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© 2002 American Society for Clinical Oncology Explaining Interindividual Variability of Docetaxel Pharmacokinetics and Pharmacodynamics in Asians Through Phenotyping and Genotyping StrategiesByFrom the Departments of Hematology-Oncology and Pharmacology, National University Hospital, Singapore; and Department of Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN. Address reprints requests to Boon-Cher Goh, MD, Department of Hematology-Oncology, National University Hospital, 5 Lower Kent Ridge Rd, Singapore 119074; email: gohbc{at}nuh.com.sg
PURPOSE: To explain the variability of docetaxel pharmacokinetics through study of CYP3A phenotype and genotype, and MDR1 genotype. PATIENTS AND METHODS: We studied the pharmacokinetics and pharmacodynamics of docetaxel in patients in whom it was indicated and who had not received known CYP3A4 substrates. Midazolam was administered intravenously to these patients at least 2 days before docetaxel treatment, and systemic clearances of both drugs were correlated. Patients were characterized for polymorphisms in the CYP3A4 promoter region, CYP3A5, and the C3435T polymorphism of MDR1. RESULTS: Thirty-two patients were enrolled, of whom 31 had full pharmacokinetic data sets. Docetaxel clearance correlated with midazolam clearance, body-surface area, serum albumin, and performance status. Docetaxel and midazolam clearances were normally distributed. In multiple linear regression analyses, midazolam clearance and performance status were the only significant covariates of docetaxel clearance, and the area under the curve of docetaxel, serum levels of alpha-1-acid glycoprotein, and ALT were significant predictors of nadir neutrophil count. No polymorphisms were detected in the 5' regulatory region of CYP3A4. Nine patients of 25 studied were homozygous for the CYP3A5*3 genotype, and had lower mean clearance of midazolam but not docetaxel. The T/T genotype at the C3435T of MDR1, which is associated with reduced P-glycoprotein function, was found in eight of 27 patients. CONCLUSION: Midazolam may be used as a probe drug for CYP3A activity to predict docetaxel clearances, hence reducing interindividual variability. Homozygotes for CYP3A5*3 and C3435T of MDR1 are common in our population, and their effects on pharmacokinetics of relevant substrates should be studied further.
CYTOTOXIC AGENTS SUCH as taxanes have narrow therapeutic windows, and interindividual variability of pharmacokinetics may account for unpredictable toxicity. This phenotypic variability extends across ethnically diverse groups,1-3 where different population patterns of genetic polymorphisms affect drug metabolism, transport, and receptor binding. Functional genetic polymorphisms that demonstrate ethnic variability have been described for several drug-metabolizing enzymes.4-7 Defining racial profiles of drug metabolism will improve the understanding of how ethnically diverse populations may be variably affected by drugs with known metabolic pathways and has the potential to individualize therapy.8-10 Our own observations of greater neutrophil toxicity and less severe fluid retention from docetaxel treatment in Asian patients led to this study to uncover possible reasons.11
Docetaxel is a broad-spectrum taxane that undergoes hydroxylation by CYP3A4 and CYP3A5 to less active metabolites, and is also a substrate of the membrane transporter P-glycoprotein.12,13 The activity and content of CYP3A4 in liver tissues show significant variability in vitro.14 We hypothesized that the observed differences in clinical toxicity to docetaxel between Asian and Western patients may be related to pharmacokinetic differences, and that ethnic diversity of polymorphisms in CYP3A isoenzymes may contribute to these differences. The in vitro activity of CYP3A4 appears to be related to mRNA expression, suggesting promoter regulation. Of pertinence is a recently described single nucleotide polymorphism (SNP) in the 5' regulatory region CYP3A4*1B that demonstrates ethnic variability and has associated clinical implications.15-17 More recently, SNPs have been described in CYP3A5, and two have been associated with functional consequences. The CYP3A5*3 (22893A Apart from metabolizing enzymes, drug pharmacokinetics may also be affected by membrane transporters.19 The MDR1 gene encodes for P-glycoprotein, an adenosine triphosphate–dependent efflux pump located on cellular membranes that influences the disposition and bioavailability of drugs, many of which are CYP3A substrates.20,21 P-glycoprotein is expressed in cells lining the intestine, the biliary tract, and the blood-brain barrier.22 In addition, P-glycoprotein may affect the extent of CYP3A-mediated metabolism of drugs by limiting the intracellular substrate availability.23 Given the role of MDR1 in affecting tissue distribution and elimination of its substrates, we sought to define the impact of the recently described C3435T polymorphism in exon 26 of MDR1 with docetaxel pharmacokinetics.24 The specific objectives of our study were (1) to study the pharmacokinetics and pharmacodynamics of docetaxel in Asian patients; (2) to phenotype these patients using midazolam pharmacokinetics, and to correlate clearance of midazolam with docetaxel; and (3) to genotype known functional SNPs of CYP3A4, CYP3A5, and MDR1, and to correlate genotype with docetaxel and midazolam pharmacokinetics.
Patient Eligibility To be eligible for this study, patients were required to have a histologically or cytologically proven solid malignancy for which docetaxel is indicated; be above 18 years; have a baseline Karnofsky performance status (KPS) of 60% or more; have adequate hematopoietic, hepatic, and renal function (defined, respectively, as an absolute neutrophil count  1.5 x 109/L, platelet count 100 x 109/L, total WBC count 3.0 x 109/L, hemoglobin 9.0 g/dL, total bilirubin concentration  3.0 mg/dL, AST and/or ALT 5 times the upper limit of normal, and serum creatinine 2.0 mg/dL or calculated glomerular filtration rate 40 mL/min); and have a life expectancy of more than 12 weeks at study entry. Patients who had any of the following were ineligible: systemic biologic or cytotoxic therapy in the previous 4 weeks, extensive radiotherapy to more than 25% of the bone marrow within the previous 4 weeks, active brain metastases, or severe intercurrent systemic disease. Patients who had received medications known to be CYP3A substrates in the previous 1 month from study entry were excluded from the study. All patients provided written informed consent in accordance with institutional and governmental guidelines.
Study Plan Docetaxel treatment. Docetaxel treatment was administered after at least 2 days after the midazolam test. Docetaxel was supplied by Aventis Pharma (Singapore). Doses of either 75 or 100 mg/m2, according to the physician’s discretion, were infused over 1 hour. Patients received routine antiemetic 5-hydroxytryptamine antagonists prophylactically. To avoid the confounding factor of variable induction of CYP3A, oral dexamethasone was given 24 hours after docetaxel treatment during the first cycle at 8 mg bid for 3 days as prophylaxis against fluid retention. In the second cycle, dexamethasone was administered 1 day before docetaxel treatment. This allowed us to evaluate the influence of dexamethasone on docetaxel pharmacokinetics. Pharmacokinetic sampling was carried out at 0, 10, 20, 30, 45, and 60 minutes; and at 2, 4, 6, 10, 24, and 48 hours from the start of the infusion. In cycle 2, limited pharmacokinetic sampling was conducted at 0, 1, and 6 hours after docetaxel infusion. Pharmacokinetic analyses. Analytic grade docetaxel, paclitaxel, and midazolam were gifts from Aventis Pharma SA (Antony Cedex, France), FH Faulding and Co, Ltd (North Victoria, Australia), and Hoffmann-La Roche Ltd (Basel, Switzerland), respectively. All solvents used were of high-performance liquid chromatography grade. Docetaxel levels were measured using a reverse-phase high-performance liquid chromatography method.25 The lower limit of quantitation of the assay was 10 ng/mL, and linearity was obtained for docetaxel concentrations between 10 and 1,000 ng/mL (r2 = 0.9985). The coefficient of variation of the interday and intraday precision of the quality control samples ranged from 7% to 14.5%, and the accuracy ranged from 85% to 112%. Midazolam and 1'-hydroxymidazolam levels were measured using selected ion monitoring gas chromatography mass spectrophotometry as described by Thummel et al.26 The coefficient of variation of the interday and intraday precision of the quality control samples ranged from 4.9% to 11.5%, and the accuracy ranged from 87% to 109%. Both compartmental and noncompartmental methods were used to study the pharmacokinetic parameters of both docetaxel and midazolam using the WINNonlin software, Version 3.1 (Pharsight Corporation, Apex, NC). For noncompartmental methods, the area under the concentration-time curve (AUC) was estimated from the log-linear concentration-time curve by the linear trapezoidal method with extrapolation of the terminal concentrations to infinity, including at least three points in the integration. Calculated parameters included clearance, half-life (t1/2), and volume of distribution at steady state. Compartmental analyses of both drugs was performed by visual inspection of plasma disposition curves followed by model fitting using two- and three-compartmental models with constant rate infusion input, first-order elimination, and weighting factor of 1/yobs2. The model of best fit was selected on the basis of the Akaike information criteria, from which the primary parameters, volume of the central compartment, transfer rate, and elimination rate constants were obtained.
Genotyping Genotyping for the MDR1 C3435T SNP. The MDR1 C3435T polymorphism was genotyped using PCR-based restriction enzyme digestion with Sau3AI as described by Cascorbi et al.27 CYP3A5 genotyping was performed at the Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, using methods established previously.18
Study Parameters
Statistical Analysis
Thirty-two patients were enrolled, of whom 31 were assessable for toxicity and had paired midazolam and docetaxel pharmacokinetic data sets. One patient died on the second day of the first treatment cycle from pulmonary embolism that was deemed not related to treatment. Patient characteristics are listed in Table 1. Sex distribution was equal. Most patients were not heavily pretreated. Twenty-four and eight patients received 75 and 100 mg/m2 docetaxel, respectively. Neutropenia was the major toxicity, with grade 3 or 4 toxicity occurring in 17 of 23 and five of eight patients at docetaxel doses of 75 and 100 mg/m2, respectively. Febrile neutropenia occurred in six of 23 and four of eight patients who received 75 and 100 mg/m2 of docetaxel, respectively, including four fatalities, all at 75 mg/m2. A1AG levels ranged from 0.50 to 2.72 g/L, with a mean of 1.25 ± 0.61 g/L.
Pharmacokinetics of Midazolam Midazolam levels declined rapidly after administration, and a two-compartment model best described its elimination kinetics. Midazolam pharmacokinetic parameters are listed in Table 2. The mean clearance was 426.1 ± 164.7 mL/min, with 5.2-fold variability, and the distribution of clearances fitted a normal distribution (Kolmogorov-Smirnov test value of .74). Linear correlation indicated no significant relationships between systemic clearance of midazolam and the plasma ratios of 1'-hydroxymidazolam to midazolam at any of the time points (data not shown). Females appeared to have faster clearance of midazolam, although the difference was not statistically significant (two-tailed t test, P = .17).
Pharmacokinetics of Docetaxel The pharmacokinetics of docetaxel from cycle 1 is summarized in Tables 3 and 4. Both two- and three-compartmental models were studied; the data fitted better using the two-compartmental model in 29 patients. Using noncompartmental methods, the mean clearance was 15.3 ± 4.0 L/h/m2. There was a 3.6-fold interindividual variability, and the distribution of patient clearances approximated a normal distribution. There were no differences between the concentrations of docetaxel at 6 hours after the start of infusion in cycles 1 and 2 for the 14 patients who had pharmacokinetic sampling for both cycles (two-tailed paired t test, P = .45), showing that dexamethasone did not significantly alter docetaxel pharmacokinetics.
Correlations of Docetaxel Clearance Univariate analyses showed significant correlations between docetaxel clearance with midazolam clearances (Fig 1), KPS, body-surface area, and serum albumin (Table 5). Midazolam clearance (P = .001) was the strongest predictor in a multiple linear regression analysis, KPS (P = .034) being the only other significant predictor (r2 = .68, P < .001). The model for docetaxel clearance was represented as follows: docetaxel clearance = -6171.0 + 22.3 x (midazolam clearance) + 236.2 x KPS. There was no significant correlation between 1'-hydroxymidazolam/midazolam ratios at any of the time points with docetaxel clearance (data not shown). There were no sex differences in docetaxel clearance.
Pharmacodynamic Correlations ANC nadir correlated significantly with docetaxel AUC (P = .001) (Fig 2), serum ALT (P < .001), and A1AG (P < .001), and the final linear model was represented by the following: logANCnadir = 0.54 - 2.53 x 10-2 * ALT + 0.41 * A1AG - 1.33 x 10-4 * AUC of docetaxel (r2 = .736, P < .001). These selected covariates were in agreement with those in previous pharmacodynamic models of docetaxel.28
Genotyping of CYP3A4 and MDR1 The 5' promoter region of CYP3A4 was sequenced in 30 patients, including the three patients with the slowest docetaxel clearance. No polymorphisms were detected. Twenty-eight patients were genotyped for the C3435T SNP of the MDR1 gene. The distribution of the genotypes was as follows: T/T, seven; C/T, 16; and C/C, five. Two of the three Malay patients had the T/T genotype. A plot of the docetaxel and midazolam clearances against the MDR1 genotype is shown in Fig 3. Mean clearances according to MDR1 genotypes for docetaxel were 24.0 ± 7.3, 23.2 ± 4.3, 30.0 ± 10.5 L/h for T/T, C/T, and C/C, respectively. For midazolam, mean clearances were 431.8 ± 151.8, 405.9 ± 146.9, and 550.5 ± 292.7 mL/min for T/T, C/T, and C/C genotypes, respectively. There were no significant differences between clearances of docetaxel (F = 1.84, P = .18) or midazolam (F = 1.22, P = .31) grouped according to MDR1 genotype. However, the two patients with the lowest and highest docetaxel clearances had T/T and C/C genotypes, respectively.
The CYP3A5 genotype was studied in 25 patients. Nine were homozygous for the CYP3A5*3 allele, 13 were heterozygous for the CYP3A5*3 and CYP3A5*1 alleles, and three were homozygous for the CYP3A5*1 allele. The docetaxel and midazolam clearances by CYP3A5 genotype are shown in Fig 4. Mean midazolam clearances of CYP3A5*3 homozygotes, CYP3A5*1/*3 heterozygotes, and CYP3A5*1 homozygotes were 385.0 ± 118.9, 490.0 ± 116.4, and 510.5 ± 281.4 mL/min, respectively. Although no statistically significant difference in clearances of the genotypic groups was found (F = 1.75, P = .2), CYP3A5*3 homozygotes had midazolam clearances that tended to be lower than heterozygotes (post hoc comparison, P = .08). Midazolam clearances in patients with at least one CYP3A5*1 allele (CYP3A5*1/*3 and CYP3A5*1/*1) was significantly lower than CYP3A5*3 homozygotes (Student’s t test, P = .03).
Mean docetaxel clearances by CYP3A5 genotype were as follows: 27.3 ± 8.1, 22.3 ± 4.1, and 19.4 ± 7.6 L/h for CYP3A5*3/*3, CYP3A5*1/*3, and CYP3A5*1/*1, respectively. There were no obvious trends in the mean clearances of docetaxel between the three genotypes (F = 2.5, P = .11). None of the 24 patients genotyped had the rare CYP3A5*6 allele.
In this study involving Asian patients, docetaxel clearance was lower than reported for whites and Japanese in the current literature.29,30 The mean clearance of docetaxel in this study was 15.3 ± 4.0 L/h/m2, compared with the reported clearance of 22 L/h/m2.29 However, this apparent difference in docetaxel clearance is inconclusive and may be accounted for by the small sample size, assay variation, and differences in sampling time points. The neutropenia observed in our patients appeared to be more significant than in Western patients; neutropenic fever occurred at a relatively high incidence of 29%. These findings are consistent with higher drug exposure, which may be explained by recent observations that Asians may have lower CYP3A activity than whites.31 Therefore, our findings suggest that more cross-ethnic studies with common study design and assays are warranted. We observed significant interindividual variability of docetaxel pharmacokinetics, and explored reasons for this variability. The first strategy used a probe drug approach to assay CYP3A activity in vivo. Several probe drugs of CYP3A activity have been used to predict docetaxel clearance, including erythromycin and hydrocortisone.32,33 The correlations between various probes for CYP3A4 have been inconsistent, and the optimal probe drug has not been established.34-36 The erythromycin breath test and its limitations have been reviewed,37-39 and include the fact that it does not measure erythromycin clearance per se. Furthermore, erythromycin is a substrate of CYP3A4, but not CYP3A5, which is also involved in docetaxel metabolism. The second method to predict docetaxel clearance used measurement of 24-hour total urinary 6-beta-hydroxycortisol after a bolus of exogenous hydrocortisone, which similarly does not directly reflect CYP3A activity.33 We chose midazolam as our probe drug, as its clearance was felt to directly represent both CYP3A4 and CYP3A5 activities, and has been validated by in vivo and in vitro correlations by other investigators.26 We found that midazolam clearance was the most significant predictor of docetaxel clearance in both univariate and multivariate analyses (r = .6, P = .0005). This suggests that midazolam can be used as a probe drug to predict docetaxel pharmacokinetics. The same strategy may potentially be applied to other CYP3A substrates. Several reasons may account for the significant unexplained residual variability. First, an alternative pathway of elimination exists for docetaxel through active efflux by P-glycoprotein in the intestine and biliary system (see below). Midazolam is almost completely metabolized, and is not affected by P-glycoprotein.40 Second, the clearances of both drugs are influenced mainly by protein-binding and metabolizing enzyme activity, and less so by hepatic blood flow, as they have low clearances. Midazolam and docetaxel bind differentially to various plasma proteins, and intraindividual and interindividual differences in fraction of free drug would affect the correlation between their clearances. Other studies have reported correlation of serum A1AG levels with docetaxel clearance41 and risk of grade 4 neutropenia28; in this study, there was a trend toward significance in its correlation with docetaxel clearance, and it was predictive of nadir neutrophil counts. In addition, variability in intrinsic enzyme activity may influence the correlation between CYP3A activity and drug clearance. Enzyme inducers and inhibitors may affect the intrinsic hepatic clearance of a drug; we attempted to reduce these influences by eliminating known CYP3A substrates in patients’ medications, although the effects of diet, including herbal remedies, which many of our patients self-administer, cannot be discounted. Another approach we took to studying variability of docetaxel clearance was through CYP3A4, CYP3A5, and MDR1 genotyping. Theoretically, genetic polymorphisms of CYP3A4, CYP3A5, and MDR1 would alter docetaxel clearance, but MDR1 genotype would not affect midazolam clearance. We found no sequence variations in the CYP3A4 promoter region; notably, the CYP3A4*1B allele was not detected in any of our patients, as is consistent with other studies that had reported this SNP to be rare in Chinese. Work is being performed to sequence the coding regions where recent SNPs have been described in Chinese.42 The CYP3A5*3 allele is common in Asians and may account for observed wide variation in overall CYP3A activity. The low midazolam clearance in CYP3A5*3 homozygotes is to our knowledge the first indication of the clinical impact of this SNP in vivo. A similar trend was not seen with docetaxel despite it being a CYP3A5 substrate. We speculate that docetaxel clearances may be influenced by both MDR1 and CYP3A5 genotypes, and possibly others as well. The fact that MDR1 activity affects cellular CYP3A activity in vitro may support this.23 The frequency distributions of the C3435T SNP of the MDR1 gene suggested that both C and T alleles existed in approximately similar frequencies in our population. The T/T genotype, which has been associated with lower membrane transport activity, may result in reduced clearance of substrates like docetaxel either by reduced biliary excretion or, more likely, by reduced enterohepatic reabsorption from the gut.43 However, in our study the clearances of both midazolam and docetaxel were not affected by MDR1 genotype. Interestingly, the T/T genotype is common in Malay patients, and ethnic variability of this SNP and its effects on drug pharmacokinetics and pharmacodynamics should be explored further in the Asian population. In conclusion, docetaxel clearance may be predicted by CYP3A phenotyping using midazolam. Variant alleles of CYP3A5 and MDR1 are common in our population, and their influences on drug pharmacokinetics are complex, warranting further studies to characterize this interaction clinically. In particular, high-throughput DNA microarray technology will find application in simultaneous genotyping for multiple isoenzymes and membrane transporters in relation to substrate phenotyping.
Supported by National Medical Research Council of Singapore grant no. NMRC/0391/1999, the Singapore Cancer Society, Aventis Pharma Singapore, and PharmGKB grant no. U01 GM61393. We thank Mark Ratain, MD, for valuable comments and May-Nah Ho, for biostatistical review.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
G) allele leads to alternative splicing that results in a truncated protein product, and is the commonest cause of loss of hepatic expression of CYP3A5. Another polymorphism, CYP3A5*6 (30597 G
