A PBPK Model to Predict Disposition of P450 2D6 and P450 1A2 Metabolized Drugs in Pregnant Women.
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: 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 01/2014; 2:9.
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ABSTRACT: Fluoxetine and its circulating metabolite norfluoxetine present a complex multiple inhibitor system that causes reversible or time-dependent inhibition of CYP2D6, CYP3A4, and CYP2C19 in vitro. While significant inhibition of all three enzymes in vivo is predicted, midazolam and lovastatin AUCs were unaffected by two week dosing of fluoxetine whereas dextromethorphan AUC was increased by 27-fold and omeprazole AUC by 7.1-fold. This observed discrepancy between in vitro risk assessment and in vivo DDI profile was rationalized by time-varying dynamic pharmacokinetic models that incorporated circulating concentrations of fluoxetine and norfluoxetine enantiomers, mutual inhibitor-inhibitor interactions and CYP3A4 induction. The dynamic models predicted all DDIs with less than 2-fold error. This study demonstrates that complex drug-drug interactions that involve multiple mechanisms, pathways and inhibitors with their metabolites can be predicted and rationalized via characterization of all the inhibitory species in vitro.Clinical Pharmacology & Therapeutics (2014); Accepted article preview online 25 February 2014. doi:10.1038/clpt.2014.50.Clinical Pharmacology & Therapeutics 02/2014; · 6.85 Impact Factor
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ABSTRACT: An important goal in drug development is to understand the effects of intrinsic and/or extrinsic factors (IEFs) on drug pharmacokinetics. Although clinical studies investigating a given IEF can accomplish this goal, they may not be feasible for all IEFs or for situations when multiple IEFs exist concurrently. Physiologically-based pharmacokinetic (PBPK) models may serve as a complementary tool for forecasting the effects of IEFs. We developed PBPK models for four drugs that are eliminated by both CYP3A4 and CYP2D6, and evaluated model prediction of the effects of co-medications and/or genetic polymorphism on drug exposure. PBPK predicted 100% and =70% of the observed results when the conventional "2-fold rule" and the more conservative 25% deviation cut-point were applied, respectively. These findings suggest PBPK can inform effects of individual or combined IEFs, and should be considered to optimize studies that evaluate these factors, specifically drug interactions and genetic polymorphism of drug metabolizing enzymes.Clinical Pharmacology & Therapeutics (2014); Accepted article preview online 20 February 2014. doi:10.1038/clpt.2014.43.Clinical Pharmacology & Therapeutics 02/2014; · 6.85 Impact Factor