title: Population Pharmacokinetic Analysis of Daclatasvir in Subjects with Chronic Hepatitis C Virus Infection.
abstract: 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.
  
  
  
  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.
  
  
  
  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 (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%.
  
  
  
  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.
authors.affiliation: Bristol-Myers Squibb Research and Development, Lawrenceville, NJ, USA. h-mchan@hotmail.com.
authors.forename: Phyllis
authors.identifier: 0000-0003-1509-1526
authors.initials: P
authors.lastname: Chan
authors.affiliation: Quantitative Solutions, Menlo Park, CA, USA.
authors.forename: Hanbin
authors.initials: H
authors.lastname: Li
authors.affiliation: Bristol-Myers Squibb Research and Development, Lawrenceville, NJ, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Bristol-Myers Squibb Research and Development, Lawrenceville, NJ, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Bifano
authors.affiliation: Bristol-Myers Squibb Research and Development, Lawrenceville, NJ, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Eley
authors.affiliation: Bristol-Myers Squibb K.K., Tokyo, Japan.
authors.forename: Mayu
authors.initials: M
authors.lastname: Osawa
authors.affiliation: Bristol-Myers Squibb K.K., Tokyo, Japan.
authors.forename: Takayo
authors.initials: T
authors.lastname: Ueno
authors.affiliation: Bristol-Myers Squibb Research and Development, Lawrenceville, NJ, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Hughes
authors.affiliation: Bristol-Myers Squibb Research and Development, Lawrenceville, NJ, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Bertz
authors.affiliation: Bristol-Myers Squibb Research and Development, Lawrenceville, NJ, USA.
authors.forename: Tushar
authors.initials: T
authors.lastname: Garimella
authors.affiliation: Bristol-Myers Squibb Research and Development, Lawrenceville, NJ, USA.
authors.forename: Malaz
authors.initials: M
authors.lastname: AbuTarif
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002219:Carbamates; D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data; D017326:Clinical Trials, Phase III as Topic / Q000706:statistics & numerical data; D005260:Female; D016174:Hepacivirus / Q000187:drug effects*; D019698:Hepatitis C, Chronic / Q000097:blood* / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D011759:Pyrrolidines; D014633:Valine / Q000031:analogs & derivatives; D055815:Young Adult
chemical_list: D002219:Carbamates; D007093:Imidazoles; D011759:Pyrrolidines; D014633:Valine; C549273:daclatasvir
keywords: Electronic Supplementary Material Table; Pharmacokinetic Parameter; Significant Covariates; Sofosbuvir; Virus Genotype