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

Bifano M, Adamczyk R, Hwang C, Kandoussi H, Marion A, Bertz RJ - Clin Drug Investig (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

No MeSH data available.


Related in: MedlinePlus

Concentration–time profiles of (a) cyclosporine (CSP) and (b) daclatasvir (DCV) administered alone and in combination, and (c) tacrolimus (TAC) and (d) DCV administered alone and in combination. SD standard deviation
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Fig1: Concentration–time profiles of (a) cyclosporine (CSP) and (b) daclatasvir (DCV) administered alone and in combination, and (c) tacrolimus (TAC) and (d) DCV administered alone and in combination. SD standard deviation

Mentions: The concentration–time profiles of single-dose cyclosporine administered alone and in combination with multiple-dose daclatasvir, and multiple-dose daclatasvir administered alone and in combination with single-dose cyclosporine, are presented in Fig. 1a, b, respectively.Fig. 1


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

Bifano M, Adamczyk R, Hwang C, Kandoussi H, Marion A, Bertz RJ - Clin Drug Investig (2015)

Concentration–time profiles of (a) cyclosporine (CSP) and (b) daclatasvir (DCV) administered alone and in combination, and (c) tacrolimus (TAC) and (d) DCV administered alone and in combination. SD standard deviation
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4544506&req=5

Fig1: Concentration–time profiles of (a) cyclosporine (CSP) and (b) daclatasvir (DCV) administered alone and in combination, and (c) tacrolimus (TAC) and (d) DCV administered alone and in combination. SD standard deviation
Mentions: The concentration–time profiles of single-dose cyclosporine administered alone and in combination with multiple-dose daclatasvir, and multiple-dose daclatasvir administered alone and in combination with single-dose cyclosporine, are presented in Fig. 1a, b, respectively.Fig. 1

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

No MeSH data available.


Related in: MedlinePlus