A PBPK Model to Predict Disposition of CYP3A‐Metabolized Drugs in Pregnant Women: Verification and Discerning the Site of CYP3A Induction

Ke, AB; Nallani, SC; Zhao, Ping; Rostami‐Hodjegan, Amin; Unadkat, Jashvant D.

doi:10.1038/psp.2012.2

Cited by 79 publications

(105 citation statements)

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“…Probe substrate studies are, however, complicated by safety concerns about administering drugs to pregnant women in the absence of clear therapeutic benefit, and the fact that pregnancy is associated with a plethora of physiologic changes that can affect probe disposition in an unpredictable or uncharacterized manner. An approach that appears to be very useful in addressing these issues is physiologically based pharmacokinetic dmd.aspetjournals.org (PBPK) modeling Gaohua et al, 2012;Ke et al, 2012). PBPK modeling allows incorporation of physiologic changes together with changes in multiple enzymes into a model that is fitted to best describe the disposition of well characterized drugs.…”

Section: Knowledge On Enzyme-specific Changes During Pregnancymentioning

confidence: 99%

Drug Metabolism and Transport During Pregnancy: How Does Drug Disposition Change during Pregnancy and What Are the Mechanisms that Cause Such Changes?

2013

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There is increasing evidence that pregnancy alters the function of drug-metabolizing enzymes and drug transporters in a gestationalstage and tissue-specific manner. In vivo probe studies have shown that the activity of several hepatic cytochrome P450 enzymes, such as CYP2D6 and CYP3A4, is increased during pregnancy, whereas the activity of others, such as CYP1A2, is decreased. The activity of some renal transporters, including organic cation transporter and P-glycoprotein, also appears to be increased during pregnancy. Although much has been learned, significant gaps still exist in our understanding of the spectrum of drug metabolism and transport genes affected, gestational age-dependent changes in the activity of encoded drug metabolizing and transporting processes, and the mechanisms of pregnancy-induced alterations. In this issue of Drug Metabolism and Disposition, a series of articles is presented that address the predictability, mechanisms, and magnitude of changes in drug metabolism and transport processes during pregnancy. The articles highlight state-of-the-art approaches to studying mechanisms of changes in drug disposition during pregnancy, and illustrate the use and integration of data from in vitro models, animal studies, and human clinical studies. The findings presented show the complex inter-relationships between multiple regulators of drug metabolism and transport genes, such as estrogens, progesterone, and growth hormone, and their effects on enzyme and transporter expression in different tissues. The studies provide the impetus for a mechanismand evidence-based approach to optimally managing drug therapies during pregnancy and improving treatment outcomes.

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Section: Knowledge On Enzyme-specific Changes During Pregnancymentioning

confidence: 99%

Drug Metabolism and Transport During Pregnancy: How Does Drug Disposition Change during Pregnancy and What Are the Mechanisms that Cause Such Changes?

2013

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“…Among these is approximately a 2-fold induction of CYP3A activity during the third trimester (T3), as measured by 19-OH-midazolam formation clearance (Hebert et al, 2008). Based on genotyping data and modeling and simulation, we have shown that this induction of CYP3A activity is primarily due to induction of hepatic CYP3A4 activity (Hebert et al, 2008;Ke et al, 2012). Many drugs routinely prescribed to pregnant women are cleared by CYP3A enzymes, such as protease inhibitors (e.g., ritonavir), antihypertensive drugs (e.g., nifedipine), and hypoglycemics (e.g., glyburide).…”

Section: Introductionmentioning

confidence: 99%

Prediction of Gestational Age–Dependent Induction of In Vivo Hepatic CYP3A Activity Based on HepaRG Cells and Human Hepatocytes

et al. 2015

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In pregnant women, CYP3A activity increases by 100% during the third trimester (T3). Due to logistical and ethical constraints, little is known about the magnitude of CYP3A induction during the first trimester (T1) and second trimester (T2). Our laboratory has shown that sandwichcultured human hepatocytes (SCHH) and HepaRG cells have the potential to predict the magnitude of in vivo induction of CYP3A activity likely to be observed in T1 and T2. Therefore, we incubated SCHH and HepaRG cells with plasma concentrations of various pregnancyrelated hormones (PRHs)-individually or in combination-observed during T1, T2, or T3 in pregnant women. Then, CYP3A activity was measured by 19-OH-midazolam formation. In all three trimesters, only cortisol (C) consistently and significantly induced CYP3A activity, while other individual hormones (progesterone, estradiol, or growth hormones) failed to induce CYP3A activity. At physiologically relevant 13 plasma concentrations, the magnitude of CYP3A induction by C or the combination of all PRHs did not change significantly with gestational age. The pattern of induction of CYP3A activity in SCHH by the hormones was similar to that in HepaRG cells. Based on these data, we conclude that C remains the major inducer of CYP3A activity earlier in gestation. Moreover, we predict that the magnitude of CYP3A induction during T1 and T2 will be similar to that observed during T3 (∼100% increase versus postpartum). This prediction is consistent with the observation of similar increases in T2 and T3 oral clearance of indinavir (a CYP3A cleared drug) versus postpartum.

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“…A maternal PBPK model incorporating known physiologic parameters as well as maternal hepatic P450 activity in each trimester was recently developed Gaohua et al, 2012;Lu et al, 2012). We refined this PBPK model and showed that the PBPK model populated with CYP3A activity change, based on CL ORAL of midazolam, could accurately predict the T 3 disposition of other CYP3A-metabolized drugs, nifedipine and indinavir (Ke et al, 2012). A sensitivity analysis suggested that CYP3A induction in T 3 is most likely hepatic and not intestinal.…”

Section: Introductionmentioning

confidence: 99%

A Physiologically Based Pharmacokinetic Model to Predict Disposition of CYP2D6 and CYP1A2 Metabolized Drugs in Pregnant Women

Nallani

Zhao

et al. 2013

Drug Metab Dispos

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Conducting pharmacokinetic (PK) studies in pregnant women is challenging. Therefore, we asked if a physiologically based pharmacokinetic (PBPK) model could be used to evaluate different dosing regimens for pregnant women. We refined and verified our previously published pregnancy PBPK model by incorporating cytochrome P450 CYP1A2 suppression (based on caffeine PK) and CYP2D6 induction (based on metoprolol PK) into the model. This model accounts for gestational age-dependent changes in maternal physiology and hepatic CYP3A activity. For verification, the disposition of CYP1A2-metabolized drug theophylline (THEO) and CYP2D6-metabolized drugs paroxetine (PAR), dextromethorphan (DEX), and clonidine (CLO) during pregnancy was predicted. Our PBPK model successfully predicted THEO disposition during the third trimester (T 3 ). Predicted mean postpartum to third trimester (PP:T 3 ) ratios of THEO area under the curve (AUC), maximum plasma concentration, and minimum plasma concentration were 0.76, 0.95, and 0.66 versus observed values 0.75, 0.89, and 0.72, respectively. The predicted mean PAR steady-state plasma concentration (C ss ) ratio (PP:T 3 ) was 7.1 versus the observed value 3.7. Predicted mean DEX urinary ratio (UR) (PP:T 3 ) was 2.9 versus the observed value 1.9. Predicted mean CLO AUC ratio (PP:T 3 ) was 2.2 versus the observed value 1.7. Sensitivity analysis suggested that a 100% induction of CYP2D6 during T 3 was required to recover the observed PP:T 3 ratios of PAR C ss , DEX UR, and CLO AUC. Based on these data, it is prudent to conclude that the magnitude of hepatic CYP2D6 induction during T 3 ranges from 100 to 200%. Our PBPK model can predict the disposition of CYP1A2, 2D6, and 3A drugs during pregnancy.

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A PBPK Model to Predict Disposition of CYP3A‐Metabolized Drugs in Pregnant Women: Verification and Discerning the Site of CYP3A Induction

Cited by 79 publications

References 36 publications

Drug Metabolism and Transport During Pregnancy: How Does Drug Disposition Change during Pregnancy and What Are the Mechanisms that Cause Such Changes?

Drug Metabolism and Transport During Pregnancy: How Does Drug Disposition Change during Pregnancy and What Are the Mechanisms that Cause Such Changes?

Prediction of Gestational Age–Dependent Induction of In Vivo Hepatic CYP3A Activity Based on HepaRG Cells and Human Hepatocytes

A Physiologically Based Pharmacokinetic Model to Predict Disposition of CYP2D6 and CYP1A2 Metabolized Drugs in Pregnant Women

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