A pregnancy physiologically based pharmacokinetic (p-PBPK) model for disposition of drugs metabolized by CYP1A2, CYP2D6 and CYP3A4.

AIMS Pregnant women are usually not part of the traditional drug development programme. Pregnancy is associated with major biological and physiological changes that alter the pharmacokinetics (PK) of drugs. Prediction of the changes to drug exposure in this group of patients may help to prevent under- or overtreatment. We have used a pregnancy physiologically based pharmacokinetic (p-PBPK) model to assess the likely impact of pregnancy on three model compounds, namely caffeine, metoprolol and midazolam, based on the knowledge of their disposition in nonpregnant women and information from in vitro studies. METHODS A perfusion-limited form of a 13-compartment full-PBPK model (Simcyp® Simulator) was used for the nonpregnant women, and this was extended to the pregnant state by applying known changes to all model components (including the gestational related activity of specific cytochrome P450 enzymes) and through the addition of an extra compartment to represent the fetoplacental unit. The uterus and the mammary glands were grouped into the muscle compartment. The model was implemented in Matlab Simulink and validated using clinical observations. RESULTS The p-PBPK model predicted the PK changes of three model compounds (namely caffeine, metoprolol and midazolam) for CYP1A2, CYP2D6 and CYP3A4 during pregnancy within twofold of observed values. The changes during the third trimester were predicted to be a 100% increase, a 30% decrease and a 35% decrease in the exposure of caffeine, metoprolol and midazolam, respectively, compared with the nonpregnant women. CONCLUSIONS In the absence of clinical data, the in silico prediction of PK behaviour during pregnancy can provide a valuable aid to dose adjustment in pregnant women. The performance of the model for drugs metabolized by a single enzyme to different degrees (high and low extraction) and for drugs that are eliminated by several different routes warrants further study.

[1]  H J Clewell,et al.  Evaluation of the uncertainty in an oral reference dose for methylmercury due to interindividual variability in pharmacokinetics. , 1999, Risk analysis : an official publication of the Society for Risk Analysis.

[2]  M. Rowland,et al.  Physiologically based pharmacokinetic modeling 1: predicting the tissue distribution of moderate-to-strong bases. , 2005, Journal of pharmaceutical sciences.

[3]  W D Wosilait,et al.  Mathematical modeling of human embryonic and fetal growth rates. , 1999, Growth, development, and aging : GDA.

[4]  Amin Rostami-Hodjegan,et al.  Simulation and prediction of in vivo drug metabolism in human populations from in vitro data , 2007, Nature Reviews Drug Discovery.

[5]  Kairui Feng,et al.  The Simcyp population-based ADME simulator. , 2009, Expert opinion on drug metabolism & toxicology.

[6]  R. Luecke,et al.  Mathematical analysis for teratogenic sensitivity. , 1997, Teratology.

[7]  C. Schlatter,et al.  The effect of pregnancy on the pharmacokinetics of caffeine. , 1982, Archives of toxicology. Supplement. = Archiv fur Toxikologie. Supplement.

[8]  W. Parsons,et al.  Delayed elimination of caffeine by women in the last 2 weeks of pregnancy. , 1982, Canadian Medical Association journal.

[9]  Richard A Corley,et al.  Evaluation of Physiologically Based Models of Pregnancy and Lactation for Their Application in Children's Health Risk Assessments , 2003, Critical reviews in toxicology.

[10]  B. Kirby,et al.  Effects of Pregnancy on CYP3A and P‐glycoprotein Activities as Measured by Disposition of Midazolam and Digoxin: A University of Washington Specialized Center of Research Study , 2008, Clinical pharmacology and therapeutics.

[11]  Kirsi Vähäkangas,et al.  Drug transporters in the human blood‐placental barrier , 2009, British journal of pharmacology.

[12]  Amin Rostami-Hodjegan,et al.  Anatomical, Physiological and Metabolic Changes with Gestational Age during Normal Pregnancy , 2012, Clinical Pharmacokinetics.

[13]  M Jamei,et al.  Physiologically-based pharmacokinetic (PBPK) models for assessing the kinetics of xenobiotics during pregnancy: achievements and shortcomings. , 2012, Current drug metabolism.

[14]  P. Wells,et al.  Participation of pregnant women in clinical trials: will they participate and why? , 2003, American journal of perinatology.

[15]  M. Rowland,et al.  Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. , 2006, Journal of pharmaceutical sciences.

[16]  Richard C. Brundage,et al.  Mixture Models and Subpopulation Classification: A Pharmacokinetic Simulation Study and Application to Metoprolol CYP2D6 Phenotype , 2007, Journal of Pharmacokinetics and Pharmacodynamics.

[17]  M. Wadelius,et al.  Induction of CYP2D6 in pregnancy , 1997, Clinical pharmacology and therapeutics.

[18]  Melinda F. Davis,et al.  Pharmacokinetics of Sertraline Across Pregnancy and Postpartum , 2008, Journal of clinical psychopharmacology.

[19]  J. Nunemacher,et al.  Optimal management of giant cell arteritis and polymyalgia rheumatica , 2012, Therapeutics and clinical risk management.

[20]  C. Schlatter,et al.  The Effect of Pregnancy on the Pharmacokinetics of Caffeine , 1981 .

[21]  G. Riquelme.  Review: Placental syncytiotrophoblast membranes--domains, subdomains and microdomains. , 2011, Placenta.

[22]  T. Tracy,et al.  Alterations in drug disposition during pregnancy: , 2007 .

[23]  P. Gaillard,et al.  The role of drug transporters at the blood-brain barrier. , 2003, Annual review of pharmacology and toxicology.

[24]  A H Neims,et al.  The disposition of caffeine during and after pregnancy. , 1981, Seminars in perinatology.

[25]  J. Coverdale,et al.  A comprehensive ethical framework for responsibly designing and conducting pharmacologic research that involves pregnant women. , 2005, American journal of obstetrics and gynecology.

[26]  G. Anderson.  Pregnancy-Induced Changes in Pharmacokinetics , 2005, Clinical pharmacokinetics.

[27]  K. Wisner,et al.  Changes in antidepressant metabolism and dosing across pregnancy and early postpartum. , 2008, The Journal of clinical psychiatry.

[28]  John F. Young,et al.  Physiological "constants" for PBPK models for pregnancy. , 1997, Journal of toxicology and environmental health.

[29]  John F. Young,et al.  A physiologically based pharmacokinetic computer model for human pregnancy. , 1994, Teratology.

[30]  A. Mcmanus,et al.  Off‐label prescribing during pregnancy in the UK: an analysis of 18 000 prescriptions in Liverpool Women's Hospital , 2010, The International journal of pharmacy practice.

[31]  W D Wosilait,et al.  A computer model and program for xenobiotic disposition during pregnancy. , 1997, Computer methods and programs in biomedicine.

[32]  W. Rayburn,et al.  Off-label drug prescribing on a state university obstetric service. , 1995, The Journal of reproductive medicine.

[33]  Y. Yonekawa,et al.  Fetal Blood-Brain Barrier P-Glycoprotein Contributes to Brain Protection During Human Development , 2008, Journal of neuropathology and experimental neurology.

[34]  Paolo Vicini,et al.  Physiologically based pharmacokinetic model of midazolam disposition during pregnancy , 2008, 2008 30th Annual International Conference of the IEEE Engineering in Medicine and Biology Society.

[35]  T. Tracy,et al.  Alterations in drug disposition during pregnancy: implications for drug therapy. , 2007, Expert opinion on drug metabolism & toxicology.

[36]  C. Funck-Brentano,et al.  Influence of CYP2D6-dependent metabolism on the steady-state pharmacokinetics and pharmacodynamics of metoprolol and nicardipine, alone and in combination. , 1993, British journal of clinical pharmacology.

[37]  C. Regårdh,et al.  Pregnancy‐induced increase in metoprolol metabolism , 1985, Clinical pharmacology and therapeutics.

[38]  Rayburn Wf,et al.  Off-label drug prescribing on a state university obstetric service. , 1995 .

[39]  M. Loriot,et al.  Xenobiotic-Metabolizing Enzymes and Transporters in the Normal Human Brain: Regional and Cellular Mapping as a Basis for Putative Roles in Cerebral Function , 2009, Drug Metabolism and Disposition.

[40]  C. Chambers,et al.  Drug Safety in Pregnant Women and Their Babies: Ignorance Not Bliss , 2008, Clinical pharmacology and therapeutics.

[41]  E. Maiorano,et al.  Glial cells and blood-brain barrier in the human cerebral cortex. , 1995, Italian journal of anatomy and embryology = Archivio italiano di anatomia ed embriologia.

[42]  I. Miyakawa,et al.  The effect of pregnancy on cytochrome P4501A2, xanthine oxidase, and N‐acetyltransferase activities in humans , 2001, Clinical pharmacology and therapeutics.

[43]  J. Antel,et al.  Glial cell influence on the human blood‐brain barrier , 2001, Glia.

[44]  W. Huisinga,et al.  Gestational influences on the pharmacokinetics of gestagenic drugs: a combined in silico, in vitro and in vivo analysis. , 2011, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[45]  S. Caritis,et al.  Temporal changes in drug metabolism (CYP1A2, CYP2D6 and CYP3A Activity) during pregnancy. , 2005, American journal of obstetrics and gynecology.

[46]  D. Mattison,et al.  Gaps in knowledge in treating pregnant women. , 2006, Gender medicine.

[47]  J L Brazier,et al.  Pharmacokinetics of caffeine during and after pregnancy. , 1983, Developmental pharmacology and therapeutics.

[48]  P. Myllynen,et al.  Developmental expression of drug metabolizing enzymes and transporter proteins in human placenta and fetal tissues , 2009, Expert opinion on drug metabolism & toxicology.

[49]  J. Keelan,et al.  Drug Transfer and Metabolism by the Human Placenta , 2004, Clinical pharmacokinetics.