A PBPK Model to Predict Disposition of P450 2D6 and P450 1A2 Metabolized Drugs in Pregnant Women.

1 University of Washington, Seattle
Drug metabolism and disposition: the biological fate of chemicals (Impact Factor: 3.25). 01/2013; 41. DOI: 10.1124/dmd.112.050161
Source: PubMed

ABSTRACT Conducting PK studies in pregnant women is challenging. Therefore, we asked if a physiologically-based pharmacokinetic (PBPK) model could be used to evaluate different dosing regimens for pregnant women. We refined and verified our previously published pregnancy PBPK model by incorporating P450 1A2 suppression (based on caffeine PK) and P450 2D6 induction (based on metoprolol PK), into the model. This model accounts for gestational age-dependent changes in maternal physiology and hepatic P450 3A activity. For verification, the disposition of P450 1A2-metabolized drug theophylline (THEO), and P450 2D6-metabolized drugs paroxetine (PAR), dextromethorphan (DEX) and clonidine (CLO) during pregnancy was predicted. Our PBPK model successfully predicted THEO disposition during T(3). Predicted mean postpartum to 3(rd) trimester (PP:T(3)) ratios of THEO AUC, C(max) and C(min) were 0.76, 0.95 and 0.72, vs. observed values 0.75, 0.89 and 0.72, respectively. Predicted mean PAR C(ss) ratio (PP:T(3)) was 7.1 vs. the observed value 3.7. Predicted mean DEX urinary ratio (UR) (PP:T(3)) was 2.9 vs. the observed value 1.9 (Tracy et al., 2005). Predicted mean CLO AUCR (PP:T(3)) was 2.2 vs. the observed value 1.7 (Buchanan et al., 2009). Sensitivity analysis suggested that a 100% induction of P450 2D6 during T(3) was required to recover the observed PP:T(3) ratios of PAR C(ss) , DEX UR and CLO AUC. Based on these data, it is prudent to conclude that the magnitude of hepatic P450 2D6 induction during T(3) ranges from 100 to 200%. Our PBPK model can predict the disposition of CYP1A2, 2D6 and 3A drugs during pregnancy.

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    ABSTRACT: 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. 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. Predicted mean postpartum 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 (Pond et al.,1985). Predicted mean postpartum 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 (Hebert et al., 2009). 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.
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