Abstract
Background and Objective
Daclatasvir 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.
Methods
A 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.
Results
The 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 (V c/F) was 58.6 L (2.00% RSE). Modest inter-individual variability was estimated for CL/F (35.1%) and V c/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 V c/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%.
Conclusions
The 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.
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Acknowledgements
The authors would like to thank Russ Wada from Quantitative Solutions for his scientific contributions in data analysis and interpretation.
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The studies described in this report were funded by Bristol-Myers Squibb.
Conflict of interest
P. Chan, L. Zhu, R. Bertz, T. Garimella, and M. AbuTarif are all employees of Bristol-Myers Squibb. M. Bifano, T. Eley, and E. Hughes are former employees of Bristol-Myers Squibb and were employed by Bristol-Myers Squibb when the studies and analyses were conducted. M. Osawa and T. Ueno are employees of Bristol-Myers Squibb K.K. Hanbin Li of Quantitative Solutions was funded by Bristol-Myers Squib to carry out the modeling analyses reported in this paper.
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The study protocols conformed to the ethical guidelines of the 1975 Declaration of Helsinki and were approved by the institutional review board/independent ethics committee at each site.
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Written informed consent was obtained from all study participants and/or their legally authorized representative.
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Chan, P., Li, H., Zhu, L. et al. Population Pharmacokinetic Analysis of Daclatasvir in Subjects with Chronic Hepatitis C Virus Infection. Clin Pharmacokinet 56, 1173–1183 (2017). https://doi.org/10.1007/s40262-016-0504-2
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DOI: https://doi.org/10.1007/s40262-016-0504-2