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Development of Physiologically Based Pharmacokinetic/Pharmacodynamic Model for Indomethacin Disposition in Pregnancy.

Alqahtani S, Kaddoumi A - PLoS ONE (2015)

Bottom Line: Findings of a recent clinical study showed indomethacin has lower plasma levels and higher steady-state apparent clearance in pregnant subjects when compared to those in non-pregnant subjects reported in separate studies.The developed PBPK model which integrates prior physiological knowledge, in vitro and in vivo data, allowed the successful prediction of indomethacin disposition during T2.Our PBPK/PD model suggested a higher indomethacin dosing requirement during pregnancy.

View Article: PubMed Central - PubMed

Affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, School of Pharmacy, Monroe, Louisiana, United States of America.

ABSTRACT
Findings of a recent clinical study showed indomethacin has lower plasma levels and higher steady-state apparent clearance in pregnant subjects when compared to those in non-pregnant subjects reported in separate studies. Thus, in the current work we developed a pregnancy physiological based pharmacokinetic/pharmacodynamic (PBPK/PD) model for indomethacin to explain the differences in indomethacin pharmacokinetics between pregnancy and non-pregnancy. A whole-body PBPK model with key pregnancy-related physiological changes was developed to characterize indomethacin PK in pregnant women and compare these parameters to those in non-pregnant subjects. Data related to maternal physiological and biological changes were obtained from literature and incorporated into the structural PBPK model that describes non-pregnant PK data. Changes in indomethacin area under the curve (AUC), maximum concentration (Cmax) and average steady-state concentration (Cave) in pregnant women were predicted. Model-simulated PK profiles were in agreement with observed data. The predicted mean ratio (non-pregnant:second trimester (T2)) of indomethacin Cave was 1.6 compared to the observed value of 1.59. In addition, the predicted steady-state apparent clearance (CL/Fss) ratio was almost similar to the observed value (0.46 vs. 0.42). Sensitivity analysis suggested changes in CYP2C9 activity, and to a lesser extent UGT2B7, as the primary factor contributing to differences in indomethacin disposition between pregnancy and non-pregnancy. The developed PBPK model which integrates prior physiological knowledge, in vitro and in vivo data, allowed the successful prediction of indomethacin disposition during T2. Our PBPK/PD model suggested a higher indomethacin dosing requirement during pregnancy.

No MeSH data available.


Related in: MedlinePlus

Simulated and observed PD effect-time profiles for indomethacin presented as % decrease in PGEM (13, 14-dihydro-15-ketoprostaglandin E2) plasma concentration vs. time after single oral administration of 25mg.The solid line represents predicted mean indomethacin profile in non-pregnant subjects. The dashed line represents predicted mean indomethacin profile in pregnant subjects. Mean observed data are overlaid for 25 mg dose in non-pregnant subjects [39]. The green and blue shaded areas represent the 90% confidence interval for the simulated data, and error bars represent ± SD.
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pone.0139762.g005: Simulated and observed PD effect-time profiles for indomethacin presented as % decrease in PGEM (13, 14-dihydro-15-ketoprostaglandin E2) plasma concentration vs. time after single oral administration of 25mg.The solid line represents predicted mean indomethacin profile in non-pregnant subjects. The dashed line represents predicted mean indomethacin profile in pregnant subjects. Mean observed data are overlaid for 25 mg dose in non-pregnant subjects [39]. The green and blue shaded areas represent the 90% confidence interval for the simulated data, and error bars represent ± SD.

Mentions: It has been reported that prostaglandin inhibition, measured by changes in PGEM concentration, correlated significantly with indomethacin concentrations in plasma and could be used to monitor the effect of this drug [39]. Models were fitted for the reported PD response after indomethacin administration based on the drug’s unbound concentration-time profiles. The three direct PD models (Log linear, Emax and Sigmoid) resulted in close matches between observed and simulated effect-time data for indomethacin PD effects measured as % decrease in PGEM plasma concentrations. The three models were used to predict effect-time profile for 25 mg oral dose of indomethacin. The Emax model gave the best prediction of maximum effect for PD effect with prediction errors of less than 5% (Fig 5). The maximum effect prediction error for the Log linear and Sigmoid models was more than 10%. The fitted PD models were then used to predict the effect of 25mg of indomethacin in T2 of pregnancy. As shown in Fig 5, 25 mg oral dose of indomethacin in pregnant women in their T2 failed to attain the PD effect of indomethacin in non-pregnant subjects indicating the possible need for dose adjustment during pregnancy.


Development of Physiologically Based Pharmacokinetic/Pharmacodynamic Model for Indomethacin Disposition in Pregnancy.

Alqahtani S, Kaddoumi A - PLoS ONE (2015)

Simulated and observed PD effect-time profiles for indomethacin presented as % decrease in PGEM (13, 14-dihydro-15-ketoprostaglandin E2) plasma concentration vs. time after single oral administration of 25mg.The solid line represents predicted mean indomethacin profile in non-pregnant subjects. The dashed line represents predicted mean indomethacin profile in pregnant subjects. Mean observed data are overlaid for 25 mg dose in non-pregnant subjects [39]. The green and blue shaded areas represent the 90% confidence interval for the simulated data, and error bars represent ± SD.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4592215&req=5

pone.0139762.g005: Simulated and observed PD effect-time profiles for indomethacin presented as % decrease in PGEM (13, 14-dihydro-15-ketoprostaglandin E2) plasma concentration vs. time after single oral administration of 25mg.The solid line represents predicted mean indomethacin profile in non-pregnant subjects. The dashed line represents predicted mean indomethacin profile in pregnant subjects. Mean observed data are overlaid for 25 mg dose in non-pregnant subjects [39]. The green and blue shaded areas represent the 90% confidence interval for the simulated data, and error bars represent ± SD.
Mentions: It has been reported that prostaglandin inhibition, measured by changes in PGEM concentration, correlated significantly with indomethacin concentrations in plasma and could be used to monitor the effect of this drug [39]. Models were fitted for the reported PD response after indomethacin administration based on the drug’s unbound concentration-time profiles. The three direct PD models (Log linear, Emax and Sigmoid) resulted in close matches between observed and simulated effect-time data for indomethacin PD effects measured as % decrease in PGEM plasma concentrations. The three models were used to predict effect-time profile for 25 mg oral dose of indomethacin. The Emax model gave the best prediction of maximum effect for PD effect with prediction errors of less than 5% (Fig 5). The maximum effect prediction error for the Log linear and Sigmoid models was more than 10%. The fitted PD models were then used to predict the effect of 25mg of indomethacin in T2 of pregnancy. As shown in Fig 5, 25 mg oral dose of indomethacin in pregnant women in their T2 failed to attain the PD effect of indomethacin in non-pregnant subjects indicating the possible need for dose adjustment during pregnancy.

Bottom Line: Findings of a recent clinical study showed indomethacin has lower plasma levels and higher steady-state apparent clearance in pregnant subjects when compared to those in non-pregnant subjects reported in separate studies.The developed PBPK model which integrates prior physiological knowledge, in vitro and in vivo data, allowed the successful prediction of indomethacin disposition during T2.Our PBPK/PD model suggested a higher indomethacin dosing requirement during pregnancy.

View Article: PubMed Central - PubMed

Affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, School of Pharmacy, Monroe, Louisiana, United States of America.

ABSTRACT
Findings of a recent clinical study showed indomethacin has lower plasma levels and higher steady-state apparent clearance in pregnant subjects when compared to those in non-pregnant subjects reported in separate studies. Thus, in the current work we developed a pregnancy physiological based pharmacokinetic/pharmacodynamic (PBPK/PD) model for indomethacin to explain the differences in indomethacin pharmacokinetics between pregnancy and non-pregnancy. A whole-body PBPK model with key pregnancy-related physiological changes was developed to characterize indomethacin PK in pregnant women and compare these parameters to those in non-pregnant subjects. Data related to maternal physiological and biological changes were obtained from literature and incorporated into the structural PBPK model that describes non-pregnant PK data. Changes in indomethacin area under the curve (AUC), maximum concentration (Cmax) and average steady-state concentration (Cave) in pregnant women were predicted. Model-simulated PK profiles were in agreement with observed data. The predicted mean ratio (non-pregnant:second trimester (T2)) of indomethacin Cave was 1.6 compared to the observed value of 1.59. In addition, the predicted steady-state apparent clearance (CL/Fss) ratio was almost similar to the observed value (0.46 vs. 0.42). Sensitivity analysis suggested changes in CYP2C9 activity, and to a lesser extent UGT2B7, as the primary factor contributing to differences in indomethacin disposition between pregnancy and non-pregnancy. The developed PBPK model which integrates prior physiological knowledge, in vitro and in vivo data, allowed the successful prediction of indomethacin disposition during T2. Our PBPK/PD model suggested a higher indomethacin dosing requirement during pregnancy.

No MeSH data available.


Related in: MedlinePlus