|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2005.09.927 on January 18 2005 © 2005 American Society of Clinical Oncology.
Role of Cytochrome P450 Phenotyping in Cancer TreatmentDepartment of Medicine, Division of Hematology/Oncology and Gastroenterology, and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC It is remarkable that cancer chemotherapies, with generally narrow therapeutic windows and possibilities for life-threatening toxicities, are usually dosed according to body-surface area (BSA). The appropriateness of BSA-based dosing has been challenged,1 but it remains ingrained in clinical oncology practice. The continued use of BSA dosing is understandable, as it applies a precise calculation to an intuitively obvious notion that to optimize treatment, larger patients should receive more drug than smaller patients. Moreover, there is no validated substitute for BSA-based dosing for most chemotherapy regimens. However, the emerging field of pharmacogenetics promises to change this situation. Interindividual variability in toxicity and therapeutic response is frequently observed, leading to potentially lethal consequences of cancer treatment. Variability in response may be due to a combination of tumor- and host-related factors. Variability in chemotherapy-associated toxicity is a host-related phenomenon that is largely a consequence of variability in absorption and distribution, and particularly of metabolism and clearance. There is a high degree of interindividual variability in the systemic clearance of many chemotherapeutic agents, primarily reflecting differences in rates of hepatic drug metabolism. The cytochrome P450 (CYP) system catalyzes the rate-limiting step in the overall metabolism and subsequent elimination of many drugs and is known to be involved in the metabolism of many anticancer drugs including ifosfamide, cyclophosphamide, etoposide, paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, and tamoxifen.2,3 The search for functional polymorphisms in the CYP genes, with the goal of using an individual patient's genotype to guide dosing, is an intense area of research interest. Although this is clearly an important area of investigation, there are factors that may limit the utility of CYP genotyping in the cancer population. CYP activity can be significantly affected by nongenetic factors, such as nutritional status, the presence of inflammatory conditions, concomitant medications that can induce or inhibit activity, and concomitant liver disease or hepatic metastases. To address the anticipated shortcomings of CYP genotyping, a growing area of research is the development of tests capable of determining patients' activity or "phenotype" for specific CYPs. CYP3A4 is generally the most abundant CYP present in the human liver and seems to be the most important in drug metabolism.2 There is marked interindividual variation in CYP3A4 activity that cannot be explained by identified genetic polymorphisms.4 Furthermore, CYP3A4 activity is particularly prone to either inhibition or induction by concomitantly administered medications. CYP3A4 would therefore seem to be an ideal candidate for a phenotype test that would predict the potential for toxicity and allow individualized dose adjustments to be made. CYP3A4 is not appreciably expressed in blood cells, so it is not possible to use a blood-based test to determine phenotype. An alternative approach is to measure the clearance, or a surrogate of clearance, of a drug whose elimination is known to be CYP3A4 dependent. The ideal "probe" should be exclusively metabolized by the enzyme in question and safely and easily administered to patients. Its clearance should be estimated by assay of a single sample of blood, urine, saliva, or breath, with quickly available results.5,6 Several probe-based tests for CYP3A4 activity have been described.7 The first suggestion that a probe-based test of CYP3A4 activity might predict clearance of a chemotherapeutic agent was the report8 that the Erythromycin Breath Test (ERMBT) result correlated significantly with clearance of docetaxel, a known substrate for CYP3A4. The ERMBT is based on the observation that CYP3A4 demethylates erythromycin, and the carbon in the methyl group is exhaled as CO2. A subject is administered a trace amount of 14C-N-methyl erythromycin (3 µCi), and CYP3A4 activity is estimated based on label collected in exhaled breath. This correlation between docetaxel clearance and the ERMBT result has been subsequently confirmed.9,10 Measures of CYP3A4 activity using three other probes, midazolam,11 dexamethasone,12 and urinary cortisol13 have also been shown to correlate with docetaxel clearance. These studies confirm that variation in CYP3A4 activity as assessed by probes is an important determinant of the disposition of docetaxel. But is knowledge of an individual's CYP3A activity really clinically useful? In this issue of the Journal of Clinical Oncology, Yamamoto et al14 present the first report of a prospective study evaluating the utility of CYP3A4 phenotyping in individualizing dosing of chemotherapy. In a prior study of 30 patients with non-small-cell lung cancer,13 the authors established that the clearance of docetaxel correlates quite well with a measurement of CYP3A4 activity that uses hydrocortisone as a probe. In this test, a 300-mg dose of hydrocortisone (cortisol) is intravenously administered, and CYP3A4 activity is inferred from the amount of 6-beta-hydroxycortisol (6-ß-OHF) excreted in urine throughout the next 24 hours. Using multivariable linear regression, they derived a formula for predicting docetaxel clearance that incorporated total 24-hour urinary 6-ß-OHF, alpha1-acid glycoprotein (AAG), AST and patient age, which they propose might be useful in individualizing dosing with docetaxel.13 In the current trial,14 the authors randomly assigned patients to receive a dose of docetaxel calculated by their model to achieve a specific target area under the curve (AUC) or a standard BSA-based dose. They enrolled 59 patients onto the study, and with more than 25 patients per arm, they had a 91% power to detect a 50% reduction in variability in AUC (as represented by a smaller standard deviation). They found that their predictive model did significantly decrease inter-patient variability in AUC relative to the BSA-dosed arm. Although the study was not powered to detect differences in pharmacodynamic end points, fewer patients in the individualized dosing arm, as compared with the BSA-based arm, experienced grade 3-4 neutropenia (86% v 93%). Interpatient variability in the proportionate decrease in absolute neutrophil count was also smaller in the individualized dosing arm. However, these differences were small and not statistically significant. What is the future of CYP phenotyping in clinical oncology? One clear limitation of this approach is that it will be useful only to the extent that pharmacokinetics determines important clinical end points. As the authors point out, no correlation has yet been found between docetaxel AUC and antitumor response. And while toxicity may correlate with docetaxel clearance or AUC,8,15 the pharmacokinetic/pharmacodynamic relationship is neither as clear nor as straightforward for all chemotherapy regimens. CYP phenotyping may have broader use in identifying outliers who currently fare poorly with BSA-based regimens. For example, in the Hirth et al study,8 there were two patients with very low breath test results who developed severe neutropenia and sepsis requiring hospitalization. These patients were not identified as being different by any standard clinical or laboratory data. Oncologists might therefore embrace pharmacogenetic tests for screening alone if they were simple, low-cost, widely available, and easily administered, in order to avoid severe unanticipated toxicity in even a few patients. The hydrocortisone technique used by Yamamoto et al is not ideal, as it requires a 24-hour urine collection. Similarly, the two most widely used CYP3A4 probe-based tests have drawbacks—the midazolam test requires pharmacologically active doses of this benzodiazepine, and the ERMBT requires a radioisotope. Until simpler and more rapid tests become commercially available, phenotyping may remain largely a research tool, or one with applicability limited to special populations likely to have significantly abnormal CYP3A4 activity, particularly those patients who are suspected to have liver disease, declining hepatic function, or who may be receiving inducers or inhibitors of CYP3A4. Baker et al10 have recently reported that CYP3A4 activity as measured by ERMBT was an important predictor of docetaxel clearance in patients with liver dysfunction (R2 = 0.79), most of whom would have been empirically dose reduced or not treated with docetaxel. The patients in the Yamamoto et al study had near-normal liver functions. Had they treated a population of patients with impaired liver function, in which the variability of docetaxel clearance would have been even more striking, clinically important differences might have been discerned. The report of Yamamoto et al14 represents an important contribution to the field of pharmacogenetics, and particularly CYP phenotyping. This is, to our knowledge, the first prospective study comparing individualized dosing of chemotherapy based on CYP phenotype to standard dosing. Yamamato et al have demonstrated that individualized dosing based on knowledge of CYP3A4 phenotype can reduce interpatient variability in systemic exposure to docetaxel relative to BSA-based dosing. However, the major issues for this and other CYP phenotyping techniques remain the same: In what patient population will phenotyping be clinically relevant, and can we develop probe-based tests that are easy to translate into the average outpatient oncology clinical setting? With refinement, pharmacogenetically based drug dosing holds great promise for optimizing doses of chemotherapy drugs or drug regimens to provide biologically active doses tailored to an individual's ability to metabolize administered agents to maximize efficacy and minimize toxicity. Authors' Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Stock Ownership: Paul B. Watkins, Metabolic Solutions Inc. For a detailed description of this category, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration form and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue. REFERENCES 1. Ratain MJ: Body-surface area as a basis for dosing of anticancer agents: Science, myth or habit? J Clin Oncol 16:2297-2298, 1998[Medline]
2. Evans WE, Relling MV: Pharmacogenomics: Translating functional genomics into rational therapeutics. Science 286:487-491, 1999 3. Vermes A, Guchelaar HJ, Koopmans RP: Individualization of cancer therapy based on cytochrome P450 polymorphism: A pharmacogenetic approach. Cancer Treat Rev 23:321-339, 1997[CrossRef][Medline] 4. Lamba JK, Lin YS, Schuetz EG, et al: Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev 54:1271-1294, 2002[CrossRef][Medline] 5. Watkins PB: Noninvasive tests of CYP3A enzymes. Pharmacogenetics 4:171-184, 1994[Medline]
6. Stewart CF, Schuetz EG: Need and potential for predictive tests of hepatic metabolism of anticancer drugs. Clin Cancer Res 6:3391-3392, 2000 7. Streetman DS, Bertino JS, Nafziger AN: Phenotyping of drug-metabolizing enzymes in adults: A review of in vivo cytochrome P450 phenotyping probes. Pharmacogenetics 10:187-216, 2000[CrossRef][Medline]
8. Hirth J, Watkins PB, Strawderman M, et al: The effect of an individual's cytochrome CYP3A4 activity on docetaxel clearance. Clin Cancer Res 6:1255-1258, 2000 9. Slaviero KA, Clarke SJ, MacLachlan AJ, et al: Population pharmacokinetics of weekly docetaxel in patients with advanced cancer. Br J Clin Pharmacol 57:44-53, 2004[CrossRef][Medline] 10. Baker SD, tenTije AJ, Carducci MA, et al: Evaluation of CYP 3A activity as a predictive covariate for docetaxel clearance. Proc Am Soc Clin Oncol 23:128s, 2004 (abstr 2006)
11. Goh B, Lee S, Wang LF, et al: Explaining interindividual variability of docetaxel pharmacokinetics and pharmacodynamics in Asians through phenotyping and genotyping strategies. J Clin Oncol 20:3683-3690, 2002 12. Puisset F, Chatelut E, Dalenc F, et al: Dexamethasone as a probe for docetaxel clearance. Cancer Chemother Pharmacol 54:265-272, 2004[Medline]
13. Yamamoto N, Tamura T, Kamiya Y, et al: Correlation between docetaxel clearance and extimated cytochrome P450 activity by urinary metabolite of exogenous cortisol. J Clin Oncol 18:2301-2308, 2000
14. Yamamoto N, Tamura T, Murakami H, et al: Randomized pharmacokinetic and pharmacodynamic study of docetaxel; body surface area based dosing versus individualized dosing based on cytochrome p450 activity estimated using a urinary metabolite of exogenous cortisol. J Clin Oncol 23:1061-1069, 2005
15. Extra JM, Rousseau F, Bruno R, et al: Phase I and pharmacokinetic study of Taxotere (RP 56976) given as a short intravenous infusion. Cancer Res 53:1037-1042, 1993
Related Article
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
