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Journal of Clinical Oncology, Vol 25, No 18 (June 20), 2007: pp. 2594-2600 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.2301 UGT1A1 Promoter Genotype Correlates With SN-38 Pharmacokinetics, but Not Severe Toxicity in Patients Receiving Low-Dose Irinotecan
From the Departments of Pharmaceutical Sciences, Oncology, and Biostatistics, St Jude Children's Research Hospital, Memphis, TN Address reprint requests to Clinton F. Stewart, PharmD, Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 332 North Lauderdale, Mail Stop 313, Memphis, TN 38105; e-mail: clinton.stewart{at}stjude.org
Purpose To study the association between UDP-glucuronosyltransferase 1A1 (UGT1A1) genotypes and severe toxicity as well as irinotecan disposition in pediatric patients with solid tumors receiving low-dose, protracted irinotecan (15 to 75 mg/m2 daily for 5 days for 2 consecutive weeks). Patients and Methods Seventy-four patients on five institutional clinical trials received irinotecan (15 to 75 mg/m2) daily intravenously or orally for 5 days for 2 consecutive weeks. Genomic DNA was genotyped for UGT1A1*28, and patients were designated as 6/6, 6/7, or 7/7 depending on the number of TA repeats in the UGT1A1 promoter region. Patients were evaluated for gastrointestinal and hematologic toxicity, as well as baseline and maximal serum bilirubin levels. Toxicity and pharmacokinetic results were evaluated during courses 1 and 2 of irinotecan therapy. Results The frequencies of 6/6, 6/7, and 7/7 genotypes were 27 (36.5%), 36 (48.6%), and 9 (12.2%) of 74 patients, respectively. Patients with 7/7 genotype had a statistically greater baseline total bilirubin than patients with 6/6 or 6/7 genotype (P = .005). UGT1A1*28 genotype was not associated with grade 3 and 4 neutropenia (P = .21 for course 1; P = .23 for course 2) or diarrhea (P = .176 for course 1; P = .87 for course 2). However, patients with the 7/7 genotype tended to have higher SN-38 area under the plasma time-concentration curve (AUC) values and lower SN-38G/SN-38 AUC ratios. Conclusion Severe toxicity was not increased in pediatric patients with the 7/7 genotype when treated with a low-dose protracted schedule of irinotecan. Therefore, UGT1A1 genotyping is not a useful prognostic indicator of severe toxicity for patients treated with this irinotecan dosage and schedule.
Irinotecan, which is currently approved by the US Food and Drug Administration (FDA) for the treatment of metastatic cancer of the colon or rectum, has shown promising antitumor activity in several pediatric solid malignancies.1-5 The most common administration schedule used to treat pediatric solid malignancies is based on preclinical studies showing the schedule-dependent activity of irinotecan in human tumor xenografts.6 In this clinical setting, irinotecan is administered at low-dosages on a protracted schedule (eg, 20 mg/m2 daily for 5 consecutive days for each of 2 consecutive weeks (once daily x 5 x 2).2,3,7 The disposition of irinotecan is a complex process involving numerous metabolic steps and efflux by active transporters.8-11 The initial step in irinotecan metabolism is de-esterification by carboxylesterase to the active metabolite, SN-38.12 Irinotecan also undergoes oxidation to APC and NPC, which is catalyzed by cytochrome P450 3A4 enzyme. The majority of irinotecan and its metabolites are excreted in the bile. SN-38 biliary excretion is enhanced by the formation of SN-38 glucuronide (SN-38G), which is catalyzed primarily by the enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1).13 UGT1A1 catalyzes transfer of a glucuronic acid moiety from the cofactor uridine diphosphoglucuronic acid (UDPGA) to bilirubin and insoluble xenobiotics (eg, SN-38). This reaction results in a glucuronidated product that is often inactive and more easily eliminated in the urine or bile. Genetic variation in the UGT1A1 gene has been extensively reviewed.14-16 The UGT1A1*28 polymorphism is due to a change in the number of TA repeats in the TATA box of the UGT1A1 promoter from the wild-type 6 repeats to the variant 7 repeats. The overall range of TA repeats is 5 to 8. Approximately 7% to 19% of the white population is homozygous (7/7) for the variant allele, which leads to reduced enzyme expression.14 Gilbert's syndrome, a mild form of unconjugated hyperbilirubinemia with no apparent pathological consequences, is associated with the UGT1A1*28 genotype.17,18 Although Gilbert's syndrome is considered benign, various factors such as stress, physical exercise, menstruation, and infection can lead to serum bilirubin concentrations that are elevated three- to four-fold.19,20 Several groups found that when patients with the UGT1A1*28 genotype are administered high-dosage irinotecan, they have altered SN-38 glucuronidation, and increased toxicities are observed.21-25 In 2005, based on the findings of these groups, the FDA added a warning to the irinotecan packaging label indicating that patients with the UGT1A1*28 genotype were at increased risk for neutropenia and that a reduced initial irinotecan dosage should be considered. However, nothing has been published regarding the relation between UGT1A1 genotype and irinotecan-induced toxicities in patients receiving protracted, low-dosage irinotecan. Thus, the primary objective of the present study was to study the association between the UGT1A1*28 genotype and severe toxicity as well as irinotecan disposition in pediatric patients with solid tumors receiving low-dose, protracted irinotecan.
Study Design and Treatment Patients were included in this study if adequate DNA was available for UGT1A1 genotyping, complete toxicity data were available from a retrospective chart review, and at least one full course of irinotecan therapy was completed on one of five institutional clinical trials (Table 1). These included two phase II clinical trials in children newly diagnosed with colorectal cancer and high-grade glioma.26 The other three studies were phase I clinical trials in previously treated patients with relapsed or refractory disease.3 Eligibility criteria for all studies included grade 2 or less elevation of hepatic enzymes and bilirubin. All patients received irinotecan daily for 5 consecutive days for each of 2 consecutive weeks (daily x 5 x 2). St. Jude Children's Research Hospital institutional review board approved all clinical trials, as well as the subsequent chart review to record toxicity data. The chart review was performed by one of the authors (L.M.M.) who was blinded to the genotype results.
Drug Administration Irinotecan (Camptosar; Pfizer Oncology, Pfizer, New York, NY) was administered as an intravenous infusion to all patients in studies 1, 2, and 4 (Table 1). In study 3, irinotecan was administered orally except for one intravenous dose, and in study 5, all irinotecan doses were intravenous except for one oral dose. Irinotecan was administered at a dosage of 20 mg/m2/d in studies 1 and 4. The irinotecan dosage was escalated within studies 2, 3, and 5 (Table 1). Irinotecan was diluted (5% dextrose or 0.9% sodium chloride to 0.12 to 2.8 mg/mL) and infused intravenously over 60 minutes or reconstituted (normal saline or 5% dextrose) then mixed with cranberry-grape juice for immediate oral use. All protocols stipulated that patients should receive atropine at 0.01 mg/kg (0.4 mg) intravenously for symptoms of acute cholinergic syndrome, and loperamide at the first indication of diarrhea.3,26
Evaluation of Clinical Toxicity
UGT1A1 Genotyping
Pharmacokinetic Studies
Pharmacokinetic Analysis
The relation between UGT1A1 genotype and irinotecan pharmacokinetics was determined using the two-stage approach for population pharmacokinetics.31 First, the irinotecan and SN-38 pharmacokinetic parameters for each individual were estimated for each course using the previously described methods. Second, the population pharmacokinetics and covariates were analyzed using linear mixed-effects modeling as implemented in S-Plus version 3.3 (Statistical Sciences, Seattle, WA).
 1 is the logarithm of the population mean parameter, k are the coefficients that describe the effects for each covariate, and  and  represent the interpatient and intrapatient (residual) variability, both of which are assumed to have zero mean. Covariate effects (UGT1A1 genotype, sex, and concomitant drug use) were investigated for their ability to significantly improve the model fit (as determined by a reduction of 3.84 (P < .05) in the negative 2 log-likelihood, based on the F test).
Statistical Analysis
Patients A total of 74 patients with UGT1A1 genotyping results and complete toxicity data were included in this retrospective analysis. All patients received all planned doses of irinotecan for each course on one of five institutional clinical trials (Table 1). All patients had a baseline serum albumin of at least 3.2 g/dL. Their characteristics, concomitant drug therapy, and genotype frequencies are summarized in Table 2. The allelic frequencies were 0.014, 0.614, and 0.372 for 5, 6, and 7 TA repeats, respectively. The 5/6 and 5/7 genotypes were observed in only one patient each and, thus, were omitted from further genotype-phenotype analyses.
UGT1A1 Genotype and Total Bilirubin As UGT1A1 catalyzes the glucuronidation and detoxification of bilirubin, the relationship between UGT1A1 genotype and baseline and highest total bilirubin levels during course 1 was compared. For course 1, patients with the 7/7 genotype had higher baseline bilirubin values than patients with 6/6 or 6/7 genotypes (P = .005). The median and range baseline bilirubin by genotype are shown in Table 3. The highest total bilirubin level during course 1 differed by genotype (Table 3; P = .044). Total bilirubin levels for patients with the 5/6 and 5/7 genotypes were not included in this analysis, but were 0.4 and 0.6 mg/dL, respectively.
UGT1A1 Genotype and Irinotecan Pharmacokinetics Of 74 patients with UGT1A1 genotype data and irinotecan toxicity available, 70 consented to participate in irinotecan pharmacokinetic studies. Of these 70 patients, 15 were on clinical trials in which they received concomitant gefitinib, whereas another 16 were on clinical trials in which they were treated with a concomitant cephalosporin (Table 2). For the purposes of analyzing the relation between UGT1A1 genotype and irinotecan pharmacokinetics, only the results of the intravenous dose pharmacokinetics were used. Depicted in Figure 1 are the irinotecan, SN-38, and SN-38G lactone plasma concentration-time data for patients who received intravenous irinotecan at 20 mg/m2/d.
The results of the pharmacokinetic analysis of irinotecan and metabolites, SN-38, and SN-38G are summarized in Table 4. A total of 37 patients received irinotecan at 20 mg/m2/d, and in those patients the population average SN-38 lactone AUC was not statistically different among the genotype groups (P = .5). Since inferences regarding SN-38 are often based on total (ie, combination of the active lactone and inactive carboxylate forms), a subset of these samples (n = 31 patients) were analyzed for total SN-38 and SN-38G. The population average SN-38 total AUC trended higher in patients with the 7/7 genotype. The SN-38 total AUC values were 27 ng/mL x hour (range, 12 to 80), 30 ng/mL x hour (range, 14 to 69), and 40 ng/mL (range, 15 to 127) for 6/6, 6/7, and 7/7 genotypes, respectively (P = .19). The SN-38G/SN-38 ratio was not statistically different among the genotype groups. SN-38G lactone and total AUC did not show any difference related to UGT1A1 genotype (P > .5). After accounting for the significant covariates of sex and dosage, the SN-38/irinotecan ratio was directly related to the number of TA7 alleles (P = .03).
Toxicity Based on prior clinical experience with low-dose irinotecan administered on a protracted schedule, myelosuppression has not been a dose-limiting toxicity. In the present study, eight patients during each of the two courses evaluated experienced grade 3 or 4 neutropenia with a median time to onset of 13 days (range, 4 to 20 days) and a median duration of 4 days (range, 1 to 12 days). As noted in Table 5, no association was found between UGT1A1 genotype and neutropenia. Grade 3 or 4 neutropenia did not develop in any of the patients homozygous for UGT1A1*28 or in the patients with genotypes of 5/7 and 5/6. Administration of a cephalosporin antibiotic was not associated with an increased risk of neutropenia (P = .52; GEE model). However, gefitinib coadministration was associated with an increased risk of developing grade 3 or 4 neutropenia (odds ratio, 5.88; 95% CI, 1.68 to 20.60; P = .006).
Severe diarrhea (grade 3 or 4) occurred in 13 patients (18%), and 7 patients (12%) during courses 1 and 2 of therapy, respectively, with a median time to onset of 11 days (range, 5 to 17 days) and a median duration of 4 days (range, 1 to 17 days). No association was found between UGT1A1*28 genotype and grade 3 or 4 diarrhea in our patient population (Table 5). Two patients with the 5/7 or 5/6 genotype were not included in this statistical analysis. However, grade 3 or 4 diarrhea was not observed in the patient with the 5/7 genotype, and diarrhea could not be accurately assessed in the patient with a 5/6 genotype due to noncompliance with loperamide treatment. Grade 3 or 4 diarrhea was not increased in patients receiving gefitinib (P = .11; GEE model) or a cephalosporin antibiotic (P = .66; GEE model). The two patients who were not assessable for gastrointestinal toxicity in course 1 (one patient with rotavirus and one who failed to comply with loperamide therapy) were excluded from the GEE model. These two patients had genotypes of 6/6 and 5/6, respectively.
Although the relation between UGT1A1 genotype and irinotecan toxicity has been widely reported in patients receiving irinotecan as a single high dosage,21-25 this is the first report of the lack of a relation in patients receiving low-dosage irinotecan on a protracted schedule. Although this study was conducted in pediatric patients, the same observation would likely occur in adults treated similarly as the observation of increased toxicity in patients with the UGT1A1*28 genotype was most likely related to the high one-time SN-38 exposure. Thus, based on data presented in this study, the recent FDA recommendations to genotype and consider a dosage adjustment in irinotecan for patients homozygous for UGT1A1*28 is not relevant to patients treated with low-dosage irinotecan. Numerous reviews and commentaries have summarized the data supporting the role that pharmacogenomics, specifically UGT1A1*28 genotype, has in predicting toxicity associated with irinotecan therapy.32-36 As stated previously, the design for the present study was different from previously published studies, with regards to the irinotecan dosage and schedule. However, the relationship between UGT1A1 genotype and serum bilirubin found in this study was consistent with previous reports.21,25 Likewise, an increased SN-38 AUC as well as a decreased SN-38G/SN-38 AUC ratio were noted in patients with the 7/7 genotype, which coincides with other studies.21,22,37 However, in our patient population receiving low-dose irinotecan, these findings did not translate to a genetic marker that would help identify patients at risk for increased toxicity. As noted by Innocenti et al,21 identifying patients at high risk for developing severe toxicity after irinotecan therapy was a crucial factor to improving the therapeutic index for this important anticancer agent. For the patients in the present study, UGT1A1 genotype was not a significant single predictor for irinotecan toxicity. Moreover, given that only one severe toxicity event occurred in a patient with the 7/7 genotype, the use of multiple regression analysis with other relevant predictive factors (eg, total bilirubin) would not be valid. Hence, other factors must be studied to identify patients at risk for severe toxicity even when treated with low-dosage irinotecan. While the vast majority of patients receive irinotecan as a single high dosage (eg, 350 mg/m2) once a month, other dosages and schedules of irinotecan administration are also used. Many patients receive lower irinotecan dosages (eg, 100 mg/m2/d) when administered in combination with other anticancer drugs.25,38,39 In addition, results of recent studies have shown that irinotecan can be administered orally.3,40,41 Several new schedules of irinotecan administration or dosage formulations (eg, nanoliposomal) are currently under investigation, which would provide an alternative to the single high dosage once a month.42-44 Lastly, although irinotecan can be administered at a lower dosage (eg, 50 mg/m2/d) on less-frequent schedules (eg, daily x 5),45 studies have suggested that even with this regimen UGT1A1 genotype does not predict for severe toxicity.46 The results of this study and the present one strongly suggest that each regimen should be individually considered with regard to the impact of UGT1A1 genotype on the risk of toxicity. A recent commentary in the Journal of Clinical Oncology very clearly summarized the relation between UGT1A1 genotype and toxicity of irinotecan-containing regimens.47 The authors of that commentary asked a series of clinically relevant questions beginning with: should every patient receiving irinotecan for the first time be considered for UGT1A1 genotyping? Although the authors indicated that all patients should be genotyped, they did acknowledge the limitations to the testing. Specifically, they indicated that not all patients with the variant genotype will have toxicities, and conversely, patients with the wild-type genotype will have severe toxicities. The results of the present study would add to this list of limitations. Clearly, our results would suggest that the dosage and schedule of irinotecan would affect how a patient with the variant genotype will tolerate irinotecan therapy. In summary, the results of this study have shown that severe toxicity after irinotecan therapy was not increased in pediatric patients with the 7/7 genotype when treated with a low-dose protracted schedule of irinotecan. Thus, with this dose and schedule, it is questionable whether UGT1A1 genotyping is a useful means to identify patients at risk for increased toxicity from irinotecan therapy.
Although all authors completed the disclosure declaration, the following authors or their immediate family members 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. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: N/A Research Funds: Wayne L. Furman, AstraZeneca, Pfizer; Lisa M. McGregor, AstraZeneca Testimony: N/A Other: N/A
Conception and design: Clinton F. Stewart, Wayne L. Furman, Lisa M. McGregor Administrative support: Clinton F. Stewart Provision of study materials or patients: Carlos Rodriguez-Galindo, Amar Gajjar, Wayne L. Furman Collection and assembly of data: Clinton F. Stewart, Melinda A. O'Shaughnessy, Stacy L. Throm, Charles H. Fraga, Thandranese Owens, Wayne L. Furman, Lisa M. McGregor Data analysis and interpretation: Clinton F. Stewart, John C. Panetta, Melinda A. O'Shaughnessy, Stacy L. Throm, Charles H. Fraga, Thandranese Owens, Tiebin Liu, Catherine Billups, Wayne L. Furman, Lisa M. McGregor Manuscript writing: Clinton F. Stewart, John C. Panetta, Melinda A. O'Shaughnessy, Stacy L. Throm, Charles H. Fraga, Thandranese Owens, Tiebin Liu, Catherine Billups, Carlos Rodriguez-Galindo, Amar Gajjar, Lisa M. McGregor Final approval of manuscript: Clinton F. Stewart, John C. Panetta, Melinda A. O'Shaughnessy, Stacy L. Throm, Charles H. Fraga, Thandranese Owens, Tiebin Liu, Catherine Billups, Carlos Rodriguez-Galindo, Amar Gajjar, Wayne L. Furman, Lisa M. McGregor
We acknowledge the contributions of Kristine Crews, PharmD, in study design and Paula Condy, Margaret Edwards, Lisa Walters, Teri Kuehner, and Sheri Ring for assistance in obtaining plasma samples. We also acknowledge the technical contributions of the Hartwell Center at St Jude Children's Research Hospital.
Supported by US Public Health Service Childhood Solid Tumor Program Grant No. CA23099, Cancer Center Support (CORE) Grant No. CA21765, and by American Lebanese Syrian Associated Charities. AstraZeneca Pharmaceuticals provided support for the conduct of the gefitinib clinical trial. Preliminary data were presented at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test, respectively. To account for toxicity during multiple courses within the same patient, the Generalized Estimating Equation (GEE) method was used. Using this approach, the association between concomitant drug use and grade 3 or 4 diarrhea or neutropenia during courses 1 and 2 of irinotecan therapy was analyzed. Odds ratios were estimated with a 95% CI. Statistical significance was set at P < .05. SAS version 9.1 (SAS Institute, Cary, NC) and StatXact version 5 (CYTEL Software Corp, Cambridge, MA) software were used to perform the statistical analysis. 
