Irinotecan is an anticancer agent widely used for the treatment of solid tumors, including colorectal and pancreatic cancers. Severe neutropenia and diarrhea are common dose-limiting toxicities of irinotecan-based therapy, and UGT1A1 polymorphisms are one of the major risk factors of these toxicities. In 2005, the US Food and Drug Administration revised the drug label to indicate that patients with UGT1A1*28 homozygous genotype should receive a decreased dose of irinotecan. However, UGT1A1*28 testing is not routinely used in the clinic, and specific reasons include lack of access to concise information on this wide issue as well as mixed recommendations by regulatory and professional entities. To assist oncologists in assessing whether and when to use UGT1A1 genetic testing in patients receiving irinotecan-based therapies, this article provided (1) essential knowledge of UGT1A1 polymorphisms; (2) an update on the impact of UGT1A1 polymorphisms on efficacy and toxicity of contemporary irinotecan-based regimens; (3) dosing adjustments based upon the UGT1A1 genotypes, and (4) recommendations from currently available guidelines from the US and international scientific consortia and major oncology societies.

BACKGROUND: Irinotecan (CPT-11) is an anticancer agent widely used to treat adult solid tumours. Large interindividual variability in the clearance of irinotecan and SN-38, its active and toxic metabolite, results in highly unpredictable toxicity. METHODS: In 217 cancer patients treated with intravenous irinotecan single agent or in combination, germline DNA was used to interrogate the variation in 84 genes by next-generation sequencing. A stepwise analytical framework including a population pharmacokinetic model with SNP-and gene-based testing was used to identify demographic/clinical/genetic factors that influence the clearance of irinotecan and SN-38. RESULTS: Irinotecan clearance was influenced by rs4149057 in SLCO1B1, body surface area, and co-administration of 5-fluorouracil/ leucovorin/bevacizumab. SN-38 clearance was influenced by rs887829 in UGT1A1, pre-treatment total bilirubin, and EGFR rare variant burden. Within each UGT1A1 genotype group, elevated pre-treatment total bilirubin and/or presence of at least one rare variant in EGFR resulted in significantly lower SN-38 clearance. The model reduced the interindividual variability in irinotecan clearance from 38 to 34% and SN-38 clearance from 49 to 32%. CONCLUSIONS: This new model significantly reduced the interindividual variability in the clearance of irinotecan and SN-38. New genetic factors of variability in clearance have been identified.

Severe neutropenia is the major dose‐liming toxicity of irinotecan‐based chemotherapy. The objective was to assess to what extent a population pharmacokinetic/pharmacodynamic model including patient‐specific demographic/clinical characteristics, individual pharmacokinetics, and absolute neutrophil counts (ANCs) can predict irinotecan‐induced grade 4 neutropenia. A semimechanistic population pharmacokinetic/pharmacodynamic model was developed to describe neutrophil response over time in 197 patients with cancer receiving irinotecan. For covariate analysis, sex, race, age, pretreatment total bilirubin, and body surface area were evaluated to identify significant covariates on system‐related parameters (mean transit time (MTT) and ɣ) and sensitivity to neutropenia effects of irinotecan and SN‐38 (SLOPE). The model‐based simulation was performed to assess the contribution of the identified covariates, individual pharmacokinetics, and baseline ANC alone or with incremental addition of weekly ANC up to 3 weeks on predicting irinotecan‐induced grade 4 neutropenia. The time course of neutrophil response was described using the model assuming that irinotecan and SN‐38 have toxic effects on bone marrow proliferating cells. Sex and pretreatment total bilirubin explained 10.5% of interindividual variability in MTT. No covariates were identified for SLOPE and γ. Incorporating sex and pretreatment total bilirubin (area under the receiver operating characteristic curve (AUC‐ROC): 50%, 95% CI 50–50%) or with the addition of individual pharmacokinetics (AUC‐ROC: 62%, 95% CI 53–71%) in the model did not result in accurate prediction of grade 4 neutropenia. However, incorporating ANC only at baseline and week 1 in the model achieved a good prediction (AUC‐ROC: 78%, 95% CI 69–88%). These results demonstrate the potential applicability of a model‐based approach to predict irinotecan‐induced neutropenia, which ultimately allows for personalized intervention to maximize treatment outcomes.

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Erythropoiesis-stimulating agents (eg, epoetin alfa) are the primary treatment for anemia in patients with end-stage renal disease. Hemoglobin variability in and out of a narrow target range is common and associated with higher morbidity and mortality risk. More robust erythropoiesis-stimulating agent response metrics are needed to define optimal dosing and their association with clinical outcomes. In this cross-sectional, single-center, retrospective study, 49 patients with end-stage renal disease on hemodialysis were followed over 12 months. To quantify hemoglobin deviations outside the target range (10-12 g/dL), the area under the curve of hemoglobin versus time over a 12-month period (AUC-HGB) was calculated using the trapezoidal rule. Patients were categorized into 4 responder groups based on AUC-HGB quartiles. Comparative analyses of demographic and clinical characteristics between responder groups were performed.Correlations between AUC-HGB,erythropoietin resistance index,and time within therapeutic range were calculated. There were no significant differences in laboratory and dialysis parameters between responder groups except hemoglobin concentration and epoetin alfa dose. There was a negative correlation between AUC-HGB and time within therapeutic range (r = -.92; P < .001) and hemoglobin concentration (r = -.85; P < .01), indicating internal validity of the metric. There was a positive correlation between AUC-HGB and erythropoietin resistance index (r = .70; P < .001) indicating external validity. The poor response group received a higher median epoetin alfa dose (160 U/kg/week) compared to the excellent response group (68.8 U/kg/week; P < .001) with a similar number of dose changes between the groups. AUC-HGB is a valid marker of epoetin alfa response and should be considered in future analyses of larger populations.