A pregnancy physiologically based pharmacokinetic (p-PBPK) model for disposition of drugs metabolized by CYP1A2, CYP2D6 and CYP3A4.
OBJECTIVE
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.
Simcyp Limited, Sheffield, UK.
Lu
L
Gaohua
Khaled
K
Abduljalil
Masoud
M
Jamei
Trevor N
TN
Johnson
Amin
A
Rostami-Hodjegan
D000328:Adult; D002110:Caffeine / Q000493:pharmacokinetics; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D015195:Drug Design; D005260:Female; D006801:Humans; D008790:Metoprolol / Q000493:pharmacokinetics; D008874:Midazolam / Q000493:pharmacokinetics; D008954:Models, Biological; D011247:Pregnancy; D011263:Pregnancy Trimester, Third; D055815:Young Adult
D002110:Caffeine; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008790:Metoprolol; D008874:Midazolam