title: Validation of a microdose probe drug cocktail for clinical drug interaction assessments for drug transporters and CYP3A.
abstract: A microdose cocktail containing midazolam, dabigatran etexilate, pitavastatin, rosuvastatin, and atorvastatin has been established to allow simultaneous assessment of a perpetrator impact on the most common drug metabolizing enzyme, cytochrome P450 (CYP)3A, and the major transporters organic anion-transporting polypeptides (OATP)1B, breast cancer resistance protein (BCRP), and MDR1 P-glycoprotein (P-gp). The clinical utility of these microdose cocktail probe substrates was qualified by conducting clinical drug interaction studies with three inhibitors with different in vitro inhibitory profiles (rifampin, itraconazole, and clarithromycin). Generally, the pharmacokinetic profiles of the probe substrates, in the absence and presence of the inhibitors, were comparable to their reported corresponding pharmacological doses, and/or in agreement with theoretical expectations. The exception was dabigatran, which resulted in an approximately twofold higher magnitude for microdose compared to conventional dosing, and, thus, can be used to flag a worst-case scenario for P-gp. Broader application of the microdose cocktail will facilitate a more comprehensive understanding of the roles of drug transporters in drug disposition and drug interactions.
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co, Kenilworth, New Jersey, USA.|Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand.
authors.forename: T
authors.initials: T
authors.lastname: Prueksaritanont
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co, Kenilworth, New Jersey, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Tatosian
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co, Kenilworth, New Jersey, USA.
authors.forename: X
authors.initials: X
authors.lastname: Chu
authors.affiliation: Department of Biostatistics and Research Decision Sciences, Merck & Co, Kenilworth, New Jersey, USA.
authors.forename: R
authors.initials: R
authors.lastname: Railkar
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co, Kenilworth, New Jersey, USA.
authors.forename: R
authors.initials: R
authors.lastname: Evers
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co, Kenilworth, New Jersey, USA.
authors.forename: C
authors.initials: C
authors.lastname: Chavez-Eng
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co, Kenilworth, New Jersey, USA.
authors.forename: R
authors.initials: R
authors.lastname: Lutz
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co, Kenilworth, New Jersey, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zeng
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co, Kenilworth, New Jersey, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yabut
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co, Kenilworth, New Jersey, USA.
authors.forename: G H
authors.initials: GH
authors.lastname: Chan
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co, Kenilworth, New Jersey, USA.
authors.forename: X
authors.initials: X
authors.lastname: Cai
authors.affiliation: Department of Pharmaceutical Sciences and Clinical Supply, Merck & Co, Kenilworth, New Jersey, USA.
authors.forename: A H
authors.initials: AH
authors.lastname: Latham
authors.affiliation: Department of Pharmaceutical Sciences and Clinical Supply, Merck & Co, Kenilworth, New Jersey, USA.
authors.forename: J
authors.initials: J
authors.lastname: Hehman
authors.affiliation: Data Management and Biometrics, Celerion, Lincoln, Nebraska, USA.
authors.forename: D
authors.initials: D
authors.lastname: Stypinski
authors.affiliation: Data Management and Biometrics, Celerion, Lincoln, Nebraska, USA.
authors.forename: J
authors.initials: J
authors.lastname: Brejda
authors.affiliation: Data Management and Biometrics, Celerion, Lincoln, Nebraska, USA.
authors.forename: C
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of Translational Pharmacology Clinical Operations, Merck & Co, Kenilworth, New Jersey, USA.
authors.forename: B
authors.initials: B
authors.lastname: Thornton
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co, Kenilworth, New Jersey, USA.
authors.forename: K P
authors.initials: KP
authors.lastname: Bateman
authors.affiliation: Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co, Kenilworth, New Jersey, USA.|Abide Therapeutics, San Diego, California, USA.
authors.forename: I
authors.initials: I
authors.lastname: Fraser
authors.affiliation: Department of Translational Pharmacology, Merck & Co, Kenilworth, New Jersey, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Stoch
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000378:metabolism; D000328:Adult; D019540:Area Under Curve; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D004338:Drug Combinations; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions / Q000201:enzymology / Q000378:metabolism; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D010599:Pharmacokinetics; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D002352:Carrier Proteins; D065692:Cytochrome P-450 CYP3A Inhibitors; D004338:Drug Combinations; D027381:Liver-Specific Organic Anion Transporter 1; D009363:Neoplasm Proteins; C503999:SLCO1B1 protein, human; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A