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A Pregnancy Physiologically-Based Pharmacokinetic (p-PBPK) Model for Disposition of Drugs Metabolized by CYP1A2, CYP3A4 and CYP2D6.

Br J Clin Pharmacol. 2012 Jun 22;

Authors: Gaohua L, Abduljalil K, Jamei M, Johnson TN, Rostami-Hodjegan A


BACKGROUND AND OBJECTIVES: Pregnant women are usually not part of the traditional drug development program. Pregnancy is associated with major biological and physiological changes that alter the pharmacokinetics (PK) of drugs. Prediction of the changes to drug exposure in this group of patients may help with under- or over-treatment. We have used a pregnancy physiologically-based pharmacokinetic (p-PBPK) model to assess the likely impact of pregnancy on 3 model compounds, caffeine, midazolam, and metoprolol based on the knowledge of their disposition in non-pregnant subjects and information from in vitro studies. METHODS: A perfusion-limited form of a 13-compartment full-PBPK model (Simcyp(®) Simulator) was used for the non-pregnant women and this was extended to pregnancy status by applying known changes to all model components (including the gestational related activity of specific cytochromes P450's) and through the addition of an extra compartment to represent the foeto-placental unit. The uterus and the mammalian glands were lumped into the muscle compartment. The model was implemented in Matlab Simulink and validated using clinical observations. RESULTS: The p-PBPK model predicted the PK changes of 3 model compounds for CYP1A2, CYP3A4 and CYP2D6 (namely caffeine, midazolam and metoprolol) during pregnancy within 2 fold of observed values. The changes during 3(rd) trimester were predicted to be a 100% increase, a 30% decrease, and a 35% decrease in the exposure of caffeine, metoprolol and midazolam, respectively, compared with the non-pregnant women. CONCLUSION: In the absence of clinical data, the in silico prediction of PK behaviour during pregnancy can provide a valuable aid to dose adjustment in pregnant women. The performance of the model for drugs metabolised by a single enzyme to different degree (high and low extraction) and for drugs which are eliminated by several different routes warrants further study.

PMID: 22725721 [PubMed - as supplied by publisher]