Dose-Limiting Toxicities and the Maximum Tolerated Dose of Irinotecan Based on <i>UGT1A1</i> Genotypes: A Systematic Review
<b>Background/Objectives:</b> Irinotecan is used in monotherapy or combined with other drugs for treating different cancer streams. SN-38, the active metabolite of irinotecan, is 70% inactivated by the uridine diphosphate (UDP) glucuronosyltransferase family 1 member A1 (UGT1A1) enzyme....
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| author | Xando Díaz-Villamarín María Teresa Nieto-Sánchez María Martínez-Pérez Paula Novo-González Emilio Fernández-Varón Alicia Torres-García Beatriz González Astorga Isabel Blancas José Cabeza-Barrera Rocío Morón |
| author_facet | Xando Díaz-Villamarín María Teresa Nieto-Sánchez María Martínez-Pérez Paula Novo-González Emilio Fernández-Varón Alicia Torres-García Beatriz González Astorga Isabel Blancas José Cabeza-Barrera Rocío Morón |
| author_sort | Xando Díaz-Villamarín |
| collection | DOAJ |
| description | <b>Background/Objectives:</b> Irinotecan is used in monotherapy or combined with other drugs for treating different cancer streams. SN-38, the active metabolite of irinotecan, is 70% inactivated by the uridine diphosphate (UDP) glucuronosyltransferase family 1 member A1 (UGT1A1) enzyme. The <i>UGT1A1</i>*6 (rs4148323) and <i>*28</i> (rs3064744) alleles in the gene encoding the enzyme lead to decreased enzyme expression and increased severe irinotecan toxicity. Carrying one or two copies of these alleles results in a UGT1A1 intermediate or poor metabolizer status (IM, PM). The Food and Drug Administration (FDA)-approved drug labels and European Medicines Agency (EMA) European Public Assessment Report (EPAR) for irinotecan recommend dose adjustments based on <i>UGT1A1</i> genotypes, but only for UGT1A1 PM patients. However, available pharmacogenetic (PGx) dosing guidelines for the <i>UGT1A1</i>–irinotecan interaction lack a consensus about considered genetic variants, genotype-translated phenotypes, and therapeutic recommendations. We aimed to describe evidence regarding the impact of the <i>UGT1A1</i> genotype in irinotecan toxicity to inform irinotecan-dosing recommendations based on possible <i>UGT1A1</i> genotypes. <b>Methods</b>: A systematic review was performed to find all the Phase I clinical trials looking for the maximum tolerated dose (MTD) or dose-limiting toxicities (DLTs) of irinotecan depending on the <i>UGT1A1</i> genotype. <b>Results</b>: Toxicity-related events and the MTD of irinotecan differ among UGT1A1 normal metabolizers (NM), IM, and PM patients considering the <i>UGT1A1*28</i> and/or *<i>6</i> variants. <b>Conclusions</b>: Dose adjustments might also be recommended for UGT1A1 IM patients (*<i>1/*28</i> or <i>*1/*6</i> genotypes), with a 15% dose reduction considered. |
| format | Article |
| id | doaj-art-46febf32f5444324b548d72b22fb164c |
| institution | OA Journals |
| issn | 1999-4923 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | MDPI AG |
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| series | Pharmaceutics |
| spelling | doaj-art-46febf32f5444324b548d72b22fb164c2025-08-20T01:56:38ZengMDPI AGPharmaceutics1999-49232025-04-0117554210.3390/pharmaceutics17050542Dose-Limiting Toxicities and the Maximum Tolerated Dose of Irinotecan Based on <i>UGT1A1</i> Genotypes: A Systematic ReviewXando Díaz-Villamarín0María Teresa Nieto-Sánchez1María Martínez-Pérez2Paula Novo-González3Emilio Fernández-Varón4Alicia Torres-García5Beatriz González Astorga6Isabel Blancas7José Cabeza-Barrera8Rocío Morón9Instituto de Investigación Biosanitaria de Granada (Ibs. Granada), 18012 Granada, SpainHospital Pharmacy, Hospital Universitario San Cecilio, 18016 Granada, SpainHospital Pharmacy, Hospital Universitario San Cecilio, 18016 Granada, SpainHospital Pharmacy, Hospital Regional Severo Ochoa, 28914 Leganés, SpainInstituto de Investigación Biosanitaria de Granada (Ibs. Granada), 18012 Granada, SpainInstituto de Investigación Biosanitaria de Granada (Ibs. Granada), 18012 Granada, SpainInstituto de Investigación Biosanitaria de Granada (Ibs. Granada), 18012 Granada, SpainInstituto de Investigación Biosanitaria de Granada (Ibs. Granada), 18012 Granada, SpainInstituto de Investigación Biosanitaria de Granada (Ibs. Granada), 18012 Granada, SpainInstituto de Investigación Biosanitaria de Granada (Ibs. Granada), 18012 Granada, Spain<b>Background/Objectives:</b> Irinotecan is used in monotherapy or combined with other drugs for treating different cancer streams. SN-38, the active metabolite of irinotecan, is 70% inactivated by the uridine diphosphate (UDP) glucuronosyltransferase family 1 member A1 (UGT1A1) enzyme. The <i>UGT1A1</i>*6 (rs4148323) and <i>*28</i> (rs3064744) alleles in the gene encoding the enzyme lead to decreased enzyme expression and increased severe irinotecan toxicity. Carrying one or two copies of these alleles results in a UGT1A1 intermediate or poor metabolizer status (IM, PM). The Food and Drug Administration (FDA)-approved drug labels and European Medicines Agency (EMA) European Public Assessment Report (EPAR) for irinotecan recommend dose adjustments based on <i>UGT1A1</i> genotypes, but only for UGT1A1 PM patients. However, available pharmacogenetic (PGx) dosing guidelines for the <i>UGT1A1</i>–irinotecan interaction lack a consensus about considered genetic variants, genotype-translated phenotypes, and therapeutic recommendations. We aimed to describe evidence regarding the impact of the <i>UGT1A1</i> genotype in irinotecan toxicity to inform irinotecan-dosing recommendations based on possible <i>UGT1A1</i> genotypes. <b>Methods</b>: A systematic review was performed to find all the Phase I clinical trials looking for the maximum tolerated dose (MTD) or dose-limiting toxicities (DLTs) of irinotecan depending on the <i>UGT1A1</i> genotype. <b>Results</b>: Toxicity-related events and the MTD of irinotecan differ among UGT1A1 normal metabolizers (NM), IM, and PM patients considering the <i>UGT1A1*28</i> and/or *<i>6</i> variants. <b>Conclusions</b>: Dose adjustments might also be recommended for UGT1A1 IM patients (*<i>1/*28</i> or <i>*1/*6</i> genotypes), with a 15% dose reduction considered.https://www.mdpi.com/1999-4923/17/5/542irinotecan<i>UGT1A1</i>maximum tolerated dosepharmacogeneticspharmacogenomicpersonalized medicine |
| spellingShingle | Xando Díaz-Villamarín María Teresa Nieto-Sánchez María Martínez-Pérez Paula Novo-González Emilio Fernández-Varón Alicia Torres-García Beatriz González Astorga Isabel Blancas José Cabeza-Barrera Rocío Morón Dose-Limiting Toxicities and the Maximum Tolerated Dose of Irinotecan Based on <i>UGT1A1</i> Genotypes: A Systematic Review Pharmaceutics irinotecan <i>UGT1A1</i> maximum tolerated dose pharmacogenetics pharmacogenomic personalized medicine |
| title | Dose-Limiting Toxicities and the Maximum Tolerated Dose of Irinotecan Based on <i>UGT1A1</i> Genotypes: A Systematic Review |
| title_full | Dose-Limiting Toxicities and the Maximum Tolerated Dose of Irinotecan Based on <i>UGT1A1</i> Genotypes: A Systematic Review |
| title_fullStr | Dose-Limiting Toxicities and the Maximum Tolerated Dose of Irinotecan Based on <i>UGT1A1</i> Genotypes: A Systematic Review |
| title_full_unstemmed | Dose-Limiting Toxicities and the Maximum Tolerated Dose of Irinotecan Based on <i>UGT1A1</i> Genotypes: A Systematic Review |
| title_short | Dose-Limiting Toxicities and the Maximum Tolerated Dose of Irinotecan Based on <i>UGT1A1</i> Genotypes: A Systematic Review |
| title_sort | dose limiting toxicities and the maximum tolerated dose of irinotecan based on i ugt1a1 i genotypes a systematic review |
| topic | irinotecan <i>UGT1A1</i> maximum tolerated dose pharmacogenetics pharmacogenomic personalized medicine |
| url | https://www.mdpi.com/1999-4923/17/5/542 |
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