Dataset Information

Clinical validity of new genetic biomarkers of irinotecan neutropenia: an independent replication study.

ABSTRACT: The overall goal of this study was to provide evidence for the clinical validity of nine genetic variants in five genes previously associated with irinotecan neutropenia and pharmacokinetics. Variants associated with absolute neutrophil count (ANC) nadir and/or irinotecan pharmacokinetics in a discovery cohort of cancer patients were genotyped in an independent replication cohort of 108 cancer patients. Patients received single-agent irinotecan every 3 weeks. For ANC nadir, we replicated UGT1A1*28, UGT1A1*93 and SLCO1B1*1b in univariate analyses. For irinotecan area under the concentration-time curve (AUC0-24), we replicated ABCC2 -24C>T; however, ABCC2 -24C>T only predicted a small fraction of the variance. For SN-38 AUC0-24 and the glucuronidation ratio, we replicated UGT1A1*28 and UGT1A1*93. In addition to UGT1A1*28, this study independently validated UGT1A1*93 and SLCO1B1*1b as new predictors of irinotecan neutropenia. Further demonstration of their clinical utility will optimize irinotecan therapy in cancer patients.

SUBMITTER: Crona DJ

PROVIDER: S-EPMC4729652 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Clinical validity of new genetic biomarkers of irinotecan neutropenia: an independent replication study.

Crona D J DJ Ramirez J J Qiao W W de Graan A-J AJ Ratain M J MJ van Schaik R H N RH Mathijssen R H J RH Rosner G L GL Innocenti F F

The pharmacogenomics journal 20150414 1

The overall goal of this study was to provide evidence for the clinical validity of nine genetic variants in five genes previously associated with irinotecan neutropenia and pharmacokinetics. Variants associated with absolute neutrophil count (ANC) nadir and/or irinotecan pharmacokinetics in a discovery cohort of cancer patients were genotyped in an independent replication cohort of 108 cancer patients. Patients received single-agent irinotecan every 3 weeks. For ANC nadir, we replicated UGT1A1* ...[more]

PMID: 25869015

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Project description: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.

Dataset Information

Clinical validity of new genetic biomarkers of irinotecan neutropenia: an independent replication study.

Publications

Clinical validity of new genetic biomarkers of irinotecan neutropenia: an independent replication study.

Similar Datasets

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