A physiologically based pharmacokinetic model to predict disposition of CYP2D6 and CYP1A2 metabolized drugs in pregnant women.
Journal: 2013/November - Drug Metabolism and Disposition
ISSN: 1521-009X
Abstract:
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 (T3). Predicted mean postpartum to third trimester (PP:T3) 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 (Css) ratio (PP:T3) was 7.1 versus the observed value 3.7. Predicted mean DEX urinary ratio (UR) (PP:T3) was 2.9 versus the observed value 1.9. Predicted mean CLO AUC ratio (PP:T3) was 2.2 versus the observed value 1.7. Sensitivity analysis suggested that a 100% induction of CYP2D6 during T3 was required to recover the observed PP:T3 ratios of PAR Css, DEX UR, and CLO AUC. Based on these data, it is prudent to conclude that the magnitude of hepatic CYP2D6 induction during T3 ranges from 100 to 200%. Our PBPK model can predict the disposition of CYP1A2, 2D6, and 3A drugs during pregnancy.
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Drug Metab Dispos 41(4): 801-813

A Physiologically Based Pharmacokinetic Model to Predict Disposition of CYP2D6 and CYP1A2 Metabolized Drugs in Pregnant Women<sup><a href="#FN3" rid="FN3" class=" fn"><img alt="An external file that holds a picture, illustration, etc. Object name is sbox.jpg" src="/pmc/articles/PMC3608458/bin/sbox.jpg"></a></sup>

Supplementary Material

Supplemental Data:
Department of Pharmaceutics, University of Washington, Seattle, Washington (A.B.K., N.I., J.D.U.); Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland (A.B.K., S.C.N., P.Z.); School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom(A.R.-H.); and Simcyp Limited, now part of Certara, Sheffield, United Kingdom (A.R-.H.)
Corresponding author.
Address correspondence to: Dr. Jashvant D. Unadkat, Department of Pharmaceutics, University of Washington, Box 357610, Seattle, WA 98195., E-mail: ude.notgnihsaw.u@hsaj
Received 2012 Nov 19; Accepted 2013 Jan 25.

Abstract

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 (T3). Predicted mean postpartum to third trimester (PP:T3) 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 (Css) ratio (PP:T3) was 7.1 versus the observed value 3.7. Predicted mean DEX urinary ratio (UR) (PP:T3) was 2.9 versus the observed value 1.9. Predicted mean CLO AUC ratio (PP:T3) was 2.2 versus the observed value 1.7. Sensitivity analysis suggested that a 100% induction of CYP2D6 during T3 was required to recover the observed PP:T3 ratios of PAR Css, DEX UR, and CLO AUC. Based on these data, it is prudent to conclude that the magnitude of hepatic CYP2D6 induction during T3 ranges from 100 to 200%. Our PBPK model can predict the disposition of CYP1A2, 2D6, and 3A drugs during pregnancy.

Abstract

Qgut, hybrid parameter of blood flow and drug permeability; Vss, volume of distribution at steady state.

Qgut, hybrid parameter of blood flow and drug permeability; Vss, volume of distribution at steady state.

Qgut, hybrid parameter of blood flow and drug permeability; Vss, volume of distribution at steady state.

Qgut, hybrid parameter of blood flow and drug permeability; Vss, volume of distribution at steady state.

Qgut, hybrid parameter of blood flow and drug permeability; Vss, volume of distribution at steady state.

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Acknowledgments

The authors thank Drs. William J. Jusko (State University of New York, Buffalo), Timothy Tracy (University of Kentucky, Lexington), Uwe Fuhr (University of Cologne, Cologne, Germany), Mia Wadelius (Uppsala University, Uppsala, Sweden), and Mary Herbert (University of Washington, Seattle) for providing clinical PK data used for model validation.

Acknowledgments

Abbreviations

ADMEabsorption, distribution, metabolism, and excretion
AUCarea under the curve
AUCRAUC ratio
B/Pblood-to-plasma concentration ratio
CIconfidence interval
CLclearance
CLHhepatic metabolic clearance
CLint,uunbound intrinsic clearance
CLORALoral clearance
CLrrenal clearance
CLOclonidine
Cmaxmaximum plasma concentration
Cminminimum plasma concentration
Csssteady-state plasma concentration
DEXdextromethorphan
DXOdextrorphan
EMextensive metabolizer
Fafraction absorbed
Fgintestinal bioavailability
Fhhepatic bioavailability
fmfraction metabolized of total body clearance
fu,pfraction unbound in plasma
GFRglomerular filtration rate
IVIVEin vitro-in vivo extrapolation
kafirst-order absorption rate constant
Kptissue-to-plasma partition coefficient
METmetoprolol
P450cytochrome P450
PARparoxetine
PBPK modelphysiologically based pharmacokinetic model
PKpharmacokinetic
PMpoor metabolizer
PPpostpartum
SDsingle dose
SSsteady state
T1T2, and T3, first, second, and third trimesters
THEOtheophylline
URurinary metabolic ratio
Abbreviations

Authorship Contributions

Participated in research design: Ke, Nallani, Zhao, Rostami-Hodjegan, Isoherranen, Unadkat.

Conducted experiments: Ke.

Contributed new reagents or analytic tools: Rostami-Hodjegan.

Performed data analysis: Ke.

Wrote or contributed to the writing of the manuscript: Ke, Nallani, Zhao, Rostami-Hodjegan, Isoherranen, Unadkat.

Authorship Contributions

Footnotes

This work was supported by the Food and Drug Administration Office of Women’s Health and a visiting fellowship from Simcyp Limited (now part of Certara). The clonidine pharmacokinetics study in pregnancy was supported in part by a grant from the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development [Grant U10HD047892]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development or the National Institutes of Health.

dx.doi.org/10.1124/dmd.112.050161.

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