A PBPK Model to Predict Disposition of P450 2D6 and P450 1A2 Metabolized Drugs in Pregnant Women.
1 University of Washington, SeattleDrug metabolism and disposition: the biological fate of chemicals (Impact Factor: 3.25). 01/2013; 41. DOI: 10.1124/dmd.112.050161
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.British Journal of Clinical Pharmacology 07/2013; 77(3). DOI:10.1111/bcp.12207 · 3.88 Impact Factor
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ABSTRACT: Pregnant women and their fetuses are orphan populations with respect to the safety and efficacy of drugs. Physiological and absorption, distribution, metabolism, and excretion (ADME) changes during pregnancy can significantly affect drug pharmacokinetics (PK) and may necessitate dose adjustment. Here, the specific aspects related to the design, execution, and analysis of clinical studies in pregnant women are discussed, underlining the unmet need for top-down pharmacometrics analyses and bottom-up modeling approaches. The modeling tools that support data analysis for the pregnancy population are reviewed, with a focus on physiologically based pharmacokinetics (PBPK) and population pharmacokinetics (POP-PK). By integrating physiological data, preclinical data, and clinical data (e.g., via POP-PK) to quantify anticipated changes in the PK of drugs during pregnancy, the PBPK approach allows extrapolation beyond the previously studied model drugs to other drugs with well-characterized ADME characteristics. Such a systems pharmacology approach can identify drugs whose PK may be altered during pregnancy, guide rational PK study design, and support dose adjustment for pregnant women.Annual Review of Pharmacology 01/2014; 54(1):53-69. DOI:10.1146/annurev-pharmtox-011613-140009 · 18.37 Impact Factor
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ABSTRACT: Use of pharmacotherapy during pregnancy is common and increasing. Physiologic changes during pregnancy may significantly alter the overall systemic drug exposure, necessitating dose changes. A search of PubMed for pharmacokinetic clinical trials showed 494 publications during pregnancy out of 35,921 total pharmacokinetic published studies (1.29%), from the late 1960s through August 31, 2013. Closer examination of pharmacokinetic studies in pregnant women published since 2008 (81 studies) revealed that about a third of the trials were for treatment of acute labor and delivery issues, a third included studies of infectious disease treatment during pregnancy, and the remaining third were for varied ante-partum indications. Approximately, two-thirds of these recent studies were primarily funded by government agencies worldwide, one-quarter were supported by private non-profit foundations or combinations of government and private funding, and slightly <10% were supported by pharmaceutical industry. As highlighted in this review, vast gaps exist in pharmacology information and evidence for appropriate dosing of medications in pregnant women. This lack of knowledge and understanding of drug disposition throughout pregnancy place both the mother and the fetus at risk for avoidable therapeutic misadventures - suboptimal efficacy or excess toxicity - with medication use in pregnancy. Increased efforts to perform and support obstetric dosing and pharmacokinetic studies are greatly needed.Frontiers in Pediatrics 02/2014; 2:9. DOI:10.3389/fped.2014.00009
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