancies in Japan. The recommended dose is 60 mg/m² every 3 weeks, which is lower than that in the United States and European countries.^22-25 Recently, Marre et al²⁶ reported that docetaxel is metabolized by hepatic CYP3A4 enzyme.

The objective of this study was to assess the predictability of the interpatient variability of CYP3A4 activity estimated by measuring urinary metabolites of cortisol after the administration of exogenous cortisol. Thus, we demonstrated the correlation between docetaxel PK and estimated interpatient variability of CYP3A4 activity by applying our method.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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: (1) age 20 years; (2) Eastern Cooperative Oncology Group performance status of 0 to 2; (3) a life expectancy of 12 weeks; (4) 4 weeks of rest from previous anticancer therapy (6 weeks for nitrosoureas); (5) adequate bone marrow (absolute neutrophil count 2,000 neutrophils/µL and platelet count 100,000 platelets/µL), renal (serum creatinine level 1.5 mg/dL), and hepatic (serum total bilirubin level 1.5 mg/dL, AST level 100 IU/L, and ALT level 100 IU/L) function. Written informed consent was obtained from all patients before they were entered onto the study.

Exclusion criteria included the following: (1) pregnancy or lactation; (2) concomitant radiotherapy for primary or metastatic sites; (3) concomitant chemotherapy with any other anticancer agents; (4) treatment with steroids or any other drugs that induce or inhibit CYP3A4 enzyme²; (5) serious preexisting medical conditions, such as uncontrolled infections, severe heart disease, diabetes, or pleural or pericardial effusions that required drainage; and (6) a known history of hypersensitivity reactions to polysorbate 80. This study was approved by the Institutional Review Board at the National Cancer Center.

Cortisol Administration and Urine Collection
Hydrocortisone (Banyu Pharmaceuticals Co, Tokyo, Japan) was obtained commercially in 2-mL vials that each contained 100 mg of the concentrated sterile drug. A dose of 300 mg of hydrocortisone was diluted in 100 mL 0.9% saline and administered intravenously (IV) for 30 minutes at 9 AM on day 1. Before cortisol administration, urine was collected for 24 hours (from 9 AM day 0 to 9 AM day 1). After cortisol administration, urine was collected for 24 hours, the collection being divided into three periods: (1) 9 AM to 12 PM (3 hours); (2) 12 PM to 3 PM (3 hours); and (3) 3 PM day 1 to 9 AM day 2 (18 hours). Urine was also collected for 24 hours after docetaxel administration.

During urine collection, urine was kept at room temperature (from 18°C to 25°C). The total volume of each collection was recorded, and a 5-mL aliquot was obtained, labeled, and frozen at -20°C until analysis.

Docetaxel Administration
Docetaxel (Taxotere; Rhone-Poulenc Rorer, Tokyo, Japan) was obtained commercially as a concentrated sterile solution that contained 80 mg of the drug in 2 mL of polysorbate 80. More than 2 days after cortisol administration, 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 IV infusion at 9 AM. No prophylactic premedication to protect against docetaxel-related hypersensitivity reactions was administered.

PK Study
Blood samples for PK studies were obtained from all patients in the first cycle of therapy. An indwelling cannula was inserted in the arm opposite to that used for drug infusion, and blood samples were taken into heparinized tubes. The blood samples were collected before infusion, 30 minutes after the beginning of infusion, at the end of infusion, and 15, 30, and 60 minutes, and 3, 5, 9, and 24 hours after the end of infusion. All blood samples were centrifuged immediately at 3,000 revolutions per minute for 15 minutes, after which the plasma was removed and the samples were placed in polypropylene tubes, labeled, and stored at -20°C or lower until analysis.

PK parameters were estimated by nonlinear least squares regression analysis (WinNonlin, Version 1.5, Bellkey Science, Inc, Chiba, Japan) with a weighting factor of 1/yr.² Individual plasma concentration-time data were fitted to two- and three-exponential equations using a zero-order infusion input and first-order elimination (corresponding to a two- and three-compartment PK model). The model was chosen on the basis of Akaike’s information criteria.²⁷ Fitted parameters (coefficients and exponent of exponential equations) permitted the computation of the following PK parameters: half-life, area under the concentration-time curve (AUC), systemic clearance (CL), and volume of distribution at steady-state.

Measurements
The concentrations of urinary 6ß-OHF and FC were measured by reverse-phase high-performance liquid chromatography (HPLC) using ultraviolet (UV) absorbance detection according to previously published methods.^28,29 Urine samples (1.0 mL) were extracted twice with ethylacetate (5.0 mL). The organic layer was washed with 2.0 mL of 1.0 N sodium hydroxide containing 20% sodium sulfate. After centrifugation, the organic phase was separated and evaporated at 40°C under a stream of nitrogen. The residue was dissolved in 300 µL of mobile phase, and 60 µL was injected into the column. The chromatographic conditions were different for each molecule.

For 6ß-OHF, the mobile phase consisted of a solution of KH₂PO₄ 0.01 mol/L freshly prepared in distilled water and to which 0.05% trichloroacetic acid 1.7 N was added. Acetonitrile was added to the prepared solution in the proportion 9/1 buffer/acetonitrile (vol/vol). The column was an L-Column (150 x 4.6 mm, Chemicals Inspection and Testing Institute, Tokyo, Japan). The flow rate was 1.0 mL/min, the detection wavelength 242 nm, and the detector sensitivity 0.0025 full-scale. The detection limit corresponded to a concentration of 20 ng/mL. The within-day coefficient of variation (CV) varied between 1.20% and 1.94%, whereas the between-day CV varied between 3.40% and 4.64%.

For FC, the mobile phase was acetonitrile/methanol/distilled water in the proportions 30/5/65 (vol/vol/vol). The column was a CAPCELL PAK C₁₈S₅AG120 (250 x 4.6 mm, Shiseido Co, Ltd, Tokyo, Japan). The flow rate was 0.8 mL/min, the detection wavelength 254 nm, and the detector sensitivity 0.0025 full-scale. The detection limit was 5 ng/mL. The within-day CV varied between 1.28% and 1.85%, whereas the between-day CV varied between 1.77% and 4.05%.

The concentrations of 6ß-OHF and FC were calculated from calibration curves made from each subject at 6ß-OHF and FC concentrations that ranged from 100 to 10,000 ng/mL and from 400 to 40,000 ng/mL, respectively. Calibration curves were linear from 100 to 10,000 ng/mL for 6ß-OHF and from 400 to 40,000 ng/mL for FC (r² .99 for both 6ß-OHF and FC). If the predicted concentration of a sample was less than the lowest standard, the predicted concentration was reported as less than the lower limit of quantification. If the predicted concentration was greater than 100% of the highest standard, the samples were diluted and reanalyzed.

Docetaxel concentrations in plasma were measured by solid-phase extraction and reverse-phase HPLC with UV detection according to the previously published method.³⁰ The drug was extracted from plasma by solid-phase extraction using C₂ (1.0 mL) Bond Elut microcolumn (Varian, Harbor City, CA). The cartridges were solved before use with 1.0 mL methanol and 1.5 mL water before plasma samples (0.5 mL) were applied. The plasma contaminant was washed to waste with 1.0 mL water and 1.0 mL 50% methanol, and docetaxel was eluted in 300 µL 90% methanol. The isolate (50 µL) was injected into the column. An internal standard, paclitaxel, was added to all samples before extraction. This HPLC system consisted of a pump (LC-6AD, Shimazu, Ltd, Kyoto, Japan), a variable-wavelength UV detector (SPD-10AV, Shimazu, Ltd), a chromatography control module (SIC-21, System Instruments Co, Ltd, Tokyo, Japan), an injector (AS-8020, Tosoh Co, Tokyo, Japan), and an Inertsil ODS-2 reverse-phase column, 250 x 4.6 mm, with 5-µm particle-size packing (GL Science, Inc, Tokyo, Japan). The mobile phase consisted of 67% methanol and 0.1% orthophosphoric acid at a flow rate of 1.0 mL/min. Peak identity was confirmed by diode array detection over the wavelength range 200 to 500 nm, and quantification of docetaxel was carried out by peak area integration at 225 nm. The detection limit corresponded to a concentration of 20 ng/mL. The within-day CV varied between 1.02% and 11.54%, whereas the between-day CV varied between 5.33% and 11.13%.

Statistical Analysis
The strength of the relationships between docetaxel PK parameters and the urinary 6ß-OHF, FC, and 6ß-OHF/FC were assessed by linear regression analysis. Selection of the best set of variables for predicting docetaxel PK parameters was performed by stepwise multiple regression analysis, whereby potential predictor (independent) variables were sequentially included or excluded from the model according to the strength of their respective partial correlations. A two-sided P value of .05 or less was considered to indicate statistical significance. All statistical analyses were performed using SPSS Version 6.1 statistical software (SPSS, Inc, Chicago, IL).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
Between January 1998 and September 1998, 30 patients were entered onto the study. One patient was not considered assessable because of incomplete urine collection after cortisol administration. The pretreatment characteristics of the 29 assessable patients are listed in Table 1. There were 19 men and 10 women, with a median age of 58 years (range, 32 to 76 years). The majority of patients (90%) had a performance status of 0 or 1. The most common histologic subtype was adenocarcinoma (79%). Seventeen patients (59%) had been treated previously with cisplatin-based chemotherapy. Only five patients (17%) had liver metastasis, and none had clinically important hepatic dysfunction. Two patients with diffuse bone metastasis had significant elevation of serum alkaline phosphatase level (698 and 930 IU/L).

Docetaxel PK
Docetaxel PK data were obtained from 29 patients in the first cycle of therapy, and PK parameters are listed in Table 3. 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 with mean alpha and beta half-lives of 10.5 minutes and 5.5 hours, respectively. Docetaxel CL was 24.5 ± 6.4 L/h/m² (mean ± SD), with approximately three-fold interindividual variability, and AUC was 2.66 ± 0.91 mg/L 8729· h. These PK parameters were compatible with those of a previous report of a Japanese phase I study.²²

View larger version (12K): [in this window] [in a new window]   Fig 1. Correlation between docetaxel CL and 6ß-OHF/FC before cortisol administration (n = 29). The solid line represents the regression line (r = .068; P = .725).

View larger version (13K): [in this window] [in a new window]   Fig 2. Correlation between docetaxel CL and 6ß-OHF/FC after cortisol administration (n = 29). The solid line represents the regression line (r = -.143; P = .465).

View larger version (13K): [in this window] [in a new window]   Fig 3. Correlation between docetaxel CL and T6ß-OHF (n = 29). The solid line represents the regression line (r = .867; P < .001).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
There is no simple and practical method for estimating the interpatient variability of CYP3A4 activity. Although three major noninvasive in vivo probes have been reported, none of these has definite advantages with respect to simplicity, practicality, and accuracy.^7-9

The erythromycin breath test is based on the N-demethylation of erythromycin using [N-methyl-¹⁴C]-erythromycin by CYP3A4 and is thought to provide the most reliable information on CYP3A4 activity. However, this method requires IV administration of radioisotope and may not be practical in routine clinical use.^34-36 A second method is the urinary dapsone recovery test, which requires administration of the antileprosy drug dapsone.^37-39 The measurement of endogenous urinary 6ß-OHF/FC is simple and completely noninvasive and could have a practical advantage over the other two methods. Although this method enables assessment of intrapatient variability, such as enzyme induction and inhibition, it has been considered impossible to estimate interpatient variability with this method.^10-13 For more precise estimation of the interpatient variability of CYP3A4 activity, we developed a simple and practical method that measures urinary 6ß-OHF after administration of exogenous cortisol.

The reason the total amount of 24-hour urinary 6ß-OHF after cortisol administration was highly correlated with docetaxel CL was not elucidated in our study. However, one possibility is that when an excess amount of substrate over enzyme capacity is administered, the metabolic capacity of the enzyme may be reflected by the production of metabolite rather than by a ratio, such as 6ß-OHF/FC. Although the other metabolic pathways might have been involved in the metabolism of the excess amount of exogenous cortisol, we could not determine their influence. However, their influence could be considered slight because an excellent correlation between the total amount of 24-hour urinary 6ß-OHF and docetaxel CL was observed in our study.

After cortisol administration, urine collection, divided into three periods, and linear regression analysis between docetaxel CL and the amount of urinary 6ß-OHF in each period (ie, 3, 6, and 24 hours) were performed. Although there was good correlation between docetaxel CL and the amount of urinary 6ß-OHF in each period, the total amount of 24-hour urinary 6ß-OHF was most strongly correlated with docetaxel CL. Additionally, the correlation between docetaxel CL and the total amount of 24-hour urinary 6ß-OHF not adjusted for BSA was assessed, and the result was quite similar to that obtained by adjusting for BSA.

We chose hydrocortisone as an exogenous cortisol because it is most similar to physiologic cortisol. Although dexamethasone induces induction of CYP3A4 enzyme, it has not been reported that cortisol induces or inhibits CYP3A4 enzyme.³⁴ Furthermore, in the total amount of urinary 6ß-OHF, FC, and 6ß-OHF/FC, there was no significant difference between that collected before cortisol administration and that collected after docetaxel administration in this study (data not shown). These results suggest that exogenous cortisol had no effect on CYP3A4 activity.

We hypothesized that a considerable amount of exogenous cortisol is required for the estimation of the interpatient variability of CYP3A4 activity but that too much cortisol might influence other metabolic pathways. Therefore, a 300-mg dose of hydrocortisone was chosen based on the nearly equivalent dose for antiemetic treatment. After cortisol administration, the total amount of 24-hour urinary 6ß-OHF increased approximately 60-fold compared with pretreatment levels. On the other hand, the total amount of 24-hour urinary FC increased approximately 300-fold compared with pretreatment levels. Although a 300-mg dose of hydrocortisone could be considered sufficient, a lower dose, such as 50 to 100 mg, might be even more useful as a predictor of docetaxel CL, because the total amount of 24-hour urinary FC increased greatly compared with that of 6ß-OHF.

We have demonstrated that our method enables the prediction of docetaxel CL. If we could individualize the dose of docetaxel for each patient by applying our method, this could contribute to the reduction not only of PK but also of pharmacodynamic variability. A significant relationship between docetaxel AUC and the percentage decrease in neutrophil count with the use of a sigmoid E_max model was reported.²⁴ In this study, a correlation between these two parameters was observed to some extent. However, the pretreatment characteristics of patients in this study were highly variable, that is, 59% of the patients had previously received cisplatin-based chemotherapy, and 41% had previously received radiotherapy. The chemotherapy-naive or minimally pretreated patients should be included in future studies.

Although the plasma concentration-time profile of docetaxel in the majority of previous studies seemed triphasic, in our data it seemed biphasic.^23,24,40,41 The reason for this difference is that the administered dose of 60 mg/m², which is the recommended dose for a single agent in Japan, was lower compared with that of 100 mg/m² used in the United States and in European countries, and the terminal elimination phase was not observed sufficiently. The plasma concentration-time profile in several other studies, in which a lower dose of docetaxel, such as 20 to 70 mg/m², was administered seemed biphasic.^24,42 Second, the detection limit of the assay for docetaxel plasma concentration was 20 ng/mL, which was insufficient compared with that of the previously published method.³²

There are several advantages to our method for the estimation of the interpatient variability of CYP3A4 activity. First, this method is simple and practical in routine clinical use. Second, this method could be especially useful for elderly patients and patients with hepatic dysfunction. Third, this method could be applicable for other anticancer drugs that are mainly metabolized by CYP3A4 enzyme (ie, vinorelbine and etoposide).

In conclusion, an excellent correlation was observed between docetaxel CL and the total amount of 24-hour urinary 6ß-OHF after cortisol administration. The interpatient variability of CYP3A4 activity in each patient could be predicted by measuring the total amount of 24-hour urinary 6ß-OHF after cortisol administration. Individualized dosing to optimize drug exposure for each patient could be performed based on this method. A prospective randomized study of fixed versus individualized dosing of docetaxel is underway to determine whether individualized chemotherapy with the application of this method can reduce PK variability and toxicity variability.

	ACKNOWLEDGMENTS

 
Supported in part by the Grant-in-Aid for Cancer Research (9-25) from the Ministry of Health and Welfare, Tokyo, Japan.

We thank Drs Reiri Onodera, Ryoji Ito, Youichi Nakamura, Yuichiro Ohe, Kaoru Kubota, Tetsu Shinkai, Tetsuro Kodama (Division of Internal Medicine, National Cancer Center Hospital, Tokyo, Japan), Toru Horie (D3 Research Laboratory, Ibaraki, Japan), and Michio Yamakido (Second Department of Internal Medicine, Hiroshima University School of Medicine, Hiroshima, Japan) for their excellent cooperation.

	NOTES

 
Presented in part at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15-18, 1999.

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Submitted October 14, 1999; accepted February 17, 2000.

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