title: In Silico Predictions and In Vivo Results of Drug-Drug Interactions by Ketoconazole and Verapamil on AZD1305, a Combined Ion Channel Blocker and a Sensitive CYP3A4 Substrate.
abstract: The objectives were to estimate and compare, in silico and in vivo, the effects of a strong and a moderate CYP3A4 inhibitor on AZD1305 pharmacokinetics. In silico, simulations were performed with the computer software Simcyp, and the predicted outcome was compared with the results observed in healthy male subjects. In silico, the geometric mean plasma exposure of AZD1305 + ketoconazole showed a 7.1-fold higher AUC and a 4.4-fold higher Cmax compared with AZD1305 alone. Coadministration with verapamil gave a 1.9-fold higher AUC and a 1.7-fold higher Cmax compared with AZD1305 alone. In vivo, the plasma exposure of AZD1305 + ketoconazole showed a 7.7-fold higher AUC and a 4.8 -fold higher Cmax compared with AZD1305 alone. Coadministration with verapamil gave a 2.2-fold higher AUC and a 2.0-fold higher Cmax compared with AZD1305 alone. The mean maximum QTcF increase from baseline was 407, 487, and 437 milliseconds for AZD1305, alone and in combination with verapamil or ketoconazole, respectively. Simcyp predicted the effects of ketoconazole and verapamil on the sensitive CYP3A4 substrate AZD1305 pharmacokinetics well. Both the in vivo study and the Simcyp predictions suggest a contraindication for strong CYP3A4 inhibitors and AZD1305 when given in combination.
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden. susanne.a.johansson@astrazeneca.com.
authors.forename: Susanne
authors.initials: S
authors.lastname: Johansson
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Boel
authors.initials: B
authors.lastname: Löfberg
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Aunes
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Helen
authors.initials: H
authors.lastname: Lunde
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Frison
authors.affiliation: Sahlgrenska Academy at Sahlgrenska University Hospital, Göteborg, Sweden.
authors.forename: Nils
authors.initials: N
authors.lastname: Edvardsson
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Cullberg
mesh_terms: D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D053961:Azabicyclo Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002219:Carbamates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003198:Computer Simulation; D018592:Cross-Over Studies; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004347:Drug Interactions; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D014700:Verapamil / Q000008:administration & dosage / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D000889:Anti-Arrhythmia Agents; D053961:Azabicyclo Compounds; D002219:Carbamates; D065692:Cytochrome P-450 CYP3A Inhibitors; C550721:tert-butyl (2-(7-(2-(4-cyano-2-fluorophenoxy)ethyl)-9-oxa-3,7-diazabicyclo(3.3.1)non3-yl)ethyl)carbamate; D014700:Verapamil; D007654:Ketoconazole
keywords: AZD1305; CYP3A4; PBPK; Simcyp; metabolic drug-drug interactions