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
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.
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.
Click here to view.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.
Abbreviations
ADME | absorption, distribution, metabolism, and excretion |
AUC | area under the curve |
AUCR | AUC ratio |
B/P | blood-to-plasma concentration ratio |
CI | confidence interval |
CL | clearance |
CLH | hepatic metabolic clearance |
CLint,u | unbound intrinsic clearance |
CLORAL | oral clearance |
CLr | renal clearance |
CLO | clonidine |
Cmax | maximum plasma concentration |
Cmin | minimum plasma concentration |
Css | steady-state plasma concentration |
DEX | dextromethorphan |
DXO | dextrorphan |
EM | extensive metabolizer |
Fa | fraction absorbed |
Fg | intestinal bioavailability |
Fh | hepatic bioavailability |
fm | fraction metabolized of total body clearance |
fu,p | fraction unbound in plasma |
GFR | glomerular filtration rate |
IVIVE | in vitro-in vivo extrapolation |
ka | first-order absorption rate constant |
Kp | tissue-to-plasma partition coefficient |
MET | metoprolol |
P450 | cytochrome P450 |
PAR | paroxetine |
PBPK model | physiologically based pharmacokinetic model |
PK | pharmacokinetic |
PM | poor metabolizer |
PP | postpartum |
SD | single dose |
SS | steady state |
T1 | T2, and T3, first, second, and third trimesters |
THEO | theophylline |
UR | urinary metabolic ratio |
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.
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.
This article has supplemental material available at dmd.aspetjournals.org.