title: An open-label investigation into drug-drug interactions between multiple doses of daclatasvir and single-dose cyclosporine or tacrolimus in healthy subjects.
abstract: OBJECTIVE
  Chronic hepatitis C virus (HCV) infection is a major cause of liver transplantation. Drug-drug interactions (DDIs) with cyclosporine and tacrolimus hindered the use of first-generation protease inhibitors in transplant recipients. The current study investigated DDIs between daclatasvir-a pan-genotypic HCV NS5A inhibitor with clinical efficacy in multiple regimens (including all-oral)-and cyclosporine or tacrolimus in healthy subjects.
  
  
  METHODS
  Healthy fasted subjects (aged 18-49 years; body mass index 18-32 kg/m(2)) received single oral doses of cyclosporine 400 mg on days 1 and 9, and daclatasvir 60 mg once daily on days 4-11 (group 1, n = 14), or a single oral dose of tacrolimus 5 mg on days 1 and 13, and daclatasvir 60 mg once daily on days 8-19 (group 2, n = 14). Blood samples for pharmacokinetic analysis [by liquid chromatography with tandem mass spectrometry (LC-MS/MS)] were collected on days 1 and 9 for cyclosporine (72 h), on days 1 and 13 for tacrolimus (168 h) and on days 8 and 9 (group 1) or on days 12 and 13 (group 2) for daclatasvir (24 h). Plasma concentrations were determined by validated LC-MS/MS methods.
  
  
  RESULTS
  Daclatasvir did not affect the pharmacokinetic parameters of cyclosporine or tacrolimus, and tacrolimus did not affect the pharmacokinetic parameters of daclatasvir. Co-administration of cyclosporine resulted in a 40 % increase in the area under the concentration-time curve of daclatasvir but did not affect its maximum observed concentration.
  
  
  CONCLUSIONS
  On the basis of these observations in healthy subjects, no clinically relevant DDIs between daclatasvir and cyclosporine or tacrolimus are anticipated in liver transplant recipients infected with HCV; dose adjustments during co-administration are unlikely to be required.
authors.affiliation: Bristol-Myers Squibb Research and Development, 311 Pennington Rock Hill Road, Hopewell, NJ, 08534, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Bifano
authors.forename: Robert
authors.initials: R
authors.lastname: Adamczyk
authors.forename: Carey
authors.initials: C
authors.lastname: Hwang
authors.forename: Hamza
authors.initials: H
authors.lastname: Kandoussi
authors.forename: Alan
authors.initials: A
authors.lastname: Marion
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bertz
mesh_terms: D000293:Adolescent; D000328:Adult; D002219:Carbamates; D016572:Cyclosporine / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D011759:Pyrrolidines; D016559:Tacrolimus / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D014633:Valine / Q000031:analogs & derivatives; D055815:Young Adult
chemical_list: D002219:Carbamates; D007093:Imidazoles; D007166:Immunosuppressive Agents; D011480:Protease Inhibitors; D011759:Pyrrolidines; D016572:Cyclosporine; D014633:Valine; C549273:daclatasvir; D016559:Tacrolimus