UGT1A1 promoter genotype correlates with SN-38 pharmacokinetics, but not severe toxicity in patients receiving low-dose irinotecan

Clinton F. Stewart, John C. Panetta, Melinda A. O'Shaughnessy, Stacy L. Throm, Charles H. Fraga, Thandranese Owens, Tiebin Liu, Catherine Billups, Carlos Rodriguez-Galindo, Amar Gajjar, Wayne L. Furman, Lisa McGregor

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Abstract

Purpose: To study the association between UDP-glucuronosyltransferase 1A1 (UGT1A1) genotypes and severe toxicity as well as irinotecan disposition in pediatric patients with solid tumors receiving low-dose, protracted irinotecan (15 to 75 mg/m2 daily for 5 days for 2 consecutive weeks). Patients and Methods: Seventy-four patients on five institutional clinical trials received irinotecan (15 to 75 mg/m2) daily intravenously or orally for 5 days for 2 consecutive weeks. Genomic DNA was genotyped for UGT1A1*28, and patients were designated as 6/6, 6/7, or 7/7 depending on the number of TA repeats in the UGT1A1 promoter region. Patients were evaluated for gastrointestinal and hematologic toxicity, as well as baseline and maximal serum bilirubin levels. Toxicity and pharmacokinetic results were evaluated during courses 1 and 2 of irinotecan therapy. Results: The frequencies of 6/6, 6/7, and 7/7 genotypes were 27 (36.5%), 36 (48.6%), and 9 (12.2%) of 74 patients, respectively. Patients with 7/7 genotype had a statistically greater baseline total bilirubin than patients with 6/6 or 6/7 genotype (P = .005). UGT1A1*28 genotype was not associated with grade 3 and 4 neutropenia (P = .21 for course 1; P = .23 for course 2) or diarrhea (P = .176 for course 1; P = .87 for course 2). However, patients with the 7/7 genotype tended to have higher SN-38 area under the plasma time-concentration curve (AUC) values and lower SN-38G/SN-38 AUC ratios. Conclusion: Severe toxicity was not increased in pediatric patients with the 7/7 genotype when treated with a low-dose protracted schedule of irinotecan. Therefore, UGT1A1 genotyping is not a useful prognostic indicator of severe toxicity for patients treated with this irinotecan dosage and schedule.

Original languageEnglish (US)
Pages (from-to)2594-2600
Number of pages7
JournalJournal of Clinical Oncology
Volume25
Issue number18
DOIs
StatePublished - Jun 20 2007

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irinotecan
Pharmacokinetics
Genotype
Bilirubin
Area Under Curve
Appointments and Schedules
UGT1A1 enzyme
Pyridinolcarbamate
Pediatrics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Stewart, Clinton F. ; Panetta, John C. ; O'Shaughnessy, Melinda A. ; Throm, Stacy L. ; Fraga, Charles H. ; Owens, Thandranese ; Liu, Tiebin ; Billups, Catherine ; Rodriguez-Galindo, Carlos ; Gajjar, Amar ; Furman, Wayne L. ; McGregor, Lisa. / UGT1A1 promoter genotype correlates with SN-38 pharmacokinetics, but not severe toxicity in patients receiving low-dose irinotecan. In: Journal of Clinical Oncology. 2007 ; Vol. 25, No. 18. pp. 2594-2600.
@article{bca526225fed47bfbbc750ddb9effbfb,
title = "UGT1A1 promoter genotype correlates with SN-38 pharmacokinetics, but not severe toxicity in patients receiving low-dose irinotecan",
abstract = "Purpose: To study the association between UDP-glucuronosyltransferase 1A1 (UGT1A1) genotypes and severe toxicity as well as irinotecan disposition in pediatric patients with solid tumors receiving low-dose, protracted irinotecan (15 to 75 mg/m2 daily for 5 days for 2 consecutive weeks). Patients and Methods: Seventy-four patients on five institutional clinical trials received irinotecan (15 to 75 mg/m2) daily intravenously or orally for 5 days for 2 consecutive weeks. Genomic DNA was genotyped for UGT1A1*28, and patients were designated as 6/6, 6/7, or 7/7 depending on the number of TA repeats in the UGT1A1 promoter region. Patients were evaluated for gastrointestinal and hematologic toxicity, as well as baseline and maximal serum bilirubin levels. Toxicity and pharmacokinetic results were evaluated during courses 1 and 2 of irinotecan therapy. Results: The frequencies of 6/6, 6/7, and 7/7 genotypes were 27 (36.5{\%}), 36 (48.6{\%}), and 9 (12.2{\%}) of 74 patients, respectively. Patients with 7/7 genotype had a statistically greater baseline total bilirubin than patients with 6/6 or 6/7 genotype (P = .005). UGT1A1*28 genotype was not associated with grade 3 and 4 neutropenia (P = .21 for course 1; P = .23 for course 2) or diarrhea (P = .176 for course 1; P = .87 for course 2). However, patients with the 7/7 genotype tended to have higher SN-38 area under the plasma time-concentration curve (AUC) values and lower SN-38G/SN-38 AUC ratios. Conclusion: Severe toxicity was not increased in pediatric patients with the 7/7 genotype when treated with a low-dose protracted schedule of irinotecan. Therefore, UGT1A1 genotyping is not a useful prognostic indicator of severe toxicity for patients treated with this irinotecan dosage and schedule.",
author = "Stewart, {Clinton F.} and Panetta, {John C.} and O'Shaughnessy, {Melinda A.} and Throm, {Stacy L.} and Fraga, {Charles H.} and Thandranese Owens and Tiebin Liu and Catherine Billups and Carlos Rodriguez-Galindo and Amar Gajjar and Furman, {Wayne L.} and Lisa McGregor",
year = "2007",
month = "6",
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doi = "10.1200/JCO.2006.10.2301",
language = "English (US)",
volume = "25",
pages = "2594--2600",
journal = "Journal of Clinical Oncology",
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Stewart, CF, Panetta, JC, O'Shaughnessy, MA, Throm, SL, Fraga, CH, Owens, T, Liu, T, Billups, C, Rodriguez-Galindo, C, Gajjar, A, Furman, WL & McGregor, L 2007, 'UGT1A1 promoter genotype correlates with SN-38 pharmacokinetics, but not severe toxicity in patients receiving low-dose irinotecan', Journal of Clinical Oncology, vol. 25, no. 18, pp. 2594-2600. https://doi.org/10.1200/JCO.2006.10.2301

UGT1A1 promoter genotype correlates with SN-38 pharmacokinetics, but not severe toxicity in patients receiving low-dose irinotecan. / Stewart, Clinton F.; Panetta, John C.; O'Shaughnessy, Melinda A.; Throm, Stacy L.; Fraga, Charles H.; Owens, Thandranese; Liu, Tiebin; Billups, Catherine; Rodriguez-Galindo, Carlos; Gajjar, Amar; Furman, Wayne L.; McGregor, Lisa.

In: Journal of Clinical Oncology, Vol. 25, No. 18, 20.06.2007, p. 2594-2600.

Research output: Contribution to journalArticle

TY - JOUR

T1 - UGT1A1 promoter genotype correlates with SN-38 pharmacokinetics, but not severe toxicity in patients receiving low-dose irinotecan

AU - Stewart, Clinton F.

AU - Panetta, John C.

AU - O'Shaughnessy, Melinda A.

AU - Throm, Stacy L.

AU - Fraga, Charles H.

AU - Owens, Thandranese

AU - Liu, Tiebin

AU - Billups, Catherine

AU - Rodriguez-Galindo, Carlos

AU - Gajjar, Amar

AU - Furman, Wayne L.

AU - McGregor, Lisa

PY - 2007/6/20

Y1 - 2007/6/20

N2 - Purpose: To study the association between UDP-glucuronosyltransferase 1A1 (UGT1A1) genotypes and severe toxicity as well as irinotecan disposition in pediatric patients with solid tumors receiving low-dose, protracted irinotecan (15 to 75 mg/m2 daily for 5 days for 2 consecutive weeks). Patients and Methods: Seventy-four patients on five institutional clinical trials received irinotecan (15 to 75 mg/m2) daily intravenously or orally for 5 days for 2 consecutive weeks. Genomic DNA was genotyped for UGT1A1*28, and patients were designated as 6/6, 6/7, or 7/7 depending on the number of TA repeats in the UGT1A1 promoter region. Patients were evaluated for gastrointestinal and hematologic toxicity, as well as baseline and maximal serum bilirubin levels. Toxicity and pharmacokinetic results were evaluated during courses 1 and 2 of irinotecan therapy. Results: The frequencies of 6/6, 6/7, and 7/7 genotypes were 27 (36.5%), 36 (48.6%), and 9 (12.2%) of 74 patients, respectively. Patients with 7/7 genotype had a statistically greater baseline total bilirubin than patients with 6/6 or 6/7 genotype (P = .005). UGT1A1*28 genotype was not associated with grade 3 and 4 neutropenia (P = .21 for course 1; P = .23 for course 2) or diarrhea (P = .176 for course 1; P = .87 for course 2). However, patients with the 7/7 genotype tended to have higher SN-38 area under the plasma time-concentration curve (AUC) values and lower SN-38G/SN-38 AUC ratios. Conclusion: Severe toxicity was not increased in pediatric patients with the 7/7 genotype when treated with a low-dose protracted schedule of irinotecan. Therefore, UGT1A1 genotyping is not a useful prognostic indicator of severe toxicity for patients treated with this irinotecan dosage and schedule.

AB - Purpose: To study the association between UDP-glucuronosyltransferase 1A1 (UGT1A1) genotypes and severe toxicity as well as irinotecan disposition in pediatric patients with solid tumors receiving low-dose, protracted irinotecan (15 to 75 mg/m2 daily for 5 days for 2 consecutive weeks). Patients and Methods: Seventy-four patients on five institutional clinical trials received irinotecan (15 to 75 mg/m2) daily intravenously or orally for 5 days for 2 consecutive weeks. Genomic DNA was genotyped for UGT1A1*28, and patients were designated as 6/6, 6/7, or 7/7 depending on the number of TA repeats in the UGT1A1 promoter region. Patients were evaluated for gastrointestinal and hematologic toxicity, as well as baseline and maximal serum bilirubin levels. Toxicity and pharmacokinetic results were evaluated during courses 1 and 2 of irinotecan therapy. Results: The frequencies of 6/6, 6/7, and 7/7 genotypes were 27 (36.5%), 36 (48.6%), and 9 (12.2%) of 74 patients, respectively. Patients with 7/7 genotype had a statistically greater baseline total bilirubin than patients with 6/6 or 6/7 genotype (P = .005). UGT1A1*28 genotype was not associated with grade 3 and 4 neutropenia (P = .21 for course 1; P = .23 for course 2) or diarrhea (P = .176 for course 1; P = .87 for course 2). However, patients with the 7/7 genotype tended to have higher SN-38 area under the plasma time-concentration curve (AUC) values and lower SN-38G/SN-38 AUC ratios. Conclusion: Severe toxicity was not increased in pediatric patients with the 7/7 genotype when treated with a low-dose protracted schedule of irinotecan. Therefore, UGT1A1 genotyping is not a useful prognostic indicator of severe toxicity for patients treated with this irinotecan dosage and schedule.

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