title: A physiologically based pharmacokinetic modeling approach to predict drug-drug interactions between domperidone and inhibitors of CYP3A4.
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.
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Templeton
authors.affiliation: Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Paulien
authors.initials: P
authors.lastname: Ravenstijn
authors.affiliation: Janssen Research & Development, LLC, Raritan, NJ, USA.
authors.forename: Carlo
authors.initials: C
authors.lastname: Sensenhauser
authors.affiliation: Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Snoeys
mesh_terms: D000293:Adolescent; D000328:Adult; D018938:Caco-2 Cells; D003198:Computer Simulation; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology*; D004294:Domperidone / Q000493:pharmacokinetics*; D018492:Dopamine Antagonists / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004917:Erythromycin / Q000494:pharmacology; D005260:Female; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D008954:Models, Biological; D055815:Young Adult
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D018492:Dopamine Antagonists; D017964:Itraconazole; D004294:Domperidone; D004917:Erythromycin; D007654:Ketoconazole
keywords: CYP3A4; domperidone; drug-drug interactions; pharmacokinetic modeling