Prediction of Irinotecan Pharmacokinetics by Use of Cytochrome P450 3A4 Phenotyping Probes

Uppsala University, Uppsala, Uppsala, Sweden
Journal of the National Cancer Institute (Impact Factor: 12.58). 11/2004; 96(21):1585-92. DOI: 10.1093/jnci/djh298
Source: PubMed


Irinotecan is a topoisomerase I inhibitor that has been approved for use as a first- and second-line treatment for colorectal cancer. The response to irinotecan is variable, possibly because of interindividual variation in the expression of the enzymes that metabolize irinotecan, including cytochrome P450 3A4 (CYP3A4) and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). We prospectively explored the relationships between CYP3A phenotype, as assessed by erythromycin metabolism and midazolam clearance, and the metabolism of irinotecan and its active metabolite SN-38.
Of the 30 white cancer patients, 27 received at least two treatments with irinotecan administered as one 90-minute infusion (dose, 600 mg) with 3 weeks between treatments, and three received only one treatment. Before the first and second treatments, patients underwent an erythromycin breath test and a midazolam clearance test as phenotyping probes for CYP3A4. Erythromycin metabolism was assessed as the area under the curve for the flux of radioactivity in exhaled CO2 within 40 minutes after administration of [N-methyl-14C]erythromycin. Midazolam and irinotecan were measured by high-performance liquid chromatography. Genomic DNA was isolated from blood and screened for genetic variants in CYP3A4 and UGT1A1. All statistical tests were two-sided.
CYP3A4 activity varied sevenfold (range = 0.223%-1.53% of dose) among patients, whereas midazolam clearance varied fourfold (range = 262-1012 mL/min), although intraindividual variation was small. Erythromycin metabolism was not statistically significantly associated with irinotecan clearance (P = .090), whereas midazolam clearance was highly correlated with irinotecan clearance (r = .745, P<.001). In addition, the presence of a UGT1A1 variant with a (TA)7 repeat in the promoter (UGT1A1*28) was associated with increased exposure to SN-38 (435 ng x h/mL, 95% confidence interval [CI] = 339 to 531 ng x h/mL in patients who are homozygous for wild-type UGT1A1; 631 ng x h/mL, 95% CI = 499 to 762 ng . h/mL in heterozygous patients; and 1343 ng x h/mL, 95% CI = 0 to 4181 ng x h/mL in patients who are homozygous for UGT1A1*28) (P = .006).
CYP3A4 phenotype, as assessed by midazolam clearance, is statistically significantly associated with irinotecan pharmacokinetics. Evaluation of midazolam clearance combined with UGT1A1*28 genotyping may assist with optimization of irinotecan chemotherapy.

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    • "Hence, better molecular markers to identify patients at risk for complications, including severe diarrhea, as well as to predict clinical response would be helpful to patients and medical oncologists. Currently, pharmacogenetic data suggest that the UGT1A1*28/*28 genotype confers the highest risk of severe neutropenia due to increased exposure to SN-38 (Ando et al., 2000; Iyer et al., 2002; Innocenti et al., 2004; Marcuello et al., 2004; Mathijssen et al., 2004; Rouits et al., 2004; de Jong et al., 2006; Massacesi et al., 2006; McLeod et al., 2006; Pillot et al., 2006; Toffoli et al., 2006; Cote et al., 2007; Hoskins et al., 2007; Kweekel et al., 2008; Ruzzo et al., 2008; Glimelius et al., 2011). Our current study confirms that this genotype is associated with an increased risk of severe neutropenia but in univariate analyses only, whereas a more comprehensive analysis of variations at the UGT1A locus suggests that other markers in the central region of the gene and in the 39UTR region might better predict this toxicity. "
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    ABSTRACT: Background: Despite the importance of UGT1A1*28 in irinotecan pharmacogenetics, our capability to predict drug-induced severe toxicity remains limited. Objective: To identify potential new molecular markers of irinotecan toxicity and response in advanced colorectal cancer patients treated with FOLFIRI-based regimens. Approach: The relationships between UGT1A candidate markers across the gene (n=21), toxicity were prospectively evaluated in 167 patients. We included variants in the 3'UTR region never studied in this context, which were further studied in 250 Italian FOLFIRI-treated patients. Results: Several functional UGT1A variants including UGT1A1*28 significantly influenced risk of severe hematological toxicity. As previously reported in the Italian cohort, a 5-markers risk haplotype (HII; UGTs 1A9/1A7/1A1) was associated with severe neutropenia in our cohort (OR=2.43; p=0.004). The inclusion of a 3'UTR SNP allowed to refine the previously defined HI, in which HIa was associatd with the absence of severe neutropenia in combined cohorts (OR=0.55; p=0.038). Among all tested UGT1A variations and upon multivariate analyses, no UGT1A1 SNPs remained significant, whereas three SNPs located in the central region of UGT1A were linked to grade 3-4 neutropenia. Haplotype analyses of these markers with the 3'UTR SNP allowed the identification of a protective HI (OR=0.50; p=0.048) and two risk haplotypes HII and HIII, characterized by 2 and 3 unfavourable alleles respectively, revealing a dosage effect (ORs of 2.15 and 5.28; p≤0.030). Conclusions: Our results suggest that specific SNPs in UGT1A other than UGT1A1*28 may influence irinotecan toxicity and thus, these polymorphisms should be considered to refine pharmacogenetic testing.
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    • "Il n'a pas été démontré de relation entre l'expression de la mutation CYP3A4*1B, fréquemment rencontrée chez les patients caucasiens, et un phénotype de diminution des capacités métaboliques liées au CYP3A4. Plusieurs autres mutations ont été recherchées par phénotypage d'activité enzymatique au moyen de substrats spécifiques (CYP3A4*2 et *3 ; CYP3A5*3 et *6), sans montrer d'effet significatif sur les profils cinétiques de l'IRI [76]. En revanche, le polymorphisme des gènes UGT1 a été largement étudié et semble plus démonstratif en termes prédictif pour la conjugaison du SN-38. "
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    ABSTRACT: Colorectal cancer (CCR), which is one of the most common causes of cancer, has benefited from the major advances in the understanding of the intracellular signaling pathways implicated in the initiation, growing and local and metastasis dissemination of tumor, which have occurred during the 20 past years. The pharmacogenomics approach, especially the determination of the genetic polymorphisms, tries to find prognosis and predictive biomarkers permitting to identify patients who could benefit from a particular treatment or those exhibiting higher risks of toxicity. Among the numerous biomarkers, which have been studied, few are currently in use in clinical practice. The phenotyping of DPD and UGT1A1 activities, and to a lesser extent, its genotyping, appears as the most useful tool in terms of prediction of toxicities induced by two major drugs: 5-FU and irinotecan. For oxaliplatin, the determination of the polymorphisms of reparases and detoxification systems such as GSTpi seems interesting, but its exact place should be more defined. It is in the field of targeted therapies that the pharmacogenomics approach seems to be the more relevant. KRAS mutation is a dramatic example of single nucleotide polymorphism, which is able to identify a priori patients that could receive or not an anti-EGFR monoclonal antibody such as cetuximab or panitumumab. It is obvious that pre-clinical identification of molecular biomarkers predictive of the sensitivity of the drug targets, which subsequently implicate the selection of patients and the rational evaluation of responses, will be the cornerstone of any clinical trials concerning targeted therapies. Besides the determination of drug target polymorphisms, it is also important to consider those related to the distribution and metabolism. In this area, the determination of enzymatic activities should recover its place besides the genomic profiling.
    Full-text · Article · Jul 2010 · Annales Pharmaceutiques Françaises
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    • "It might be simply related to the hepatic dysfunction that is associated with high cortisol biotransformation in this group of patients. Nevertheless, it appears tempting to propose the use of a pretreatment CY3A4 determination for predicting this major side effect of irinotecan, using, for instance, the cortisol 6b-hydroxyla- tion approach or another one, such as the determination of midazolam clearance, which has been shown to be significantly associated with irinotecan clearance (Mathijssen et al, 2004). As a conclusion, our studies have revealed several interesting tracks concerning the prediction of irinotecan toxicity and some new insights on the metabolism – pharmacodynamic relationships of this major drug. "
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    ABSTRACT: This study aims at establishing relationships between genetic and non-genetic factors of variation of the pharmacokinetics of irinotecan and its metabolites; and also at establishing relationships between the pharmacokinetic or metabolic parameters and the efficacy and toxicity of irinotecan. We included 49 patients treated for metastatic colorectal cancer with a combination of 5-fluorouracil and irinotecan; a polymorphism in the UGT1A1 gene (TA repeat in the TATA box) and one in the CES2 gene promoter (830C>G) were studied as potential markers for SN-38 glucuronidation and irinotecan activation, respectively; and the potential activity of CYP3A4 was estimated from cortisol biotransformation into 6 beta-hydroxycortisol. No pharmacokinetic parameter was directly predictive of clinical outcome or toxicity. The AUCs of three important metabolites of irinotecan, SN-38, SN-38 glucuronide and APC, were tentatively correlated with patients' pretreatment biological parameters related to drug metabolism (plasma creatinine, bilirubin and liver enzymes, and blood leukocytes). SN-38 AUC was significantly correlated with blood leukocytes number and SN-38G AUC was significantly correlated with plasma creatinine, whereas APC AUC was significantly correlated with plasma liver enzymes. The relative extent of irinotecan activation was inversely correlated with SN-38 glucuronidation. The TATA box polymorphism of UGT1A1 was significantly associated with plasma bilirubin levels and behaved as a significant predictor for neutropoenia. The level of cortisol 6 beta-hydroxylation predicted for the occurrence of diarrhoea. All these observations may improve the routine use of irinotecan in colorectal cancer patients. UGT1A1 genotyping plus cortisol 6 beta-hydroxylation determination could help to determine the optimal dose of irinotecan.
    Full-text · Article · Sep 2008 · British Journal of Cancer
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