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PHARMACOGENOMICS |
From the Office of Clinical Pharmacology (Dr Ramchandani, Dr Wang, Dr Booth, Dr Rahman, Dr Mehta, Dr Gobburu) and the Office of Oncology Drug Products (Dr Ibrahim, Dr Johnson), Center for Drug Evaluation and Research, Food and Drug Administration (FDA), Silver Spring, Maryland, and the Department of Medicine, Committee on Clinical Pharmacology and Pharmacogenomics and Cancer Research Center, University of Chicago, Chicago, Illinois (Dr Innocenti, Dr Ratain).
Address for reprints: Roshni P. Ramchandani, PhD, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, WO21 Rm 3667, 10903 New Hampshire Ave, Silver Spring, MD 20993; e-mail: roshni.ramchandani{at}fda.hhs.gov.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Irinotecan • SN-38 • neutropenia • UDP-glucuronosyltransferase • genetic polymorphisms
The UGT1 gene is located on chromosome 2 and consists of at least 13 different first exons, each with its own promoter, spliced to common exons 2 to 5, resulting in 9 different isoforms.5,6 Several genetic polymorphisms in the UGT1A1 gene have been reported, with the most extensively evaluated being the variation in the number of TA repeats in the TATA box of the promoter. The presence of 7 TA repeats, instead of the wild-type 6 TA repeats, results in a 70% reduction in transcriptional activity of UGT1A1.7 Patients who are either heterozygous or homozygous for this variant allele (designated as UGT1A1*28) exhibit an attenuated expression of the isozyme. The UGT1A1 isozyme is extremely important in bilirubin glucuronidation, and mutations in UGT1A1 are responsible for mild (Gilbert's syndrome) and severe (Crigler-Najjar syndrome) forms of hyperbilirubinemia.8,9
Patients with the UGT1A1*28 polymorphism have a decreased ability to glucuronidate SN-38,10 resulting in higher SN-38 exposures. This is thought to be associated with an increased risk of severe toxicity, primarily diarrhea and neutropenia. Other recent studies have also suggested a relationship between UGT1A1*28 polymorphism and increased risk of diarrhea, neutropenia, or both.11-14
Innocenti et al15 prospectively examined the effect of irinotecan on the incidence of severe neutropenia in patients who were homozygous for UGT1A1*28 (7/7), compared to patients with the 6/6 and 6/7 genotypes. Sixty-six patients with advanced cancers refractory to other treatments received irinotecan 350 mg/m2 every 3 weeks. There was an overall 9.5% incidence of severe grade 4 neutropenia. Patients with the 7/7 genotype showed a 50% (3 of 6) incidence, whereas patients with the 6/7 genotype showed 12.5% (3 of 24) and 6/6 genotype showed 0% (0 of 29) incidence of severe grade 4 neutropenia. Iyer et al11 investigated the influence of genotype on toxicity in 20 patients receiving 300 mg/m2 every 3 weeks. Patients with the 7/7 genotype showed a higher incidence of severe neutropenia.
In this report, we present the analysis of the combined data from Innocenti et al15 and Iyer et al.11 This analysis, which includes an increased sample size and range of exposures, would allow confirmation of the findings of the 2 individual studies and enable a more reliable estimate of the influence of risk factors, including UGT1A1*28 polymorphism, baseline bilirubin, and SN-38 exposure on reductions in absolute neutrophil counts (ANC) following irinotecan.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Venous blood (7 mL) for pharmacokinetic analysis was collected on day 1 of cycle 1 prior to irinotecan infusion and at 0.5, 1.0, 1.5, 1.67, 1.83, 2.0, 2.25, 2.5, 3.0, 3.5, 5.5, 7.5, 13.5, and 25.5 hours after the start of the infusion. Chromatography and pharmacokinetic analyses were performed, as previously described,11 for concentrations of irinotecan and metabolites SN-38, SN-38 glucuronide (SN-38G), and APC (aminopentanoic acid metabolite formed via CYP3A4-mediated oxidative metabolism). The analytical method used was reverse-phase highperformance liquid chromatography (HPLC) with fluorescence detection. Standard curves were linear within the range of 9.7 to 6180 ng/mL for irinotecan and 4.3 to 778 ng/mL for SN-38. The intra-assay coefficients of variation (%CV) and accuracy were within acceptable limits. At irinotecan concentrations between 15.1 and 2045.8 ng/mL, the %CVs and accuracy ranged from 2.5% to 11.9% and 91.6% to 103.4%, respectively. For SN-38 (range, 4.7-111.6 ng/mL), the %CVs and accuracy varied from 0.8% to 10.2% and 98.5% to 103%, respectively. The interassay reproducibility and accuracy were also within acceptable limits. The %CVs and accuracy for irinotecan (range, 15.1-2045.8 ng/mL) ranged from 0.4% to 4.1% and 92.6% to 102.3%, respectively. For SN-38 (range, 4.7-111.6 ng/mL), the %CVs and accuracy ranged from 0% to 4.0% and 97.3% to 103.6%, respectively. Pharmacokinetic parameters were determined using noncompartmental methods (WinNonlin, Pharsight Corp, Apex, NC). The primary measure of exposure used was the area under the concentration-time curve (AUC) for SN-38 following irinotecan.
The database also included severity grade (National Cancer Institute Common Toxicity Criteria version 2.0) for diarrhea and neutropenia, as well as actual ANC levels at 4 time points: baseline and weeks 1, 2, and 3 following irinotecan administration. The toxicity data (diarrhea, neutropenia) evaluated in the current analysis were based on events observed during the first cycle of treatment.
Model Development
The full data set consisted of 86 patients. Data for 5 patients were excluded from analysis: 1 patient had no individual genotype data, and 4 patients had UGT1A1 alleles (ie, 5 or 8 TA repeats) other than the polymorphism of primary interest (UGT1A1*28).
Characterization of Variability in SN-38 AUC
The effect of the UGT1A1*28 polymorphism and baseline bilirubin levels in explaining the variability in SN-38 AUC following irinotecan was evaluated. Because data for both 300- and 350-mg/m2 doses were used in this analysis, SN-38 AUC normalized to the dose of irinotecan was used in the analysis. Visual examination of the data suggested lognormal distributions of the variables. The Kolmogorov-Smirnov test for normality indicated that the distribution of dosenormalized SN-38 AUC was significantly different from normal. Hence, the data were log-transformed and analyzed using linear regression. Two indicator variables, coded as IS67 and IS77, were defined to evaluate the 3 UGT1A1 genotypes across patients (IS77 = 1 for 7/7 and IS77 = 0 for 6/6 or 6/7; IS67 = 1 for 6/7 and IS67 = 0 for either 6/6 or 7/7). The inclusion of indicator variables for both heterozygotes (6/7) and homozygotes (7/7) would help determine if the effect of the polymorphism is dominant, recessive, or additive.
Initially, univariate analysis was conducted to evaluate each factor (ie, genotype and bilirubin) individually, following which the full model, including both factors, was evaluated (equation (1)).
 | (1) |
where Btot is the baseline bilirubin level, MeanBtot is the mean baseline bilirubin level in the sample, and E0, E77, E67, and EB are the model parameters. E0 is the intercept, and in the full model, it signifies Ln(SN-38 AUC) for a patient with wild-type 6/6 genotype and the mean baseline bilirubin level; E77 and E67 signify the effects of the 7/7 and 6/7 variant genotypes, respectively; and EB signifies the effect of baseline bilirubin levels. For the genotype model, the parameter EB was fixed to 0, and for the bilirubin model, the parameters E77 and E67 were fixed to 0.
Comparison of models was based on the log-likelihood ratio test, coefficient of determination (R2), and visual examination of observed data and predicted values. The level of significance (
) was set at .05. Group differences among genotypes were evaluated using CONTRAST statements in SAS. A Bonferroni correction was applied to multiple comparisons.
Characterization of Exposure-Response Relationship for Decrease in Absolute Neutrophil Counts
In the next stage of the analysis, the effect of predictive factors such as SN-38 AUC, baseline bilirubin levels, and UGT1A1 genotypes on the decrease in ANC (nadir) were examined. Two indicator variables, IS67 and IS77, were defined to evaluate the 3 UGT1A1 genotypes, as described above. Visual examination of these data also suggested lognormal distributions of the variables, with the Kolmogorov-Smirnov test for normality indicating that the distribution of the ANC nadir was significantly different from normal. Hence, linear regression analysis was used on log-transformed data. Initial models using individual predictors were analyzed, following which pairs of independent variables and, ultimately, a full model (equation (2)) incorporating all 3 variables were examined:
 | (2) |
where Btot is the baseline bilirubin level, MeanBtot is the mean baseline bilirubin level in the patients, and E0, ESN-38, E77, E67, and EB are the model parameters. ESN-38 signifies the effect of SN-38 exposure, and the other parameters are as described above. E0 is the intercept, and in the full model, it signifies Ln(ANC) for a patient with the wild-type 6/6 genotype and the mean baseline bilirubin level; E77 and E67 signify the effects of the 7/7 and 6/7 variant genotypes, respectively; and EB signifies the effect of baseline bilirubin levels. For the genotype model, the parameter EB was fixed to 0, and for the bilirubin model, the parameters E77 and E67 were fixed to 0.
Selection of independent variables was based on the log-likelihood ratio test, coefficient of determination (R2), and visual examination of observed data and predicted values. The level of significance () was set at .05. Database management and analysis were conducted using SAS (version 8, SAS Institute, Cary, NC).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The addition of baseline bilirubin to the genotype model resulted in an increase in R2 to .18. However, in this model, UGT1A1 genotype was no longer significant. This could be because of the association between baseline bilirubin levels and the UGT1A1 genotypes. As shown in Figure 2, patients with the 7/7 genotype had significantly higher bilirubin levels, consistent with prior studies.8,9
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Characterization of the Exposure-Response Relationship for Decrease in Absolute Neutrophil Counts
Table II shows the results of model fitting for the ANC nadir following irinotecan. Initial analyses indicated that each of the factors (SN-38 AUC, baseline bilirubin, and the genotypes), tested individually, was a significant predictor of ANC nadir, with SN-38 AUC showing the highest R2 of .37, whereas baseline bilirubin and UGT1A1*28 each showed an R2 of .22.
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The full model incorporating all 3 predictors showed an R2 of .51, although the baseline bilirubin and IS67 indicator variable were not statistically significant (Table II).
Thus, the final model (R2 = .49; intercept = 12.308, SE = .739; P < .0001) included SN-38 AUC (coefficient = -·768, SE = .121; P < .0001) and UGT1A1*28 (coefficient = -·951, SE = .238; P = .0001). Figure 3 shows the ANC nadir versus SN-38 AUC plot for the patients in the data set and the best-fit curves from the final model. The fitted curves indicate that in addition to the SN-38 AUC, patients with the 7/7 genotype had a significant independent effect on the ANC nadir (ie, at the same SN-38 exposure, the 7/7 genotypes show a lower ANC nadir compared with the 6/6 and the 6/7 genotypes).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Evaluation of determinants of SN-38 exposure showed that both baseline bilirubin and UGT1A1 genotypes were significant predictors of SN-38 AUC. In addition, there was a significant, though modest, association (R2 = .17) between the baseline bilirubin and UGT1A1*28. There was substantial variability seen in SN-38 AUCs that was not explained by the UGT1A1 genotype or baseline bilirubin levels, suggesting that these factors alone cannot be used to adequately predict the SN-38 exposure (AUC). The formation of SN-38 from irinotecan occurs predominantly via carboxylesterases in the liver. Hepatic glucuronidation is the major pathway of elimination of SN-38, although a fraction of SN-38 is also transported directly via the ABC transporters into the bile and released into the intestine.10 In the intestine, SN-38 could undergo glucuronidation via intestinal UGT1A isozymes or be excreted unchanged in the feces. These multiple complex pathways can all contribute to the interindividual variability in SN-38 exposure, which might explain why the UGT1A1*28 polymorphism or baseline bilirubin levels explain only a small fraction of the overall variability in SN-38 AUC.
Evaluation of the exposure-response relationship for the decrease in ANC showed significant effects of both SN-38 AUC and the UGT1A1 genotype. An increase in SN-38 AUC and the presence of the UGT1A1 7/7 genotype both resulted in a greater decrease in the ANC nadir. The final model indicated that patients with the 7/7 genotype showed a lower ANC nadir at the same SN-38 AUC compared to the other genotypes. The effect of the UGT1A1 7/7 genotype was found to be significant in addition to the effect of SN-38 exposure, suggesting that the effect of genotype extended beyond the increased exposure seen in these patients. The reasons for this additional genotype effect are unknown and need further examination. In addition, the lack of significant effects for the heterozygous 6/7 genotype group on the ANC nadir suggests that the genotypic effect may be a recessive effect, requiring the presence of both variant alleles to be manifested.
The baseline bilirubin level was also found to be a significant predictor of the maximum decrease in ANC, but only in models that did not include SN-38 AUC. Thus, in the absence of data on SN-38 exposure (eg, prior to initiation of treatment), baseline bilirubin along with the UGT1A1 genotype can be used to predict decreases in ANC.
The final model, which included SN-38 AUC and the UGT1A1 7/7 genotype, explained 49% of the variability in the ANC nadir. Baseline bilirubin levels did not add anything substantial to the model, probably due to the association between baseline bilirubin and UGT1A1 genotype. In the absence of UGT1A1 genotypic information, using the combination of SN-38 AUC and baseline bilirubin explained 44% of the variability in the ANC nadir, and using only SN-38 AUC as the predictor explained 37% of the variability in the ANC nadir. In the absence of information on SN-38 exposure, using a combination of baseline bilirubin and UGT1A1 genotype explained 32% of the variability in the ANC nadir. Using either independent variable individually explained only 22% of the variance in the ANC nadir. This suggests that using both baseline bilirubin and the UGT1A1 genotype was better than using either variable alone in the prediction of the ANC nadir following irinotecan.
The results from this study are consistent with findings from other studies. In a preliminary study with 9 patients, Ando et al16 observed a lower glucuronidation rate of SN-38 in a patient with genotype 7/7 versus those with genotypes 6/7 (n = 1) and 6/6 (n = 7). In a subsequent retrospective and casecontrolled study in 118 Japanese cancer patients, the authors observed a 3.5-fold higher incidence of the UGT1A1*28 allele in patients with severe diarrhea or leucopenia compared with patients without this allele (P < .0001).12 Marcuello et al13 examined the influence of the UGT1A1 polymorphisms on the toxicity profile, response rate, and overall survival in 95 patients with metastatic colorectal cancer treated with an irinotecan-containing regimen. The authors observed severe diarrhea in 7 of 10 (70%) patients homozygous for UGT1A1*28 and 15 of 45 (33%) heterozygous patients in comparison to 7 of 40 (17%) wild-type patients (P = .005). The presence of severe hematological toxicity increased from wild-type patients to UGT1A1*28 homozygous patients, but it did not achieve statistical significance (P = .2). Other variables included in the model but with no statistical significance were age, gender, performance status, pretreatment levels of serum bilirubin, previous surgery or radiotherapy, chemotherapy regimen, and lines of chemotherapy.13 In another study, 75 patients with advanced colorectal cancer treated with irinotecan and 5-FU were evaluated for the UGT1A1*28 polymorphism and mutations in the coding regions.14 Patients were also assessed for both biochemical and clinical evaluation and tolerance to treatment. Frequencies for UGT1A1 genotypes were 41%, 47%, and 9% for wild-type 6/6, heterozygous 6/7, and homozygous 7/7, respectively. Tolerance to treatment decreased with increased number of TA repeats, with 71% of the patients in the 7/7 group showing grade 3/4 toxicity, including neutropenia, compared to 60% of heterozygous 6/7 patients and 32% of wild-type 6/6 patients.
The pharmacogenetic assessment of UGT1A1 polymorphisms was also investigated in 20 patients with several primary malignancies who were treated with irinotecan at a dose of 300 mg/m2 every 3 weeks.11 Circulating levels of SN-38 were higher, and the ratio of plasma concentrations of SN-38G to SN-38 was lower in patients carrying the UGT1A1*28 allele compared to patients with the wild-type allele. In addition, all the patients with wild-type alleles in this small sample had no/low diarrhea or mild leucopenia. Another recent study showed a decrease in the SN-38G/SN-38 AUC ratio, reflecting decreased glucuronidation, with an increase in the number of UGT1A1*28 alleles.17 On the other hand, a study of irinotecan in combination with docetaxel in non-small-cell lung cancer patients failed to show an association between UGT1A1*28 polymorphisms and incidence of toxicity.18
Studies have also evaluated other UGT1A1 polymorphisms on irinotecan disposition and incidence of toxicity. Sai et al19 evaluated several UGT1A1 haplotypes and their association with glucuronidation rates and bilirubin levels in Japanese cancer patients receiving irinotecan. Results indicated that the UGT1A1*28 as well as UGT1A1*6 polymorphisms were associated with lower ratios of SN-38G/SN-38, indicating a reduced glucuronidation and increased total bilirubin levels. Innocenti et al15 evaluated several UGT1A1 polymorphisms in addition to UGT1A1*28 and found an association between the -3156G>A polymorphism and incidence of severe neutropenia in patients receiving irinotecan. A recent study found an association between the -3279G>T polymorphism (in the phenobarbital-responsive enhancer module [PBREM] of the UGT1A1 promoter region), which was in linkage disequilibrium with UGT1A1*28, and the incidence of severe (grade 4) leucopenia and/or severe (grade 3/4) diarrhea in 119 Japanese cancer patients receiving irinotecan.20
The association between UGT1A1 variation and increased incidence of toxicity following irinotecan treatment suggests that knowledge of the UGT1A1*28 polymorphism may help in identifying individuals at increased risk. This is particularly relevant as irinotecan is an important drug in the armamentarium of effective anticancer agents and is used widely in patients for first-line or second-line treatment of colorectal cancers. Based on the current analysis, as well as other published data, the US Food and Drug Administration recommended several changes to the label of irinotecan. These changes include information about the role of UGT1A1 genotypes in the metabolism of irinotecan, the increased risk of severe neutropenia in patients with reduced UGT1A1 activity, and recommendations for a lower starting dose of irinotecan in patients homozygous for the UGT1A1*28 allele.2
The findings from the current prospective study, as well as other studies, provide important information about the quantitative relationship between SN-38 exposure and the ANC nadir, as well as the effect of UGT1A1 polymorphism and baseline bilirubin levels. This model can be used to predict the magnitude of decrease in ANC, which can guide safer dosing regimens of irinotecan. However, we believe that the model could be further refined to have greater predictive power and better clinical utility. The results of this study provide direction for the design of future studies to further elaborate the genotype-exposuretoxicity relationship for irinotecan. Modeling of data collected from ongoing large prospective cooperative group trials as well as other future studies will confirm the effect of SN-38 exposure, UGT1A1*28 genotype, and baseline bilirubin levels on the ANC nadir following irinotecan. This would further help refine dosing adjustments to minimize toxicity in patients with the homozygous 7/7 genotype. These future studies will provide data to extend the model to include other factors that may help researchers understand the variability in SN-38 and irinotecan pharmacokinetics as a result of other genetic polymorphisms in UGT1A1, such as UGT1A1*6 and the PBREM of the UGT1A1 promoter, as well as genetic variation in other metabolizing enzymes (CES2, CYP3A4) and transporters (ABCB1, ABCC1, and ABCG2) involved in the elimination of irinotecan and its metabolites.
The data employed for the current analysis are from definitive studies focused on toxicity and not effectiveness. Although these definitive studies help generate hypotheses to be tested in future trials, such analyses need to be conducted using data collected in large well-controlled registration trials. These analyses can provide valuable insights into the benefit-risk relationship for drugs and lead to a more rational approach to deriving dosing adjustments. Unfortunately, registration trials in general do not plan to collect pharmacokinetic data, limiting the ability to learn about improving the overall therapeutic benefit of a drug regimen.
In conclusion, combined data from 2 trials11,15 that tested different dosing regimens were analyzed to establish the relationship between SN-38 exposure, UGT1A1*28 genotype, and absolute neutrophil counts. The findings from Innocenti et al15 that both genotype and exposure predict toxicity are corroborated by the current combined analysis. The pooled analysis also permitted a more reliable estimation of the risk factors given the increased sample size (n = 86) and exposure range (300 and 350 mg/m2).
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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1. Rothenberg ML. Efficacy and toxicity of irinotecan in patients with colorectal cancer. Semin Oncol. 1998;25: 39-46.[Web of Science][Medline] [Order article via Infotrieve]
2. Camptosar (Irinotecan) Label: Center for Drug Evaluation and Research, US Food and Drug Administration. Available from http://www.fda.gov/cder/foi/label/2005/020571s024,027,028lbl.pdf. Accessed March 6, 2006.
3. Mathijssen RHJ, van Alphen RJ, Verweij J, et al. Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res. 2001;7: 2182-2194.
4. Slatter JG, Su P, Sams JP, Schaaf LJ, Wienkers LC. Bioactivation of the anticancer agent CPT-11 to SN-38 by human hepatic microsomal carboxylesterases and the in vitro assessment of potential drug interactions. Drug Metab Dispos. 1997;25: 1157-1164.
5. Ritter JK, Chen F, Sheen YY, et al. A novel complex locus UGT1 encodes human bilirubin, phenol, and other UDP-glucuronosyltransferase isozymes with identical carboxyl termini. J Biol Chem. 1992;267: 3257-3261.
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8. Monaghan G, Ryan M, Seddon R, Hume R, Burchell B. Genetic variation in bilirubin UPD-glucuronosyltransferase gene promoter and Gilbert's syndrome. Lancet. 1996;347: 578-581.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
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10. Iyer L, King CD, Whitington PF, et al. Genetic predisposition to the metabolism of irinotecan (CPT-11): Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite SN-38 in human liver microsomes. J Clin Invest. 1998;101: 847-854.[Web of Science][Medline] [Order article via Infotrieve]
11. Iyer L, Das S, Janisch L, et al. UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics J. 2002;2: 43-47.[CrossRef][Medline] [Order article via Infotrieve]
12. Ando Y, Ueoka H, Sugiyama T, Ichiki M, Shimokata K, Hasegawa Y. Polymorphisms of UDP-glucuronosyltransferase and pharmacokinetics of irinotecan. Ther Drug Monit. 2002;24: 111-116.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
13. Marcuello E, Altés A, Menoyo A, del Rio E, Gómez-Pardo M, Baiget M. UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer. Br J Cancer. 2004;91: 678-682.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
14. Rouits E, Boisdron-Celle M, Dumont A, Guérin O, Morel A, Gamelin E. Relevance of different UGT1A1 polymorphisms in irinotecan-induced toxicity: a molecular and clinical study of 75 patients. Clin Cancer Res. 2004;10: 5151-5159.
15. Innocenti F, Undevia SD, Iyer L, et al. Genetic variation in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol. 2004;22: 1382-1388.
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17. Paoluzzi L, Singh AS, Price DK, et al. Influence of genetic variants in UGT1A1 and UGT1A9 on the in vivo glucuronidation of SN-38. J Clin Pharmacol. 2004;44: 854-860.
18. Font A, Sanchez JM, Taron M, et al. Weekly regimen of irinotecan/docetaxel in previously treated non-small cell lung cancer patients and correlation with uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) polymorphism. Invest New Drugs. 2003;21: 435-443.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
19. Sai K, Saeki M, Saito Y, et al. UGT1A1 haplotypes associated with reduced glucuronidation and increased serum bilirubin in irinotecan-administered Japanese patients with cancer. Clin Pharmacol Ther. 2004;75: 501-515.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
20. Kitagawa C, Ando M, Ando Y, et al. Genetic polymorphism in the phenobarbital-responsive enhancer module of the UDP-glucuronosyltransferase 1A1 gene and irinotecan toxicity. Pharmacogenet Genomics. 2005;15: 35-41.[Medline]
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