Expansion of a PBPK model to predict disposition in pregnant women of drugs cleared via multiple CYP enzymes, including CYP2B6, CYP2C9 and CYP2C19. (March 2014)

• Record Type: Journal Article
• Authors: Ke, Alice Ban; Nallani, Srikanth C.; Zhao, Ping; Rostami‐Hodjegan, Amin; Unadkat, Jashvant D.
• Is Part Of: British journal of clinical pharmacology. Volume 77:Number 3(2014:Mar.)
• Page Start: 554
• Page End: 570
• Publication Date: 2014-03
• Subjects: Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.12207
• Languages: English
• ISSNs: 0306-5251

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bcp12207-sec-0001" sec-type="section"> <title>Aim</title> <p>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.</p> </sec> <sec id="bcp12207-sec-0002" sec-type="section"> <title>Methods</title> <p>We expanded and verified our previously published pregnancy PBPK model by incorporating hepatic CYP2B6 induction (based on <italic>in vitro</italic> 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.</p> </sec> <sec id="bcp12207-sec-0003" sec-type="section"> <title>Results</title> <p>Predicted mean post‐partum to second trimester (PP : T<sub>2</sub>) ratios of methadone AUC, <italic>C</italic><sub>max</sub> and <italic>C</italic><sub>min</sub> were 1.9, 1.7 and 2.0, <italic>vs.</italic> observed values 2.0, 2.0 and 2.6, respectively. Predicted mean post‐partum to third trimester (PP : T<sub>3</sub>) ratios of methadone AUC, <italic>C</italic><sub>max</sub> and <italic>C</italic><sub>min</sub> were 2.1, 2.0 and 2.4, <italic>vs.</italic> observed values 1.7, 1.7 and 1.8, respectively. Predicted PP : T<sub>3</sub> ratios of glyburide AUC, <italic>C</italic><sub>max</sub> and <italic>C</italic><sub>min</sub> were 2.6, 2.2 and 7.0 <italic>vs.</italic> observed values 2.1, 2.2 and 3.2, respectively.</p> </sec> <sec id="bcp12207-sec-0004" sec-type="section"> <title>Conclusions</title> <p>Our PBPK model integrating prior physiological knowledge, <italic>in vitro</italic> and <italic>in vivo</italic> 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.</p> </sec> </abstract>