title: Pharmacokinetics and dose recommendations for cyclosporine and tacrolimus when coadministered with ABT-450, ombitasvir, and dasabuvir.
abstract: ABT-450, ombitasvir, and dasabuvir are direct-acting antiviral agents (DAAs) that have been developed for combination treatment of chronic hepatitis C virus (HCV) infection. Because these DAAs have metabolic and transporter profiles that overlap with cyclosporine and tacrolimus disposition, there is potential for drug interactions. Two Phase 1 studies assessed effects of ABT-450 (150 mg coadministered with ritonavir 100 mg once daily), ombitasvir (25 mg once daily), and dasabuvir (400 mg twice daily) on the pharmacokinetics, safety, and tolerability of a single dose of cyclosporine (30 mg) or tacrolimus (2 mg) in healthy volunteers (N = 12 per study). In the presence of steady-state concentrations of all 3 DAAs, dose-normalized cyclosporine concentration at 24 hours (C₂₄), and area under the concentration-time curve from time 0 to infinity (AUC(∞)) were 15.8-fold and 5.8-fold, respectively, and dose-normalized tacrolimus C₂₄ and AUC(∞) were 17-fold and 57-fold, respectively, of either agent alone. Cyclosporine and tacrolimus half-lives increased from 7 to 25 h and 32 to 232 h, respectively. There were no major safety or tolerability issues in these studies. The results suggest that cyclosporine and tacrolimus doses and dosing frequency should be reduced in HCV-infected posttransplant patients being treated with this 3-DAA regimen.
authors.affiliation: AbbVie Inc., North Chicago, IL.
authors.forename: P
authors.initials: P
authors.lastname: Badri
authors.forename: S
authors.initials: S
authors.lastname: Dutta
authors.forename: E
authors.initials: E
authors.lastname: Coakley
authors.forename: D
authors.initials: D
authors.lastname: Cohen
authors.forename: B
authors.initials: B
authors.lastname: Ding
authors.forename: T
authors.initials: T
authors.lastname: Podsadecki
authors.forename: B
authors.initials: B
authors.lastname: Bernstein
authors.forename: W
authors.initials: W
authors.lastname: Awni
authors.forename: R
authors.initials: R
authors.lastname: Menon
mesh_terms: D015081:2-Naphthylamine; D000293:Adolescent; D000328:Adult; D000813:Anilides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019540:Area Under Curve; D002219:Carbamates / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003521:Cyclopropanes; D016572:Cyclosporine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D064368:Healthy Volunteers; D016174:Hepacivirus / Q000187:drug effects; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D011392:Proline / Q000031:analogs & derivatives; D013449:Sulfonamides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D014633:Valine; D055815:Young Adult
chemical_list: D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; C586094:ombitasvir; D014498:Uracil; D016572:Cyclosporine; D011392:Proline; D015081:2-Naphthylamine; C588260:dasabuvir; D014633:Valine; C585405:paritaprevir; D016559:Tacrolimus
keywords: calcineurin inhibitor: cyclosporine A (CsA); calcineurin inhibitor: tacrolimus; clinical research/practice; immunosuppressant; infection and infectious agents; infectious disease; liver transplantation/hepatology; pharmacokinetics/pharmacodynamics; pharmacology; viral: hepatitis C