Uridine Glucuronosyltransferase 2B7 Polymorphism-Based Pharmacogenetic Dosing of Epirubicin in FEC Chemotherapy for Early-Stage Breast Cancer

Joy, Anil A.; Vos, Larissa J.; Pituskin, Edith; Cook, Sarah F.; Bies, Robert R.; Vlahadamis, Ann; King, Karen; Basi, Sanraj; Meza–Junco, Judith; Mackey, John R.; Stanislaus, Avalyn; Damaraju, Vijaya L.; Damaraju, Sambasivarao; Sawyer, Michael B.

doi:10.1016/j.clbc.2021.03.001

Cited by 3 publications

(2 citation statements)

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“…The most notable example of pharmacogenomic-guided epirubicin dosing involved the UGT2B7 -161C>T SNP. This SNP has been associated with a reduction in epirubicin clearance and increased AUC [22,23]; importantly, this SNP has also been demonstrated to predict grade 3 4 leucopenia in early breast cancer patients treated with adjuvant or neoadjuvant FEC100 (5-fluorouracil 500 mg/m 2 , Epirubicin 100 mg/m 2 and cyclophosphamide 500 mg/m 2 ).…”

Section: Introductionmentioning

confidence: 95%

A Physiologically Based Pharmacokinetic Model to Predict Determinants of Variability in Epirubicin Exposure and Tissue Distribution

2023

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Background: Epirubicin is an anthracycline antineoplastic drug that is primarily used in combination therapies for the treatment of breast, gastric, lung and ovarian cancers and lymphomas. Epirubicin is administered intravenously (IV) over 3 to 5 min once every 21 days with dosing based on body surface area (BSA; mg/m2). Despite accounting for BSA, marked inter-subject variability in circulating epirubicin plasma concentration has been reported. Methods: In vitro experiments were conducted to determine the kinetics of epirubicin glucuronidation by human liver microsomes in the presence and absence of validated UGT2B7 inhibitors. A full physiologically based pharmacokinetic model was built and validated using Simcyp® (version 19.1, Certara, Princeton, NJ, USA). The model was used to simulate epirubicin exposure in 2000 Sim-Cancer subjects over 158 h following a single intravenous dose of epirubicin. A multivariable linear regression model was built using simulated demographic and enzyme abundance data to determine the key drivers of variability in systemic epirubicin exposure. Results: Multivariable linear regression modelling demonstrated that variability in simulated systemic epirubicin exposure following intravenous injection was primarily driven by differences in hepatic and renal UGT2B7 expression, plasma albumin concentration, age, BSA, GFR, haematocrit and sex. By accounting for these factors, it was possible to explain 87% of the variability in epirubicin in a simulated cohort of 2000 oncology patients. Conclusions: The present study describes the development and evaluation of a full-body PBPK model to assess systemic and individual organ exposure to epirubicin. Variability in epirubicin exposure was primarily driven by hepatic and renal UGT2B7 expression, plasma albumin concentration, age, BSA, GFR, haematocrit and sex.

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Section: Introductionmentioning

confidence: 95%

A Physiologically Based Pharmacokinetic Model to Predict Determinants of Variability in Epirubicin Exposure and Tissue Distribution

2023

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“…UGTs metabolize a variety of anticancer drugs (e.g., irinotecan and epirubicin) and thus affect their efficacy and toxicity [ 10 , 11 , 12 , 13 , 14 , 15 ]. For example, low-activity UGT1A1 alleles (e.g., UGT1A1*28 and UGT1A1*6 ) are associated with an increased risk for severe or life-threatening neutropenia and myelosuppression during and after irinotecan administration [ 10 , 16 , 17 , 18 , 19 , 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

The Somatic Mutation Landscape of UDP-Glycosyltransferase (UGT) Genes in Human Cancers

Marri

Hulin

et al. 2022

Cancers

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The human UDP-glycosyltransferase (UGTs) superfamily has a critical role in the metabolism of anticancer drugs and numerous pro/anti-cancer molecules (e.g., steroids, lipids, fatty acids, bile acids and carcinogens). Recent studies have shown wide and abundant expression of UGT genes in human cancers. However, the extent to which UGT genes acquire somatic mutations within tumors remains to be systematically investigated. In the present study, our comprehensive analysis of the somatic mutation profiles of 10,069 tumors from 33 different TCGA cancer types identified 3427 somatic mutations in UGT genes. Overall, nearly 18% (1802/10,069) of the assessed tumors had mutations in UGT genes with huge variations in mutation frequency across different cancer types, ranging from over 25% in five cancers (COAD, LUAD, LUSC, SKCM and UCSC) to less than 5% in eight cancers (LAML, MESO, PCPG, PAAD, PRAD, TGCT, THYM and UVM). All 22 UGT genes showed somatic mutations in tumors, with UGT2B4, UGT3A1 and UGT3A2 showing the largest number of mutations (289, 307 and 255 mutations, respectively). Nearly 65% (2260/3427) of the mutations were missense, frame-shift and nonsense mutations that have been predicted to code for variant UGT proteins. Furthermore, about 10% (362/3427) of the mutations occurred in non-coding regions (5′ UTR, 3′ UTR and splice sites) that may be able to alter the efficiency of translation initiation, miRNA regulation or the splicing of UGT transcripts. In conclusion, our data show widespread somatic mutations of UGT genes in human cancers that may affect the capacity of cancer cells to metabolize anticancer drugs and endobiotics that control pro/anti-cancer signaling pathways. This highlights their potential utility as biomarkers for predicting therapeutic efficacy and clinical outcomes.

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Novel epirubicin-loaded nanoformulations: Advancements in polymeric nanocarriers for efficient targeted cellular and subcellular anticancer drug delivery

Pourmadadi

Ostovar

Ruiz-Pulido

et al. 2023

Inorganic Chemistry Communications

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Uridine Glucuronosyltransferase 2B7 Polymorphism-Based Pharmacogenetic Dosing of Epirubicin in FEC Chemotherapy for Early-Stage Breast Cancer

Cited by 3 publications

References 46 publications

A Physiologically Based Pharmacokinetic Model to Predict Determinants of Variability in Epirubicin Exposure and Tissue Distribution

A Physiologically Based Pharmacokinetic Model to Predict Determinants of Variability in Epirubicin Exposure and Tissue Distribution

The Somatic Mutation Landscape of UDP-Glycosyltransferase (UGT) Genes in Human Cancers

Novel epirubicin-loaded nanoformulations: Advancements in polymeric nanocarriers for efficient targeted cellular and subcellular anticancer drug delivery

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