[Influence of genetic polymorphisms in UGT1A1, UGT1A7 and UGT1A9 on the pharmacokynetics of irinotecan, SN-38 and SN-38G].

Abstract

OBJECTIVE:

To evaluate the influence of genetic polymorphism in UGT1A1, UGT1A7 and UGT1A9 on the population pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38G.

METHODS:

Plasma concentrations of irinotecan, SN-38 and SN- 38G from 72 patients were pooled to develop a population pharmacokinetic model using NONMEM VII. M3 method was used to account for plasma concentrations below the limit quantification. The effect of age, sex, body surface area, total bilirubin, co-medication, tumor type, and UGT1A1, UGT1A7 and UGT1A9 genotypes on the model parameters was evaluated. The model was internally validated using normalized visual predictive check (NVPC) and normalized predictive distribution errors (NPDE).

RESULTS:

The typical values (between-subject variability; %) of the irinotecan, SN-38 and SN-38G clearances were 42,9 L/h (56,4%), 1340 L/h (76,8%) and 188 L/h (70,1%), respectively. The presence of UGT1A1*28, UGT1A7*3, UGT1A9*22 genotypes decreases SN-38 clearance between 20 and 36%. Internal validation confirms the population pharmacokinetic model describe the time course of irinotecan, SN-38 and SN-38G plasma concentration and their associated variability in cancer patients.

CONCLUSION:

The inclusion of pharmacokinetic-pharmacogenomic information can add value to the individualized dose adjustment of irinotecan, because it will let quantitatively handle dose reductions in patients with iatrogenic toxicity due to UGT1A1 genetic polymorphisms.

• Authors: B Valenzuela Jiménez, M González Sales, V Escudero Ortiz, E Martínez Navarro, C Pérez Ruixo, J Rebollo Liceaga, R González Manzano, J J Pérez Ruixo
• Journal: Farmacia hospitalaria : organo oficial de expresion cientifica de la Sociedad Espanola de Farmacia Hospitalaria (Farm Hosp) 2013 Mar-Apr Vol. 37 Issue 2 Pg. 111-27 ISSN: 2171-8695 [Electronic] Spain
• Vernacular Title: Influencia de los polimorfismos genéticos en UGT1A1, UGT1A7 y UGT1A9 sobre la farmacocinética de irinotecán, SN-38 y SN-38G.
• PMID: 23789755 (Publication Type: Journal Article)
• Copyright: Copyright © 2013 SEFH. Published by AULA MEDICA. All rights reserved.

Chemical References

• 7-ethyl-10-hydroxycamptothecin beta-glucuronide
• Antineoplastic Agents, Phytogenic
• Glucuronates
• UGT1A9 protein, human
• Irinotecan
• UGT1A1 enzyme
• Glucuronosyltransferase
• UDP-Glucuronosyltransferase 1A9
• UGT1A7 protein, human
• Camptothecin

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents, Phytogenic (blood, pharmacokinetics, therapeutic use)
• Camptothecin (analogs & derivatives, blood, pharmacokinetics, therapeutic use)
• Female
• Glucuronates (blood, pharmacokinetics, therapeutic use)
• Glucuronosyltransferase (genetics)
• Humans
• Irinotecan
• Male
• Middle Aged
• Neoplasms (drug therapy, genetics)
• Polymorphism, Genetic
• UDP-Glucuronosyltransferase 1A9