Irinotecan Therapy and UGT1A1 Genotype

Irinotecan (brand name Camptosar) is a topoisomerase I inhibitor widely used in the treatment of cancer. It is most frequently used in combination with other drugs to treat advanced or metastatic colorectal cancer. However, irinotecan therapy is associated with a high incidence of toxicity, including severe neutropenia and diarrhea (1).Irinotecan is converted in the body to an active metabolite known as SN-38, which is then inactivated and detoxified by a UDP-glucuronosyltransferase (UGT) enzyme encoded by the UGT1A1 gene. The UGT enzymes are responsible for glucuronidation, a process that transforms lipophilic metabolites into water-soluble metabolites that can be excreted from the body.The risk of irinotecan toxicity increases with genetic variants associated with reduced UGT enzyme activity, such as UGT1A1*28. The presence of this variant results in reduced excretion of irinotecan metabolites, which leads to increased active irinotecan metabolites in the blood. Approximately 10% of North Americans carry 2 copies of the UGT1A1*28 allele (homozygous, UGT1A1 *28/*28), and are more likely to develop neutropenia following irinotecan therapy (1-3).The FDA-approved drug label for irinotecan states that “when administered as a single-agent, a reduction in the starting dose by at least one level of irinotecan hydrochloride injection should be considered for patients known to be homozygous for the UGT1A1*28 allele. However, the precise dose reduction in this patient population is not known and subsequent dose modifications should be considered based on individual patient tolerance to treatment” (Table 1) (1).The Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP) recommends starting with 70% of the standard dose for homozygous carriers of the UGT1A1*28 allele. If the patient tolerates this initial dose, the dose can be increased guided by the neutrophil count. They state that no action is needed for heterozygous carriers of the UGT1A1*28 allele (e.g., UGT1A1 *1/*28) (Table 2) (4). In addition, the French National Network of Pharmacogenetics (RNPGx) has proposed a decision tree for guiding irinotecan prescribing based on the UGT1A1 genotype and irinotecan dose (Table 3) (5).