Document Detail


A pregnancy physiologically based pharmacokinetic (p-PBPK) model for disposition of drugs metabolized by CYP1A2, CYP2D6 and CYP3A4.
MedLine Citation:
PMID:  22725721     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
AIMS: Pregnant women are usually not part of the traditional drug development programme. 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 to prevent under- or overtreatment. We have used a pregnancy physiologically based pharmacokinetic (p-PBPK) model to assess the likely impact of pregnancy on three model compounds, namely caffeine, metoprolol and midazolam, based on the knowledge of their disposition in nonpregnant women and information from in vitro studies.
METHODS: A perfusion-limited form of a 13-compartment full-PBPK model (Simcyp® Simulator) was used for the nonpregnant women, and this was extended to the pregnant state by applying known changes to all model components (including the gestational related activity of specific cytochrome P450 enzymes) and through the addition of an extra compartment to represent the fetoplacental unit. The uterus and the mammary glands were grouped 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 three model compounds (namely caffeine, metoprolol and midazolam) for CYP1A2, CYP2D6 and CYP3A4 during pregnancy within twofold of observed values. The changes during the third 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 nonpregnant women.
CONCLUSIONS: 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 metabolized by a single enzyme to different degrees (high and low extraction) and for drugs that are eliminated by several different routes warrants further study.
Authors:
Lu Gaohua; Khaled Abduljalil; Masoud Jamei; Trevor N Johnson; Amin Rostami-Hodjegan
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Validation Studies    
Journal Detail:
Title:  British journal of clinical pharmacology     Volume:  74     ISSN:  1365-2125     ISO Abbreviation:  Br J Clin Pharmacol     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-09     Completed Date:  2013-03-06     Revised Date:  2013-11-06    
Medline Journal Info:
Nlm Unique ID:  7503323     Medline TA:  Br J Clin Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  873-85     Citation Subset:  IM    
Copyright Information:
© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.
Affiliation:
Simcyp Limited, Sheffield, UK.
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MeSH Terms
Descriptor/Qualifier:
Adult
Caffeine / pharmacokinetics
Cytochrome P-450 CYP1A2 / metabolism*
Cytochrome P-450 CYP2D6 / metabolism*
Cytochrome P-450 CYP3A / metabolism*
Drug Design
Female
Humans
Metoprolol / pharmacokinetics
Midazolam / pharmacokinetics
Models, Biological*
Pregnancy
Pregnancy Trimester, Third
Young Adult
Chemical
Reg. No./Substance:
37350-58-6/Metoprolol; 58-08-2/Caffeine; 59467-70-8/Midazolam; EC 1.14.13.67/CYP3A4 protein, human; EC 1.14.14.1/Cytochrome P-450 CYP1A2; EC 1.14.14.1/Cytochrome P-450 CYP2D6; EC 1.14.14.1/Cytochrome P-450 CYP3A
Comments/Corrections

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