Irinotecan Pharmacogenetics: A Finished Puzzle?

The discipline of pharmacogenetics aims to describe variations in drug pharmacokinetics and pharmacodynamics that result from inherited genetic variations in drug metabolizing enzymes, drug transporters, and/or drug targets between individual patients. Collectively, these inherited variations are presumed to be responsible for a large portion of interpatient variability in drug exposure or effects. Severe toxicity might occur in the absence of typical metabolism of active compounds, whereas the therapeutic effect of a drug could be diminished with reduced activation of a prodrug, such as irinotecan. The importance and detectability of polymorphisms for a given enzyme or transporter depend on the contribution of the variant gene product to a pharmacologic response, the availability of alternative pathways of elimination, and the frequency of occurrence of the variant allele in a given population. Although many substrates have been identified for the known polymorphic drug metabolizing enzymes and transporters, the contribution of a genetically determined source of interindividual pharmacokinetic and pharmacodynamic variability has been convincingly established for only a few cancer agents. Most of these cases either involve agents for which elimination is critically dependent on a rate-limiting breakdown or conjugation by a polymorphic enzyme (eg, the irinotecan metabolite SN-38 by UDP-glucuronosyltransferase 1A1 [UGT1A1]), or a polymorphic enzyme that is involved in the formation of a toxic metabolite (eg, tamoxifen by CYP2D6). The therapeutic range for most established cytotoxic anticancer agents is extremely narrow, and in most cases, no information is available before therapy on the patient’s tolerability of a given dose for a particular agent. Hence, the dosage of virtually all chemotherapeutic agents remains largely empirical, and it is typically only normalized to an individual’s body-surface area (BSA), despite the fact that pharmacogenetic-guided dosing of several of these agents has been a point of discussion for decades. For established drugs, this conservative strategy makes sense, given that historical data on most existing therapies have been generated using dose considerations that are derived from the maximum tolerable dose concept, irrespective of an individual’s genetic constitution. However, in the present era of personalized medicine, new paradigms are developing and not so new, yet still untested, paradigms are finally being evaluated prospectively. The study reported by Innocenti et al that accompanies this editorial presents compelling data that support consideration for alternative dosing and dose-finding strategies for irinotecan, and it is among the first of single-agent phase I studies to use germline genetics to individualize dosing of a cancer agent. Despite the widespread usage of irinotecan, the unpredictability of its dose-limiting toxicities, including neutropenia and diarrhea, are cause for grave concern among patients and health care professionals alike. Indeed, severe, occasionally fatal toxicity occurs even in otherwise low-risk patients participating in well-controlled clinical trials. Irinotecan is a prodrug of the topoisomerase I inhibitor SN-38 that, in turn, can be conjugated by UGT1A1 to form an inactive -glucuronic acid derivative, SN-38-glucuronide. The amount of circulating SN-38 in individual patients is highly variable and is at least in part associated with a variant allele in the proximal promoter region of UGT1A1 (UGT1A1*28) that causes reduced protein expression. The clearance of SN-38 via this pathway provides a pertinent, wellestablished mechanism that contributes to interindividual variability in irinotecan-induced toxicity. The concept of UGT1A1 genotype–directed dosing of irinotecan has been explored previously in patients receiving combination therapy involving irinotecan with fluorouracil, capecitabine, capecitabine and oxaliplatin, or irinotecan as a single agent in an every-2week regimen. Despite the differences in the applied regimens and studied patient population, the findings by Innocenti et al using single-agent irinotecan in an every-3-week regimen are in general agreement with these previous studies in that patients with the *28/*28 genotype are at the highest risk of therapy-related toxicity and require a reduction in dose of up to 40%. Importantly, patients with the *1/*28 and *1/*1 genotypes can tolerate substantially higher doses than the standard dose of 350 mg/m, by approximately 10% and 34%, respectively, suggesting that the vast majority of patients of European ancestry receiving standard-dose irinotecan are undertreated. Another important aspect of the study reported by Innocenti et al is that the starting dose of irinotecan and subsequent increments were fixed and not normalized to an individual’s BSA. This approach has been advocated by the authors for many years and is supported by the previous demonstration that BSA is not significantly related to the marked differences between patients in exposure to SN-38. The study by Innocenti et al also demonstrated with flat dosing that BSA was not a significant predictor of the absolute neutrophil count nadir, a measure of irinotecan-induced myelosuppression. Despite these observations and a wealth of cumulative evidence that BSA dose normalization does not reduce variability nor improve outcomes with irinotecan therapy, many prescribers and regulators maintain the erroneous belief that a patient with a larger BSA will always require a higher dose to induce the same drug effects. Therefore, it is JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 22 AUGUST 1 2014