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

• Published in: PloS one Vol. 10; no. 10; p. e0139762
• Main Authors: Alqahtani, Saeed, Kaddoumi, Amal
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 02.10.2015; Public Library of Science (PLoS)
• Subjects: Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Chromatography; Comparative analysis; Computer simulation; Cytochrome; Cytochrome P-450; Dosage and administration; Drug dosages; Drug therapy; Enzymes; Female; Gynecology; Health aspects; Humans; Indomethacin; Indomethacin - pharmacokinetics; Indomethacin - pharmacology; Mathematical models; Metabolism; Metabolites; Models, Biological; Obstetrics; Pharmaceutical sciences; Pharmacodynamics; Pharmacokinetics; Pharmacology; Pharmacy; Physiological aspects; Physiology; Plasma levels; Predictions; Pregnancy; Pregnant women; Sensitivity analysis; Steady state; Studies; Womens health; Louisiana; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0139762

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.