Affiliations of authors: Departments of Medical Oncology (RHJM, FADJ, PDB, JV), Clinical Chemistry (RHNVS), Internal Medicine (TR), and Biostatistics (WJG), Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden (LEF); Clinical Pharmacology Research Core, National Cancer Institute, Bethesda, MD (ERL, WDF, AS)
Correspondence to: Alex Sparreboom, PhD, Clinical Pharmacology Research Core, National Cancer Institute, 9000 Rockville Pike, Bldg. 10, Rm. 5A01, Bethesda, MD 20892 (e-mail sparreba{at}mail.nih.gov)
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ABSTRACT |
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INTRODUCTION |
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Irinotecan pharmacokinetic variability between individuals is large. Pathways that eliminate irinotecan contain the cytochrome P450 3A subfamily members CYP3A4 and CYP3A5 (collectively referred to as CYP3A); the uridine diphosphate glucuronosyltransferase 1A subfamily members UGT1A1, UGT1A3, UGT1A7, and UGT1A9 (collectively referred to as UGT1A); and drug transporting proteins, including ABCB1 (P-glycoprotein) (5) (Fig. 1). Recent investigations have also indicated that genetic polymorphisms (8), herbal supplements (9), and concomitantly administered allopathic drugs (10) can alter the activity and/or expression levels of these proteins and change the rate of irinotecan elimination. Thus far, only limited attempts have been made to incorporate this knowledge into clinical practice. Because dosing strategies that are based on body surface area do not reduce interindividual variability in irinotecan pharmacokinetics (1113), other measures to predict the pharmacologic profile of irinotecan in individual patients are needed. One possibility is to assess the phenotype of CYP3A because CYP3A is involved in the metabolism of about half of all prescribed drugs (14) and plays a principal role in the metabolism of irinotecan (5). In vivo probe drugs such as cortisol, dextromethorphan, erythromycin, and midazolam are widely used for evaluating CYP3A activity in humans (1517), and such probes accurately predict the activity of CYP3A (1820) and the clearance of docetaxel, another anticancer drug that is a CYP3A substrate (2124). Consequently, we prospectively explored the relationship between CYP3A phenotype, as assessed with the probe drugs erythromycin and midazolam, and the metabolism of irinotecan and its active metabolite SN-38 by white patients with cancer.
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PATIENTS AND METHODS |
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Eligible patients had a solid tumor for which irinotecan was considered the treatment of choice or for which no standard treatment option was available. Patients were treated with irinotecan (Aventis, Hoevelaken, The Netherlands) once every 3 weeks as a 90-minute intravenous infusion at a fixed dose of 600 mg. If excessive toxicity (e.g., diarrhea and neutropenia) was detected, the next course was postponed for a week and/or the dose was reduced by 25%. Thirty cancer patients received irinotecan chemotherapy; all but three received two treatments. Eligibility and exclusion criteria (including acceptable liver functions and a World Health Organization performance score of 1), premedication, and protocols for treatment of drug-induced side effects (e.g., diarrhea with the use of loperamide and/or antibiotics) were identical to those used earlier (25). No patient was allowed to use drugs, food supplements, and/or herbal preparations that were known to interfere with the function or expression of proteins involved in irinotecan disposition. The clinical protocol was approved by the Erasmus Medical Center Ethics Board, and all patients provided written informed consent before study entry.
Erythromycin Breath Test
Five microcuries (µCi; 0.07 mg or 0.1 µmol) of [N-methyl-14C]erythromycin (American Radiolabeled Chemicals, St. Louis, MO) in 4 mL of a solution of 2.5% glucose and 0.45% sodium chloride (final erythromycin concentration, 17.5 µg/mL or 1.19 µCi/g) was injected intravenously through an infusion set in less than 30 seconds, 48 days before the first treatment with irinotecan. In half of the patients, this test was repeated before the second course; in the other half, a second midazolam clearance test was given. The metabolism of erythromycin in the liver involves the CYP3A4-catalyzed cleavage of the N-methyl group from erythromycin and, after a series of nonrate-limiting steps, the formation of CO2 from the cleaved formaldehyde (20). Inclusion of 14C-labeled N-methyl moieties in erythromycin results in the production of 14CO2 (26). Patients exhaled 14CO2 through a drinking straw into a solution of 2.00 mL of 1 M hyamine hydroxide in methanol (Packard Instrument, Meriden, CT) and 2 mL of thymolphthalein (60 mg/L in ethanol). 14CO2 and CO2 in the breath sample were absorbed by the hyamine hydroxide, and the indicator thymolphthalein (60 mg/L in ethanol) changed color from blue to clear when the hyamine hydroxide was saturated with CO2. Aspiration of liquid as the patient breathed was prevented by safety valves. After combining the 4-mL breath sample solution with 5 mL of Insta-Gel Plus liquid scintillation fluid (Packard), we determined the amount of 14CO2 in a breath sample by liquid scintillation counting on a Packard TRI-CARB Liquid Scintillation Analyzer 1900 TR, as described elsewhere (27). The amount of radioactivity was expressed as disintegrations per minute (dpm). Eight breath samples were taken over a 40-minute period (i.e., immediately before treatment and 5, 10, 15, 20, 25, 30, and 40 minutes after infusion ended). The flux of radioactivity (14C) in exhaled CO2 at each time tx (CERtx), expressed as a percentage of the erythromycin dose of radioactivity per minute, was calculated as follows:
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where the first two terms, (dpmtx dpmt0)/2.222 x 106 dpm/µCi and 1/2.00 ml x 0.972 M CO2, refer to the measured dose in microcuries (first term) per captured millimole (second term) of CO2 at time tx, and in the third term 1.19 µCig x weight is the administered dose in microcuries, and 100 corrects for percentage. In the equation, dpmtx is the amount of radioactivity (expressed in disintegrations per minute) for each breath sample obtained, and weight is the mass (expressed in grams) of solution injected. The product of the first three terms is the percentage of administered dose per exhaled millimole of CO2 at time x. Multiplying this product by the fourth term (5 mmol CO2/min/m2 x BSA) corrects for CO2 output of individuals on the basis of 5 mmol of CO2 exhaled per minute per square meter of body surface area (BSA), to give the flux of exhaled 14C expressed as percentage of the dose per minute (28). The most commonly used parameter from the erythromycin breath test is CER040, the area under the curve for the flux of radioactivity (14C) in exhaled CO2 from 0 to 40 minutes (19), and it served as the primary parameter to predict total body clearance of irinotecan.
Midazolam Clearance Test
Midazolam (0.025 mg/kg of body weight, Roche Laboratories, Mijdrecht, The Netherlands) was injected intravenously within a 30-second period, 48 days before the first treatment with irinotecan. In patients not undergoing a second erythromycin breath test, the midazolam clearance test was repeated before the second treatment with irinotecan. Blood samples of 7 mL were collected immediately before infusion and 5 and 30 minutes and 1, 2, 4, 5, and 6 hours after the infusion ended. These blood samples were centrifuged immediately after collection for 10 minutes at 2000g (4 °C), and plasma supernatants were stored at 20 °C on the day of collection and then at 80 °C until the day of analysis. After the addition of 25 µL of the internal standard (a solution of lorazepam at 4 µg/mL of methanol), 600 µL of plasma was extracted in one step with ethyl acetate. Midazolam and lorazepam were separated by high-performance liquid chromatography on a column (150 x 4.6 mm, internal diameter) with a matrix of 5-µm Zorbax Eclipse XDB-C8 and with a mobile phase composed of methanol and 10 mM aqueous ammonium acetate (60 : 40, vol/vol). Column effluents were analyzed by mass spectrometry with an atmospheric pressure chemical ionization interface (29). Calibration curves for midazolam were linear from 1.00 to 200 ng/mL. The accuracy and precision of measurements ranged from 92.8% to 112% and from 0.056% to 13.4%, respectively, for four concentrations of quality control samples analyzed in triplicate on eight separate occasions.
Irinotecan Pharmacokinetics
Blood samples of 5 mL were collected in heparin-containing tubes during the first and second irinotecan treatments at the following times: immediately before infusion; 30 minutes after the start of infusion; immediately before the end of infusion; and 10, 20, and 30 minutes and 1, 1.5, 2, 3.5, 5, 6.5, 23, 31, 47, and 55 hours after the end of infusion. In addition, patients were asked to provide a blood sample during their weekly outpatient visit on days 7, 14, and 20 after infusion. Blood samples were handled as described previously (30), and concentrations of irinotecan, SN-38, and SN-38 glucuronide (SN-38G) were determined by reversed-phase high-performance liquid chromatography with fluorescence detection as described previously (31,32).
Genotyping Procedures
DNA was isolated from 0.2 mL of whole blood or plasma with a Total Nucleic Acid Extraction kit on a MagNA Pure LC (Roche Molecular Biochemicals, Mannheim, Germany) and amplified by polymerase chain reaction. Restriction fragment length polymorphism analysis was used to identify specific variations in the genes ABCB1 (i.e., ABCB11236CT [ABCB1*8], ABCB1 2677G
A/T [ABCB1*7], and ABCB1 3435C
T [ABCB1*6]), CYP3A4 (CYP3A4*1B, CYP3A4*2, CYP3A4*3, CYP3A4*17, and CYP3A4*18), and CYP3A5 (CYP3A5*3 and CYP3A5*6) (33,34). The number of TA repeats in the promoter of the UGT1A1 gene was determined by sizing of products from the polymerase chain reaction obtained with the UGT1A1-specific primers 5'-6-carboxyfluorescein-AAGTGAACTCCCTGCTACCT-3' and 5'-AAAGTGAACTCCCTGCTACC-3', followed by fragment analysis carried out with the automated capillary electrophoresis instrument ABI310 (Applied BioSystems, Foster City, CA).
Pharmacokinetic Analysis
For pharmacokinetic modeling, we used a previously developed population model (35) to estimate individual pharmacokinetic parameters of irinotecan, SN-38, and SN-38G, which included the accumulated area under the plasma concentration versus time curve (AUC) and clearance. The AUC was determined for irinotecan and its metabolites in all patients from 0 to 100 hours after start of infusion for a dose corrected to 600 mg. In this analysis, interoccasion variability in the parameters was also considered. The analysis was performed with NONMEM version VI (S. L. Beal and L. B. Sheiner, San Francisco, CA). The relative extent of conversion (irinotecan to SN-38) was calculated as the ratio of the AUC of SN-38 and the AUC of irinotecan, and the relative extent of glucuronidation (SN-38 to SN-38G) was calculated as the ratio of the AUC of SN-38G and the AUC of SN-38. WinNonlin version 4.0 (Pharsight, Mountain View, CA) was used to calculate pharmacokinetics parameters for the erythromycin breath test and midazolam clearance test data. Uniform weighted percentages of the administered dose per minute (CERtx) as input for a one-compartment model yielded the following parameters for the erythromycin breath test: the maximal CER (CERmax), tmax, and its reciprocal 1/tmax. The area under the CER curve from 0 to 40 minutes (CER040) was calculated by use of noncompartmental analysis, and the percentage of the administered dose per minute in the sample obtained at the 20-minute point was noted. The clearance was calculated as the ratio of dose and AUC extrapolated to infinity obtained from a linear one-compartment model. For the midazolam clearance test, the clearance and the midazolam concentration obtained at the 4-hour sampling point (t4) were evaluated as potential predictors of irinotecan pharmacokinetics (36). The midazolam concentration at the 4-hour sampling point is a commonly used parameter that has been extensively evaluated in limited sampling schemes to determine the reproducibility of estimating midazolam AUC by use of only one time point (37).
Pharmacodynamic Evaluation
Complete blood cell counts and blood chemistry data were obtained for each patient before study entry and before each chemotherapy course, and these tests were repeated once a week during the patients' outpatient visits. If severe hematologic toxicity was detected, blood cell counts were measured daily or as clinically indicated. Diarrhea was scored by use of the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0 (available at: http://ctep.info.nih.gov/reporting/ctc.html [last accessed September 28, 2004]).
Statistical Considerations
Pharmacokinetic data are presented as mean values and 95% confidence intervals (CIs), unless stated otherwise. Before genotype and phenotype analysis, AUC values were logarithmically transformed. Associations between irinotecan pharmacokinetics obtained during the first irinotecan treatment and the CYP3A phenotype as determined by the erythromycin breath test or the midazolam clearance test were evaluated by use of Pearson's correlation coefficient. The influence of the various genetic variants on irinotecan pharmacokinetics and pharmacodynamics during the first irinotecan treatment was assessed by use of a KruskalWallis one-way analysis of variance or a nonparametric trend analysis. Although this study was mainly exploratory in intent, a Hochberg adjustment was used to evaluate the statistical significance of the multiple comparisons (38). All statistical tests were two-sided. With both the KruskalWallis and the trend analysis tests, P values of less than .01 were regarded as statistically significant, and those less than .05 were considered a nonstatistically significant trend (i.e., a P<.05 and .01 corresponds with some evidence of difference, but the evidence is not strong enough to declare it to be statistically significant). These levels were chosen to reduce the risk of finding purely coincidental associations in view of the number of parameters analyzed. Statistical calculations were performed with SPSS version 10.1 (Paris, France) or Stata version 8.2 (Stata, College Station, TX).
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RESULTS |
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A total of 30 eligible adult white patients with cancer (16 males and 14 females) with a median age of 55 years (range = 3873 years) were recruited to this study between January 1, 2002, and July 31, 2003 (Table 1). All but three of them received at least two courses of chemotherapy. The most frequent primary tumor types were lung cancer (n = 10) and colorectal cancer (n = 12). All patients received the planned fixed irinotecan dose of 600 mg during the first irinotecan treatment, but four of them received a 25% dose reduction during the second irinotecan treatment because of severe side effects experienced with the first administration, as required by the protocol.
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Plasma concentrations of irinotecan, SN-38, and SN-38G as a function of time were accurately predicted by a modified version of a previous population model (35), as determined by goodness-of-fit plots (data not shown). The typical irinotecan clearance was 31.8 L/h (95% CI = 28.4 L/h to 35.1 L/h), the mean relative extent of irinotecan to SN-38 conversion was 0.0263 (95% CI = 0.0218 to 0.0307), and the mean relative extent of SN-38 to SN-38G glucuronidation was 6.95 (95% CI = 5.23 to 8.66), consistent with earlier data (Table 2) (35). The interoccasion variability in irinotecan clearance was estimated to be 11.0%. The relative intrapatient variation in parameter estimates was minimal, with mean values for the ratio of the AUC in the second irinotecan treatment to the AUC in the first irinotecan treatment of 0.90, 0.87, and 0.86 for irinotecan, SN-38, and SN-38G, respectively.
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CYP3A phenotypic parameterserythromycin metabolism (erythromycin breath test parameters of the percentage of the administered dose in the sample obtained at the 20-minute point [r = .846 and P<.001] and the area under the CER curve from 0 to 40 minutes [r = .840 and P<.001]) and midazolam metabolism (midazolam clearance [r = .661 and P = .010])during the first and second irinotecan treatments were highly correlated, suggesting limited intraindividual variability in CYP3A expression and function within the study period. CYP3A activity as determined from the erythromycin breath test data from the first irinotecan treatment varied about sevenfold (area under the CER curve from 0 to 40 minutes range = 0.223%1.53% of dose) among the patients and as determined from the midazolam clearance test data varied about fourfold (midazolam clearance range = 2621012 mL/min).
Conventional parameters for the erythromycin breath test (including the percentage of the administered dose in the sample obtained at the 20-minute point, the area under the CER curve from 0 to 40 minutes, and 1/tmax) were not statistically significantly associated with irinotecan clearance, the AUC of SN-38, or the relative extent of conversion (Table 3). In contrast, midazolam clearance (r = .745, P<.001) and the midazolam concentration at the 4-hour sampling point (r = .416, P = .022) were correlated with irinotecan clearance (Fig. 2 and Table 3). A sex difference in midazolam clearance was not observed (P = .260). A weak correlation was found between the dose-normalized AUC values for midazolam and SN-38G (r = .368, P = .046). In contrast to earlier findings (39), some of the erythromycin breath test parameters, including the percentage of the administered dose in the sample obtained at the 20-minute point and the area under the CER curve from 0 to 40 minutes, were statistically significantly correlated with midazolam clearance (r = .529 and P = .003 for the percentage of the administered dose in the sample obtained at the 20-minute point; and r = .556 and P = .001 for the area under the CER curve from 0 to 40 minutes) and the midazolam concentration at the 4-hour sampling point (r = .503 and P = .005 for the percentage of the administered dose in the sample obtained at the 20-minute point; and r = .653 and P<.001 for the area under the CER curve from 0 to 40 minutes).
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Among the five genetic variants CYP3A4*2, CYP3A4*3, CYP3A4*17, CYP3A4*18, and CYP3A5*6, only the wild-type sequence was found, indicating that for these variants none of the patients in the studied cohort carried a mutant allele. The absence of these variants is consistent with previously published data obtained in the general European white population (40,41). For the other six variants (ABCB1*8, ABCB1*7, ABCB1*6, CYP3A4*1B, CYP3A5*3, and UGT1A1*28) studied, the frequency of the variant allele (q) was highly variable, with only four patients carrying at least one variant allele for CYP3A4*1B (allele frequency, 0.09) and as many as 29 patients carrying at least one variant allele for CYP3A5*3 (allele frequency, 0.87) (Table 4).
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DISCUSSION |
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We did not observe statistically significant correlations between common parameters (CER20, area under the CER040, and 1/tmax) for the erythromycin breath test and irinotecan pharmacokinetics, but we did obtain a highly statistically significant correlation between midazolam clearance and irinotecan clearance. From this correlation analysis, we predict that, in the patient cohort in our study, 56% of total interindividual variability in irinotecan clearance can be explained by variation in CYP3A function. The discrepant findings between the erythromycin breath test and the midazolam clearance test may be related to the relatively slow and inefficient metabolism of midazolam, which more closely resembles the CYP3A-mediated metabolism of irinotecan than the fast and extensive CYP3A-mediated metabolism of erythromycin (39). We also cannot exclude the possibility that ABCB1 plays a minor role in clearance of irinotecan and a larger role in the clearance of erythromycin and that this difference confounds pharmacokinetic interrelationships. We also observed a trend for a relationship between the AUC for midazolam and exposure to SN-38G. This finding was unexpected because SN-38G is formed from SN-38 through UGT1A-mediated conjugation that is independent of CYP3A activity. A possible explanation may be found in the indirect formation of SN-38 and SN-38G from 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin (NPC), which results from a ring-opening oxidation of the terminal piperidine ring of irinotecan that is mediated by CYP3A4 (46) (Fig. 1).
Although irinotecan is considered a prodrug with little inherent antitumor activity, the ability to accurately predict its clearance may be clinically relevant. First, the etiology of irinotecan-mediated side effects is still not completely understood, and circulating concentrations of the parent drug may predict hematologic toxicity associated with irinotecan treatment (47). Furthermore, the ratio of concentration of total unbound irinotecan to the concentration of total unbound SN-38 is similar to their potency ratio in vitro, and so both irinotecan and SN-38 are likely to be effective in vivo (5). Second, SN-38 may be formed both peripherally in the intestines, liver, and blood, as well as in the tumor from the conversion of irinotecan by carboxylesterase 2 (hCE2), which may be more important than previously thought and may contribute to the variable response to irinotecan chemotherapy for solid tumors (48,49). Consequently, knowledge of phenotypic CYP3A activity, as a predictor of irinotecan clearance in individual patients, may help to reduce the pharmacokinetic and subsequent pharmacodynamic variability associated with irinotecan treatment.
We found that certain genetic variants in polymorphic proteins are associated with differences in the elimination of irinotecan or its metabolites, as predicted previously (50). We also confirmed earlier preliminary observations that the UGT1A1*28 genotype is independently associated with the pharmacokinetic profile of irinotecan (5153) and that ABCB1*8 has a smaller association (54). Genotyping for CYP3A4 and CYP3A5 did not result in statistically significant correlations with irinotecan pharmacokinetics, perhaps because of the low allele frequency of most CYP3A variant genotypes (e.g., CYP3A4*17, CYP3A4*18, and CYP3A5*1) in the white population (40,41) or because of the absence of a clinically important effect on enzyme activity in vivo (e.g., CYP3A4*1B) (55,56). Because CYP3A is a complex enzyme system that is easily influenced by environmental (i.e., comedication, herbal preparations, and/or food substances) and physiologic (i.e., aging, disease state, and altered liver and renal function) factors (5), the role of CYP3A genotyping in the chemotherapeutic treatment of cancer remains uncertain.
In conclusion, CYP3A phenotype (as determined by midazolam clearance) and UGT1A1*28 genotype appear to be statistically significant predictors of irinotecan and SN-38 pharmacokinetics, respectively. A prospective study to validate the usefulness of these phenotyping and genotyping strategies to optimize chemotherapeutic treatment with irinotecan for individual patients is currently under way. In addition, limited sampling strategies are being developed by use of data obtained in a larger cohort of patients to further optimize the clinical applicability of the midazolam clearance test.
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NOTES |
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We thank Dr. Wim van den Berg, Inge van den Bos, Dirk Buijs, Dr Sjaak Burgers, Jan Francke, Ilse van der Heiden, Hans van der Meulen, Tatjana Pronk, Martin van Vliet, and Marloes van der Werf (all from Rotterdam) and Dr. Nicola F. Smith (from Bethesda, MD) for their contribution to this work.
Presented, in part, at the 22nd and 23rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31, 2003, and New Orleans, LA, June 6, 2004.
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REFERENCES |
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1 Grothey A, Sargent D, Goldberg RM, Schmoll HJ. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 2004;22:120914.
2 Perez EA, Hillman DW, Mailliard JA, Ingle JN, Ryan JM, Fitch TR, et al. Randomized phase II study of two irinotecan schedules for patients with metastatic breast cancer refractory to an anthracycline, a taxane, or both. J Clin Oncol 2004;22:284955.
3 Ribrag V, Koscielny S, Vantelon JM, Ferme C, Rideller K, Carde P, et al. Phase II trial of irinotecan (CPT-11) in relapsed or refractory non-Hodgkin's lymphomas. Leuk Lymphoma 2003;44:152933.[CrossRef][ISI][Medline]
4 Langer CJ. The global role of irinotecan in the treatment of lung cancer: 2003 update. Oncology (Huntingt) 2003;17:3040.[Medline]
5 Mathijssen RH, van Alphen RJ, Verweij J, Loos WJ, Nooter K, Stoter G, et al. Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res 2001;7:218294.
6 Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000;343:90514.
7 Vanhoefer U, Harstrick A, Achterrath W, Cao S, Seeber S, Rustum YM. Irinotecan in the treatment of colorectal cancer: clinical overview. J Clin Oncol 2001;19:150118.
8 Evans WE, Relling MV. Moving towards individualized medicine with pharmacogenomics. Nature 2004;429:4648.[CrossRef][ISI][Medline]
9 Sparreboom A, Cox MC, Acharya MR, Figg WD. Herbal remedies in the United States: potential adverse interactions with anticancer agents. J Clin Oncol 2004;22:2489503.
10 Rivory LP. Drug interactions. In: Figg WD, McLeod HL, editors. Handbook of anticancer pharmacokinetics and pharmacodynamics. Totawa (NJ): Humana Press; 2004. p. 24566.
11 Baker SD, Verweij J, Rowinsky EK, Donehower RC, Schellens JH, Grochow LB, et al. Role of body surface area in dosing of investigational anticancer agents in adults, 1991-2001. J Natl Cancer Inst 2002;94:18838.
12 Mathijssen RH, Verweij J, de Jonge MJ, Nooter K, Stoter G, Sparreboom A. Impact of body-size measures on irinotecan clearance: alternative dosing recommendations. J Clin Oncol 2002;20:817.
13 de Jong FA, Mathijssen RH, Xie R, Verweij J, Sparreboom A. Flat-fixed dosing of irinotecan: influence on pharmacokinetic and pharmacodynamic variability. Clin Cancer Res 2004;10:406871.
14 Guengerich FP. Cytochrome P-450 3A4: regulation and role in drug metabolism. Annu Rev Pharmacol Toxicol 1999;39:117.[CrossRef][ISI][Medline]
15 Agundez JA. Cytochrome p450 gene polymorphism and cancer. Curr Drug Metab 2004;5:21124.[ISI][Medline]
16 Kivisto KT, Kroemer HK. Use of probe drugs as predictors of drug metabolism in humans. J Clin Pharmacol 1997;37:40S8S.[Abstract]
17 Tanaka E, Kurata N, Yasuhara H. How useful is the "cocktail approach" for evaluating human hepatic drug metabolizing capacity using cytochrome P450 phenotyping probes in vivo? J Clin Pharm Ther 2003;28:15765.[CrossRef][ISI][Medline]
18 Streetman DS, Bertino JS Jr, Nafziger AN. Phenotyping of drug-metabolizing enzymes in adults: a review of in-vivo cytochrome P450 phenotyping probes. Pharmacogenetics 2000;10:187216.[CrossRef][ISI][Medline]
19 Rivory LP, Watkins PB. Erythromycin breath test. Clin Pharmacol Ther 2001;70:3959.[ISI][Medline]
20 Rivory LP, Slaviero KA, Hoskins JM, Clarke SJ. The erythromycin breath test for the prediction of drug clearance. Clin Pharmacokinet 2001;40:1518.[ISI][Medline]
21 Hirth J, Watkins PB, Strawderman M, Schott A, Bruno R, Baker LH. The effect of an individual's cytochrome CYP3A4 activity on docetaxel clearance. Clin Cancer Res 2000;6:12558.
22 Yamamoto N, Tamura T, Kamiya Y, Sekine I, Kunitoh H, Saijo N. Correlation between docetaxel clearance and estimated cytochrome P450 activity by urinary metabolite of exogenous cortisol. J Clin Oncol 2000;18:23018.
23 Goh BC, Lee SC, Wang LZ, Fan L, Guo JY, Lamba J, et al. Explaining interindividual variability of docetaxel pharmacokinetics and pharmacodynamics in Asians through phenotyping and genotyping strategies. J Clin Oncol 2002;20:368390.
24 Puisset F, Chatelut E, Dalenc F, Busi F, Cresteil T, Azema J, et al. Dexamethasone as a probe for docetaxel clearance. Cancer Chemother Pharmacol 2004;54:26572.[ISI][Medline]
25 de Jonge MJ, Sparreboom A, Planting AS, van der Burg ME, de Boer-Dennert MM, ter Steeg J, et al. Phase I study of 3-week schedule of irinotecan combined with cisplatin in patients with advanced solid tumors. J Clin Oncol 2000;18:18794.
26 Lane EA, Parashos I. Drug pharmacokinetics and the carbon dioxide breath test. J Pharmacokinet Biopharm 1986;14:2949.[ISI][Medline]
27 Ghoos YF, Maes BD, Geypens BJ, Mys G, Hiele MI, Rutgeerts PJ, et al. Measurement of gastric emptying rate of solids by means of a carbon-labeled octanoic acid breath test. Gastroenterology 1993;104:16407.[ISI][Medline]
28 Watkins PB, Murray SA, Winkelman LG, Heuman DM, Wrighton SA, Guzelian PS. Erythromycin breath test as an assay of glucocorticoid-inducible liver cytochromes P-450. Studies in rats and patients. J Clin Invest 1989;83:68897.[ISI][Medline]
29 Lepper ER, Hicks JK, Verweij J, Zhai S, Figg WD, Sparreboom A. Determination of midazolam in human plasma by liquid chromatography with mass-spectrometric detection. J Chromatogr B Analyt Technol Biomed Life Sci 2004;806:30510.[ISI][Medline]
30 Sparreboom A, de Jonge MJ, de Bruijn P, Brouwer E, Nooter K, Loos WJ, et al. Irinotecan (CPT-11) metabolism and disposition in cancer patients. Clin Cancer Res 1998;4:274754.[Abstract]
31 de Bruijn P, Verweij J, Loos WJ, Nooter K, Stoter G, Sparreboom A. Determination of irinotecan (CPT-11) and its active metabolite SN-38 in human plasma by reversed-phase high-performance liquid chromatography with fluorescence detection. J Chromatogr B Biomed Sci Appl 1997;698:27785.[CrossRef][Medline]
32 de Bruijn P, de Jonge MJ, Verweij J, Loos WJ, Nooter K, Stoter G, et al. Femtomole quantitation of 7-ethyl-10-hydroxycamptothecine (SN-38) in plasma samples by reversed-phase high-performance liquid chromatography. Anal Biochem 1999;269:1748.[CrossRef][ISI][Medline]
33 Hesselink DA, van Schaik RH, van der Heiden IP, van der Werf M, Gregoor PJ, Lindemans J, et al. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther 2003;74:24554.[CrossRef][ISI][Medline]
34 Dai D, Tang J, Rose R, Hodgson E, Bienstock RJ, Mohrenweiser HW, et al. Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos. J Pharmacol Exp Ther 2001;299:82531.
35 Xie R, Mathijssen RH, Sparreboom A, Verweij J, Karlsson MO. Clinical pharmacokinetics of irinotecan and its metabolites in relation with diarrhea. Clin Pharmacol Ther 2002;72:26575.[CrossRef][ISI][Medline]
36 Kanto JH. Midazolam: the first water-soluble benzodiazepine. Pharmacology, pharmacokinetics and efficacy in insomnia and anesthesia. Pharmacotherapy 1985;5:13855.[ISI][Medline]
37 Kim JS, Nafziger AN, Tsunoda SM, Choo EE, Streetman DS, Kashuba AD, et al. Limited sampling strategy to predict AUC of the CYP3A phenotyping probe midazolam in adults: application to various assay techniques. J Clin Pharmacol 2002;42:37682.[Abstract]
38 Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika 1988;75:8002.[ISI]
39 Kinirons MT, O'Shea D, Kim RB, Groopman JD, Thummel KE, Wood AJ, et al. Failure of erythromycin breath test to correlate with midazolam clearance as a probe of cytochrome P4503A. Clin Pharmacol Ther 1999;66:22431.[ISI][Medline]
40 van Schaik RH, de Wildt SN, Brosens R, van Fessem M, van den Anker JN, Lindemans J. The CYP3A4*3 allele: is it really rare? Clin Chem 2001;47:11046.
41 van Schaik RH, van der Heiden IP, van den Anker JN, Lindemans J. CYP3A5 variant allele frequencies in Dutch Caucasians. Clin Chem 2002;48:166871.
42 Santos A, Zanetta S, Cresteil T, Deroussent A, Pein F, Raymond E, et al. Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans. Clin Cancer Res 2000;6:201220.
43 Kehrer DF, Mathijssen RH, Verweij J, de Bruijn P, Sparreboom A. Modulation of irinotecan metabolism by ketoconazole. J Clin Oncol 2002;20:31229.
44 Mathijssen RH, Verweij J, de Bruijn P, Loos WJ, Sparreboom A. Effects of St. John's wort on irinotecan metabolism. J Natl Cancer Inst 2002;94:12479.
45 Kim RB, Wandel C, Leake B, Cvetkovic M, Fromm MF, Dempsey PJ, et al. Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein. Pharm Res 1999;16:40814.[CrossRef][ISI][Medline]
46 Haaz MC, Riche C, Rivory LP, Robert J. Biosynthesis of an aminopiperidino metabolite of irinotecan [7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecine] by human hepatic microsomes. Drug Metab Dispos 1998;26:76974.
47 de Jonge MJ, Verweij J, de Bruijn P, Brouwer E, Mathijssen RH, van Alphen RJ, et al. Pharmacokinetic, metabolic, and pharmacodynamic profiles in a dose- escalating study of irinotecan and cisplatin. J Clin Oncol 2000;18:195203.
48 Xu G, Zhang W, Ma MK, McLeod HL. Human carboxylesterase 2 is commonly expressed in tumor tissue and is correlated with activation of irinotecan. Clin Cancer Res 2002;8:260511.
49 Zhang W, Xu G, McLeod HL. Comprehensive evaluation of carboxylesterase-2 expression in normal human tissues using tissue array analysis. Appl Immunohistochem Mol Morphol 2002;10:37480.[ISI][Medline]
50 Mathijssen RH, Marsh S, Karlsson MO, Xie R, Baker SD, Verweij J, et al. Irinotecan pathway genotype analysis to predict pharmacokinetics. Clin Cancer Res 2003;9:32518.
51 Iyer L, Das S, Janisch L, Wen M, Ramirez J, Karrison T, et al. UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics J 2002;2:437.[CrossRef][Medline]
52 Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, et al. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 2004;22:13828.
53 Sai K, Saeki M, Saito Y, Ozawa S, Katori N, Jinno H, et al. UGT1A1 haplotypes associated with reduced glucuronidation and increased serum bilirubin in irinotecan-administered Japanese patients with cancer. Clin Pharmacol Ther 2004;75:50115.[CrossRef][ISI][Medline]
54 Sai K, Kaniwa N, Itoda M, Saito Y, Hasegawa R, Komamura K, et al. Haplotype analysis of ABCB1/MDR1 blocks in a Japanese population reveals genotype-dependent renal clearance of irinotecan. Pharmacogenetics 2003;13:74157.[CrossRef][ISI][Medline]
55 Xie HG, Wood AJ, Kim RB, Stein CM, Wilkinson GR. Genetic variability in CYP3A5 and its possible consequences. Pharmacogenomics 2004;5:24372.[CrossRef][ISI][Medline]
56 Floyd MD, Gervasini G, Masica AL, Mayo G, George AL Jr, Bhat K, et al. Genotype-phenotype associations for common CYP3A4 and CYP3A5 variants in the basal and induced metabolism of midazolam in European- and African-American men and women. Pharmacogenetics 2003;13:595606.[CrossRef][ISI][Medline]
Manuscript received June 22, 2004; revised August 26, 2004; accepted September 20, 2004.
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