Physiologically Based Pharmacokinetic (PBPK) Modeling of Midazolam Disposition in Pregnant and Postpartum Women
M. Andrew (1,2,3), M. Hebert (4,5), P. Vicini (1,6)
(1) Department of Bioengineering, University of Washington, Seattle, WA, USA; (2) Applied Physics Laboratory, University of Washington, Seattle, WA; (3) now with Department of Biopharmaceutical Sciences, Uppsala University, Uppsala, Sweden; (4) Department of Pharmacy, University of Washington, Seattle, WA; (5) Department of Obstetrics and Gynecology, University of Washington, Seattle, WA; (6) now with Pfizer Global Research & Development, La Jolla, CA USA
Objectives: Pregnancy alters the pharmacokinetics of midazolam (MDZ) , a probe for CYP 3A activity. The aim of this study was to investigate physiological mechanisms responsible for altered MDZ disposition.
Methods: The model was developed in MATLAB (The Mathworks); maternal and fetal circuits were coupled through the placenta. Previously published volumes and flows  were scaled for gestational age, while partition coefficient and protein binding parameters were obtained from a previously published modeling study . Small intestine (duodenum, jejunum and ileum) and hepatic metabolism were described by Michaelis-Menten kinetics ; metabolism could be varied independently in each tissue. Intestinal metabolism only occurred during first pass, while hepatic metabolism occurred both first pass and systemically.
Results: Predictions first were compared with observations following 7.5, 15, and 30 mg PO dosing in healthy, non-pregnant subjects . Comparison of AUC, CLsys, Cmax and Tmax demonstrated good (within 2 fold) agreement when metabolic expression was altered from base by 1.7 fold. Base expression in the model was thus ‘tuned’ to this value. Predictions then were compared to observations following IV and PO dosing in women undergoing Caesarian section [6,7]. Three to 5 fold increases in hepatic metabolic expression were required to achieve good agreement between prediction and observation, but did not fully explain observations. Lastly, predictions were compared to observations following 2 mg PO dose to women in late pregnancy . Simulations required 7 fold and 5 fold increases in the tuned hepatic expression rate in late pregnancy and 10 weeks postpartum, respectively, to obtain good agreement with observations, although the model still over-predicted the elimination phase of the time course. Good agreement was obtained between predicted and observed maternal-fetal plasma concentration ratio shortly after maternal dosing, but not several hours post-dosing. Sensitivity analysis was used to identify parameters influencing key portions of the predicted time courses.
Conclusions: The PBPK model can be used to predict MDZ time courses in pregnant and 10 weeks postpartum women; however, hepatic metabolic expression required substantial increases to describe observations compared to those required to describe observations in non-pregnant subjects. Research is needed to further explore metabolic mechanisms and the potential effects of altered intestinal and hepatic blood flow on pharmacokinetics during gestation.
 Hebert MF et al. Clin Pharmacol Ther, Feb 2008.
 ICRP Publication 89. Ann ICRP, 32(3-4):5-265, 2002.
 Björkman S. Br J Clin Pharmacol, 59(6):691-704, 2005.
 Paine MF et al. J Pharmacol Exp Ther, 283(3):1552-1562, 1997.
 Bornemann LD et al. Eur J Clin Pharmacol, 29(1):91-95, 1985.
 Kanto, J et al. Clin Pharmacol Ther. 33;786-791,1983.
 Kanto, J et al. Acta Anaesthesiol Scand. 28:116-118,1984.