NDLI: An open-label investigation into drug-drug interactions between multiple doses of daclatasvir and single-dose cyclosporine or tacrolimus in healthy subjects.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Bifano, Marc Adamczyk, Robert Hwang, Carey Kandoussi, Hamza Marion, Alan Bertz, Richard J.
Description	Country affiliation: United States Author Affiliation: Bifano M ( Bristol-Myers Squibb Research and Development, 311 Pennington Rock Hill Road, Hopewell, NJ, 08534, USA.)
Abstract	BACKGROUND AND 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. CONCLUSION: 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.
File Format	HTM / HTML
ISSN	11732563
e-ISSN	11791918
DOI	10.1007/s40261-015-0279-5
Journal	Clinical Drug Investigation
Issue Number	5
Volume Number	35
Language	English
Publisher	Springer
Publisher Date	2015-05-01
Publisher Place	New Zealand (Aotearoa)
Access Restriction	Open
Subject Keyword	Discipline Pharmacology Cyclosporine Administration & Dosage Pharmacokinetics Imidazoles Tacrolimus Adolescent Adverse Effects Blood Drug Interactions Healthy Volunteers Immunosuppressive Agents Protease Inhibitors Clinical Trial, Phase I Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Pharmacology (medical)

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