A Semi-Mechanistic Metabolism Model of CYP3A Substrates in Pregnancy: Predicting Changes in Midazolam and Nifedipine Pharmacokinetics.
CPT Pharmacometrics Syst Pharmacol
; 1: e2, 2012 Sep 26.
Article
em En
| MEDLINE
| ID: mdl-23835882
ABSTRACT
Physiological changes in pregnancy, including changes in body composition and metabolic enzyme activity, can alter drug pharmacokinetics. A semi-mechanistic metabolism model was developed to describe the pharmacokinetics of two cytochrome P450 3A (CYP3A) substrates, midazolam and nifedipine, in obstetrics patients. The model parameters were optimized to fit the data of oral midazolam pharmacokinetics in pregnant women, by increasing CYP3A-induced hepatic metabolism 1.6-fold in the model with no change in gut wall metabolism. Fetal metabolism had a negligible effect on maternal plasma drug concentrations. Validation of the model was performed by applying changes in volume of distribution and metabolism, consistent with those observed for midazolam, to the pharmacokinetics parameters of immediate-release nifedipine in healthy volunteers. The predicted steady-state areas under the concentration-time curve (AUCs) for nifedipine were within 15% of the data observed in pregnant women undergoing treatment for preterm labor. This model predicts the pharmacokinetics of two CYP3A substrates in pregnancy, and may be applicable to other CYP3A substrates as well.CPT Pharmacometrics & Systems Pharmacology (2012) 1, e2; doi10.1038/psp.2012.5; advance online publication 26 September 2012.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article