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

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. Plasma concentrations of irinotecan, SN-38 and SN- 38G from 72 patients were pooled to develop a population pharmacokinetic model usi...

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Published in:	Farmacia hospitalaria : organo oficial de expresion cientifica de la Sociedad Espanola de Farmacia Hospitalaria Vol. 37; no. 2; p. 111
Main Authors:	Valenzuela Jiménez, B, González Sales, M, Escudero Ortiz, V, Martínez Navarro, E, Pérez Ruixo, C, Rebollo Liceaga, J, González Manzano, R, Pérez Ruixo, J J
Format:	Journal Article
Language:	Spanish
Published:	Spain 01-03-2013
Subjects:	Adult Aged Aged, 80 and over Antineoplastic Agents, Phytogenic - blood Antineoplastic Agents, Phytogenic - pharmacokinetics Antineoplastic Agents, Phytogenic - therapeutic use Camptothecin - analogs & derivatives Camptothecin - blood Camptothecin - pharmacokinetics Camptothecin - therapeutic use Female Glucuronates - blood Glucuronates - pharmacokinetics Glucuronates - therapeutic use Glucuronosyltransferase - genetics Humans Male Middle Aged Neoplasms - drug therapy Neoplasms - genetics Polymorphism, Genetic
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Summary:	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. 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). 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 UGT1A128, UGT1A73, 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. 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.
ISSN:	0214-753X