Population Pharmacokinetic Analysis of Daclatasvir in Subjects with Chronic Hepatitis C Virus Infection View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2017-01-09

AUTHORS

Phyllis Chan, Hanbin Li, Li Zhu, Marc Bifano, Timothy Eley, Mayu Osawa, Takayo Ueno, Eric Hughes, Richard Bertz, Tushar Garimella, Malaz AbuTarif

ABSTRACT

Background and ObjectiveDaclatasvir is a potent, pangenotypic once-daily hepatitis C virus (HCV) NS5A inhibitor that is approved for the treatment of chronic HCV infection. The objective of this analysis was to characterize the pharmacokinetics of daclatasvir in subjects with chronic HCV infection.MethodsA population pharmacokinetic (PPK) model was developed to evaluate effects of covariates on daclatasvir pharmacokinetics in subjects with chronic HCV infection (n = 2149 from 11 studies). All significant demographic, laboratory, prognostic and treatment covariates (p < 0.05) from univariate screening were included in the full model. The final model was reached by backward elimination (p < 0.001) and simulations were performed to further evaluate the effects of covariates on daclatasvir exposures. The plasma pharmacokinetics of daclatasvir was described by a two-compartment model with linear elimination. Absorption was modeled as a zero-order release followed by a first-order absorption into the central compartment.ResultsThe typical value of apparent clearance (CL/F) was 5.7 L/h (1.58% relative standard error [RSE]) and of apparent volume of the central compartment (Vc/F) was 58.6 L (2.00% RSE). Modest inter-individual variability was estimated for CL/F (35.1%) and Vc/F (29.5%). Statistically significant covariates in the final model were sex, race, virus genotype, baseline creatinine clearance, and alanine aminotransferase (ALT) on CL/F and sex, race, and body weight on Vc/F. Covariate effects demonstrated a 30% higher area under the plasma concentration–time curve at steady state (AUCss) in female subjects; effects of all other covariates were <16%.ConclusionsThe model adequately described the daclatasvir pharmacokinetics and estimated relatively small covariate effects. Considering the exposure range for the therapeutic dose of daclatasvir 60 mg once daily and the favorable safety profile, the small difference in exposures due to these covariates is not considered clinically relevant. More... »

PAGES

1173-1183

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s40262-016-0504-2

DOI

http://dx.doi.org/10.1007/s40262-016-0504-2

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1024885262

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28066880


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