A semi-mechanistic metabolism model of CYP3A substrates in pregnancy: Predicting changes in midazolam and nifedipine pharmacokinetics

S. K. Quinney, A. N. Mohamed, M. F. Hebert, D. M. Haas, Shannon Clark, J. G. Umans, S. N. Caritis, L. Li

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere2
JournalCPT: Pharmacometrics and Systems Pharmacology
Volume1
Issue number1
DOIs
StatePublished - 2012

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Nifedipine
Midazolam
Cytochrome P-450 CYP3A
Pharmacokinetics
Pregnancy
Metabolism
Substrate
Substrates
Pregnant Women
Drugs
Obstetrics
Model
Premature Obstetric Labor
Enzyme activity
Body Composition
Pharmaceutical Preparations
Healthy Volunteers
Enzymes
Fold
Plasma

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

A semi-mechanistic metabolism model of CYP3A substrates in pregnancy : Predicting changes in midazolam and nifedipine pharmacokinetics. / Quinney, S. K.; Mohamed, A. N.; Hebert, M. F.; Haas, D. M.; Clark, Shannon; Umans, J. G.; Caritis, S. N.; Li, L.

In: CPT: Pharmacometrics and Systems Pharmacology, Vol. 1, No. 1, e2, 2012.

Research output: Contribution to journalArticle

Quinney, S. K. ; Mohamed, A. N. ; Hebert, M. F. ; Haas, D. M. ; Clark, Shannon ; Umans, J. G. ; Caritis, S. N. ; Li, L. / A semi-mechanistic metabolism model of CYP3A substrates in pregnancy : Predicting changes in midazolam and nifedipine pharmacokinetics. In: CPT: Pharmacometrics and Systems Pharmacology. 2012 ; Vol. 1, No. 1.
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