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

Abstract

AIMConducting 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. METHODSWe 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. RESULTSPredicted 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. CONCLUSIONSOur 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. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• During pregnancy, changes in physiology and absorption, distribution, metabolism and excretion (ADME) processes can significantly affect the disposition of drugs. Such changes may require adjustments in the dosing regimen of the drug.• Since conducting pharmacokinetic (PK) studies in pregnant women is challenging, alternative approaches that can predict adjustment of drug dosing regimens (if any) are highly desirable. WHAT THIS STUDY ADDS• We expanded and verified a physiologically based PK model, which incorporated gestational age-dependent changes in maternal physiology and major hepatic CYP enzyme activity, to predict disposition during pregnancy of drugs cleared by multiple CYP enzymes (e.g. glyburide and methadone).

Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation Approaches: A Systematic Review of Published Models, Applications, and Model Verification

“…The development of sophisticated models that allow for the simulation of multiple inhibitors or inducers, relevant metabolites, and multiple mechanisms of interaction have permitted the prediction of complex DDIs involving enzymes, transporters, and multiple interaction mechanisms Reki c et al, 2011;Varma et al, 2012Varma et al, , 2013Dhuria et al, 2013;Gertz et al, 2013Gertz et al, , 2014Guo et al, 2013;Kudo et al, 2013;Siccardi et al, 2013;Wang et al, 2013a;Sager et al, 2014;Chen et al, 2015;Shi et al, 2015). Furthermore, the mechanistic understanding of ADME changes that occur in different age groups or disease states has improved, and consequently PBPK modeling has been used to simulate drug disposition in special populations including hepatic (Johnson et al, 2014) and renal impairment populations (Li et al, 2012;Zhao et al, 2012a;Lu et al, 2014;Sayama et al, 2014), children (Leong et al, 2012), and pregnant women (Andrew et al, 2008;Gaohua et al, 2012;Horton et al, 2012;Ke et al, 2012Ke et al, , 2013Ke et al, , 2014Lu et al, 2012).…”

Pharmacologic studies in vulnerable populations: Using the pediatric experience

“…A few exemplary studies exist in pregnant women, including one that used the physiologically-based PK approach to predict gestational age-dependent changes in drug exposure for methadone and glyburide, and another that used this approach to predict changes in exposure to caffeine, metoprolol, and midazolam. 26,27 …”

Translational Systems Pharmacology Studies in Pregnant Women

“…Interestingly, we and others have demonstrated that hepatic, but not gut wall, CYP3A activity seems to be increased during pregnancy . This approach has also been used to estimate the altered activity of other CYP450 enzymes during pregnancy . However, verification of pharmacokinetic models in pregnancy is complicated by a lack of clinical drug concentration data from pregnant women.…”