A physiologically based pharmacokinetic modeling approach to predict drug–drug interactions between domperidone and inhibitors of CYP3A4. (January 2016)

• Record Type: Journal Article
• Authors: Templeton, Ian; Ravenstijn, Paulien; Sensenhauser, Carlo; Snoeys, Jan
• Is Part Of: Biopharmaceutics & drug disposition. Volume 37:Number 1(2016:Jan.)
• Page Start: 15
• Page End: 27
• Publication Date: 2016-01
• Subjects: domperidone -- CYP3A4 -- pharmacokinetic modeling -- drug‐drug interactions; Biopharmaceutics -- Periodicals; Drugs -- Metabolism -- Periodicals; Pharmacology -- Periodicals; Biopharmaceutics -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; 615.19
• DOI: 10.1002/bdd.1992
• Languages: English
• ISSNs: 0142-2782

Abstract

Abstract: Domperidone is a dopamine receptor antagonist and a substrate of CYP3A4, hence there is a potential for CYP3A inhibition‐based drug–drug interactions (DDI). A physiologically based pharmacokinetic model was developed to describe DDIs between domperidone and three different inhibitors of CYP3A4. Simcyp V13.1 was used to simulate human domperidone pharmacokinetics and DDIs. Inputs included domperidone chemical and physical properties (LogP, pKa, etc.), in vitro human liver microsomal data and pharmacokinetic parameters from single‐dose intravenous clinical studies in healthy participants. The simulated mean maximum domperidone plasma concentration and AUC after single‐ and multiple‐oral doses under diverse conditions were within 1.1–1.4 fold of the observed values. The simulated intestinal availability, hepatic availability and the fraction absorbed were 0.45 ± 0.14, 0.31 ± 0.10 and 0.89 ± 0.11, respectively, and comparable to observed in vivo values. The simulated ratios of AUC and C max in the presence of ketoconazole, erythromycin or itraconazole to baseline were consistent with the observed ratios. Simulated ketoconazole, erythromycin, itraconazole and C max, ss and AUC ss were within 1.5‐fold of the observed values. Copyright © 2016 John Wiley & Sons, Ltd.