The effects of CYP3A4 inhibition on erlotinib pharmacokinetics: computer-based simulation (SimCYP) predicts in vivo metabolic inhibition.
Eur J Clin Pharmacol
; 64(1): 31-41, 2008 Jan.
Article
em En
| MEDLINE
| ID: mdl-18000659
ABSTRACT
BACKGROUND:
Erlotinib is an orally active antitumor agent. Analyses in vitro using human liver microsomes and recombinant enzymes showed that erlotinib was metabolized primarily by CYP3A4, with a secondary contribution from CYP1A2.METHODS:
A computer-based simulation model, SimCYP, predicted that CYP3A4 contributed to approximately 70% of the metabolic elimination of erlotinib, with CYP1A2 being responsible for the other approximately 30%. A drug-drug interaction study was therefore conducted for erlotinib and a potent CYP3A4 inhibitor, ketoconazole, in healthy male volunteers to evaluate the impact of CYP3A4 inhibition on erlotinib exposure.RESULTS:
Ketoconazole caused an almost two-fold increase in erlotinib plasma area under the concentration curve and in maximum plasma concentration. This is consistent with the SimCYP prediction of a two-fold increase in erlotinib AUC, further validating a primary (approximately 70%) role of CYP3A4 in erlotinib elimination.CONCLUSION:
Prediction of clinically important drug-drug interaction with SimCYP using in vitro human metabolism data can be a powerful tool during early clinical development to ensure safe administration of anticancer drugs, which are often co-administered at maximum tolerated doses with other drugs as part of a palliative treatment regimen.
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Base de dados:
MEDLINE
Assunto principal:
Quinazolinas
/
Inibidores de Proteínas Quinases
/
Inibidores Enzimáticos
/
Citocromo P-450 CYP3A
Idioma:
En
Ano de publicação:
2008
Tipo de documento:
Article