UGT1A1*28 Genotype and Irinotecan-Induced Neutropenia: Dose Matters

Abstract

The Food and Drug Administration and Pfizer changed the package insert for irinotecan to include a patient's UGT1A1*28 genotype as a risk factor for severe neutropenia on the basis of the findings of four pharmacogenetic studies, which found that irinotecan-treated patients who were homozygous for the UGT1A1*28 allele had a greater risk of hematologic toxic effects than patients who had one or two copies of the wild-type allele (UGT1A1*1). Findings of subsequent irinotecan pharmacogenetic studies have been inconsistent. In a meta-analysis, we reviewed data presented in nine studies that included a total of 10 sets of patients (for a total of 821 patients) and assessed the association of irinotecan dose with the risk of irinotecan-related hematologic toxicities (grade III-IV) for patients with a UGT1A1*28/*28 genotype. The risk of toxicity was higher among patients with a UGT1A1*28/*28 genotype than among those with a UGT1A1*1/*1 or UGT1A1*1/*28 genotype at both medium (odds ratio [OR] = 3.22, 95% confidence interval [CI] = 1.52 to 6.81; P = .008) and high (OR = 27.8, 95% CI = 4.0 to 195; P = .005) doses of irinotecan. However, risk was similar at lower doses (OR = 1.80, 95% CI = 0.37 to 8.84; P = .41). Low doses of irinotecan (100-125 mg/m2) are in the commonly used therapeutic range. The risk of experiencing irinotecan-induced hematologic toxicity for patients with a UGT1A1*28/*28 genotype thus appears to be a function of the dose of irinotecan administered.

Population Pharmacokinetics of Liposomal Irinotecan in Patients With Cancer

“…In patients treated with nonliposomal irinotecan, the associations between UGT1A1*28 7/7 homozygosity and hematological toxicity were observed only in patients treated with doses >150 mg/m 2 ; however, similar hematological toxicities were observed for both UGT1A1*28 homozygous and nonhomozygous patients with a lower dose of nonliposomal irinotecan of 100–125 mg/m 2 every week 25. The association between UGT1A1*28 7/7 homozygosity and SN‐38 concentrations are also dependent on the dose of nonliposomal irinotecan, with much higher SN‐38 concentrations observed for 6/7 and 7/7 (compared to 6/6) when irinotecan was administered at a dose of 300 mg/m 2 than when it was administered at a dose of 15–75 mg/m 2 daily for 5 days for 2 consecutive weeks 26, 27.…”

Germline pharmacogenomics in oncology: Decoding the patient for targeting therapy

“…In the largest such study of 250 metastatic colorectal cancer patients, the odds ratio of risk of cycle 1 grade 3 or 4 neutropenia was w9, although the relationship did not persist for subsequent cycles (Toffoli et al, 2006). A meta-analysis of published studies on UGT1A1-irinotecan (including 821 patients) also confirmed the association for patients homozygous for the UGT1A1*28 allele who are receiving higher doses of irinotecan ( 150 mg/m 2 ) (Hoskins et al, 2007). Including other risk alleles within UGT1A in a haplotype-based analysis may increase the predictive value of pharmacogenomic testing, since several other variants in these genes have now also been shown to alter enzymatic activity and impact irinotecan-related outcomes (Cecchin et al, 2009).…”

“…The reduced penetrance could be due to direct effects of the other drugs, plus potentially the reduced effect on the drug of interest, especially if there was dose reduction. This issue has now been suggested to be important for both the tamoxifen (Kiyotani et al, 2010) and irinotecan examples (Hoskins et al, 2007). Third, one of the common problems confounding oncology pharmacogenomics is that evaluated studies often lack a control group (the relatively well-performed study referenced above on tamoxifendwhich diddis an exception).…”

Role of pharmacogenetics in public health and clinical health care: a SWOT analysis

“…26,29 Recent studies have uncovered numerous genetic linkages with drug-induced toxicity and/or side effects, where knowledge of the individual genetic profile can indicate the likelihood of an undesirable outcome and direct the physician towards alternative medications if necessary and available. Abacavir and carbamazepine are two prime examples, especially as patients who do not carry the HLA-B*57:01 and HLA-B*15:02 alleles, respectively, for the two drugs will almost never experience abacavir-induced hypersensitivity or carbamazepine-induced Stevens-Johnson syndrome.…”