Expansion of a PBPK model to predict disposition in pregnant women of drugs cleared via multiple CYP enzymes, including CYP2B6, CYP2C9 and CYP2C19

Br J Clin Pharmacol. 2014 Mar;77(3):554-70. doi: 10.1111/bcp.12207.

Abstract

Aim: Conducting PK studies in pregnant women is challenging. Therefore, we asked if a physiologically-based pharmacokinetic (PBPK) model could be used to predict the disposition in pregnant women of drugs cleared by multiple CYP enzymes.

Methods: We expanded and verified our previously published pregnancy PBPK model by incorporating hepatic CYP2B6 induction (based on in vitro data), CYP2C9 induction (based on phenytoin PK) and CYP2C19 suppression (based on proguanil PK), into the model. This model accounted for gestational age-dependent changes in maternal physiology and hepatic CYP3A, CYP1A2 and CYP2D6 activity. For verification, the pregnancy-related changes in the disposition of methadone (cleared by CYP2B6, 3A and 2C19) and glyburide (cleared by CYP3A, 2C9 and 2C19) were predicted.

Results: Predicted mean post-partum to second trimester (PP : T2 ) ratios of methadone AUC, Cmax and Cmin were 1.9, 1.7 and 2.0, vs. observed values 2.0, 2.0 and 2.6, respectively. Predicted mean post-partum to third trimester (PP : T3 ) ratios of methadone AUC, Cmax and Cmin were 2.1, 2.0 and 2.4, vs. observed values 1.7, 1.7 and 1.8, respectively. Predicted PP : T3 ratios of glyburide AUC, Cmax and Cmin were 2.6, 2.2 and 7.0 vs. observed values 2.1, 2.2 and 3.2, respectively.

Conclusions: Our PBPK model integrating prior physiological knowledge, in vitro and in vivo data, allowed successful prediction of methadone and glyburide disposition during pregnancy. We propose this expanded PBPK model can be used to evaluate different dosing scenarios, during pregnancy, of drugs cleared by single or multiple CYP enzymes.

Keywords: CYP2B6; CYP2C19; CYP2C9; PBPK; pharmacokinetics; pregnancy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Aryl Hydrocarbon Hydroxylases / metabolism*
  • Biotransformation
  • Computer Simulation
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP2C19
  • Cytochrome P-450 CYP2C9
  • Female
  • Glyburide / pharmacokinetics*
  • Hepatocytes / enzymology*
  • Humans
  • Methadone / pharmacokinetics*
  • Mice
  • Models, Biological*
  • Pregnancy
  • Substrate Specificity
  • Workflow

Substances

  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • CYP2B6 protein, human
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP2C19
  • Glyburide
  • Methadone