title: The utility of in vitro data in making accurate predictions of human P-glycoprotein-mediated drug-drug interactions: a case study for AZD5672.
abstract: To support drug development and registration, Caco-2 cell monolayer assays have previously been set up and validated to determine whether candidate drugs are substrates or inhibitors of human P-glycoprotein (P-gp). In this study, the drug-drug interaction (DDI) potential of N-(1-{(3R)-3-(3,5-difluorophenyl)-3-[4-methanesulfonylphenyl]propyl}piperidin-4-yl)-N-ethyl-2-[4-methanesulfonylphenyl]acetamide (AZD5672) was assessed accordingly, and a subsequent clinical digoxin interaction study was performed. AZD5672 (1-500 μM) demonstrated concentration-dependent efflux across cell monolayers, which was abolished in the presence of ketoconazole and quinidine, identifying AZD5672 as a P-gp substrate. In addition, P-gp-mediated digoxin transport was inhibited in a concentration-dependent manner by AZD5672 (IC(50) = 32 μM). Assessment of the calculated theoretical gastrointestinal inhibitor concentration ([I(2)]) and predicted steady-state maximum total plasma inhibitor concentration ([I(1)]) indicated the potential for a DDI at the intestinal but not the systemic level after the predicted therapeutic dose of AZD5672 (100 mg). A clinical study was performed and the plasma pharmacokinetics [observed maximum plasma drug concentration (C(max)) and area under the plasma concentration versus time curve from 0 to 72 h postdose (AUC(0-72 h))] of orally dosed digoxin (0.5 mg) were found to be unaffected by coadministration of AZD5672 (50 mg) at steady state. In contrast, a 150-mg dose of AZD5672 significantly increased digoxin C(max) and AUC(0-72 h) by 1.82- and 1.33-fold, respectively. Concentration-time profile comparisons indicated that digoxin elimination was unchanged by AZD5672, and the interaction was most likely to have resulted from inhibition of intestinal P-gp leading to increased digoxin absorption. The observed dose-dependent clinically significant interaction was accurately predicted using calculated [I(2)] and in vitro P-gp inhibition data, confirming AZD5672 to be a P-gp inhibitor in vivo.
authors.affiliation: Clinical Pharmacology and DMPK, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK. robert.elsby@astrazeneca.com
authors.forename: Robert
authors.initials: R
authors.lastname: Elsby
authors.forename: Michael
authors.initials: M
authors.lastname: Gillen
authors.forename: Caroline
authors.initials: C
authors.lastname: Butters
authors.forename: Gemma
authors.initials: G
authors.lastname: Imisson
authors.forename: Pradeep
authors.initials: P
authors.lastname: Sharma
authors.forename: Veronica
authors.initials: V
authors.lastname: Smith
authors.forename: Dominic D
authors.initials: DD
authors.lastname: Surry
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D044482:Benzeneacetamides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001692:Biological Transport; D018938:Caco-2 Cells; D004077:Digoxin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D015195:Drug Design; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D015394:Molecular Structure; D013379:Substrate Specificity; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D044482:Benzeneacetamides; C553747:N-(1-(3-(3,5-difluorophenyl)-3-(4-methanesulfonylphenyl)propyl)piperidin-4-yl)-N-ethyl-2-(4-methanesulfonylphenyl)acetamide; D013449:Sulfonamides; D004077:Digoxin