title: Physiologically based pharmacokinetic modeling to predict complex drug-drug interactions: a case study of AZD2327 and its metabolite, competitive and time-dependent CYP3A inhibitors.
abstract: 4-{(R)-(3-Aminophenyl)[4-(4-fluorobenzyl)-piperazin-1-yl]methyl}-N,N-diethylbenzamide (AZD2327) is a highly potent and selective agonist of the δ-opioid receptor. AZD2327 and N-deethylated AZD2327 (M1) are substrates of cytochrome P450 3A (CYP3A4) and comprise a complex multiple inhibitory system that causes competitive and time-dependent inhibition of CYP3A4. The aim of the current work was to develop a physiologically based pharmacokinetic (PBPK) model to predict quantitatively the magnitude of CYP3A4 mediated drug-drug interaction with midazolam as the substrate. Integrating in silico, in vitro and in vivo PK data, a PBPK model was successfully developed to simulate the clinical accumulation of AZD2327 and its primary metabolite. The inhibition of CYP3A4 by AZD2327, using midazolam as a probe drug, was reasonably predicted. The predicted maximum concentration (Cmax) and area under the concentration-time curve (AUC) for midazolam were increased by 1.75 and 2.45-fold, respectively, after multiple dosing of AZD2327, indicating no or low risk for clinically relevant drug-drug interactions (DDI). These results are in agreement with those obtained in a clinical trial with a 1.4 and 1.5-fold increase in Cmax and AUC of midazolam, respectively. In conclusion, this model simulated DDI with less than a two-fold error, indicating that complex clinical DDI associated with multiple mechanisms, pathways and inhibitors (parent and metabolite) can be predicted using a well-developed PBPK model.
authors.affiliation: DMPK, AstraZeneca LP, Waltham, MA, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Guo
authors.affiliation: Quantitative Clinical Pharmacology, AstraZeneca LP, Waltham, MA, USA.
authors.forename: Diansong
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Clinical Sample Science, AstraZeneca LP, Waltham, MA, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Quantitative Clinical Pharmacology, AstraZeneca LP, Waltham, MA, USA.
authors.forename: Bui H
authors.initials: BH
authors.lastname: Khanh
mesh_terms: D001549:Benzamides / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D001667:Binding, Competitive; D018938:Caco-2 Cells; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D004347:Drug Interactions; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D008874:Midazolam / Q000493:pharmacokinetics*; D008954:Models, Biological; D010879:Piperazines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D011485:Protein Binding; D017465:Receptors, Opioid, delta / Q000819:agonists*; D011994:Recombinant Proteins; D013379:Substrate Specificity; D013997:Time Factors
chemical_list: C560622:4-((3-aminophenyl)(4-(4-fluorobenzyl)piperazin-1-yl)methyl)-N,N-diethylbenzamide; D001549:Benzamides; D065692:Cytochrome P-450 CYP3A Inhibitors; D010879:Piperazines; D017465:Receptors, Opioid, delta; D011994:Recombinant Proteins; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam
keywords: AZD2327; drug-drug interaction; pharmacokinetics; physiologically based pharmacokinetic (PBPK) model; simulation