Background.
Daclatasvir (DCV) is a potent hepatitis C virus (HCV) NS5A replication complex inhibitor
with pangenotypic (GT 1-6) activity in vitro. Asunaprevir (ASV) is a selective NS3
protease inhibitor with in vitro activity against GT 1, 4, 5 and 6. These two direct-acting
antivirals (DAA) are in phase 3 development and regulatory review as a dual-DAA regimen
(DCV + ASV) for the treatment of HCV GT 1b. DCV and ASV both inhibit P-glycoprotein
(P-gp) and individually increase plasma concentrations of the P-gp substrate digoxin
(DIG), increasing DIG Cmax by 65 and 9% and AUCTAU by 27 and 30%, respectively. The
combined effect of DCV + ASV on the pharmacokinetics (PK) of DIG was therefore assessed
in healthy subjects.
Methods.
A single sequence, open-label, one-way interaction study assessed the effect of steady-state
DCV (60 mg QD) plus ASV (100 mg BID [softgel capsule]) on the PK of single-dose 0.25
mg DIG in healthy subjects. Subjects (N = 16) received DIG on Day 1 and 16, and DCV
+ ASV on Days 6–20. Serial samples for DIG plasma concentrations were collected up
to 120 h postdose on Day 1 and Day 16. Non-compartmental DIG PK parameters were derived.
Geometric mean ratios (GMR) and 90% confidence intervals (90%CI) for DIG Cmax and
AUCinf were derived from linear mixed effects models.
Results.
All subjects (69% male, aged 23-45 years) completed the study. DCV + ASV dosed with
DIG resulted in a 77% increase in DIG Cmax and a 29% increase in AUCinf (Table). Study
drugs were well tolerated; all AEs were mild in intensity except 2 AEs of increased
blood creatinine phosphokinase (1 moderate, 1 severe). No AEs were considered study
drug-related and all resolved by study end.
With DCV+ASV
Adj. Geo. Mean
(90%CI)
W/O DCV+ASV
Adj. Geo. Mean
(90%CI)
GMR
(90%CI)
DIG Cmax
,
pg/mL
1593 (1407, 1803)
902 (797,1021)
1.766 (1.504, 2.073)
DIG AUCinf
, pg×h/mL
23293 (21522, 25209)
18090 (15818, 20689)
1.288 (1.197, 1.385)
Conclusion.
DCV and ASV effects on DIG PK are not additive and are similar to DCV alone. Caution
is warranted when dosing DCV + ASV with DIG and other P-gp substrates with a narrow
therapeutic window; a priori dose modification does not appear to be required. Therapeutic
drug monitoring, if available, may be considered.
Disclosures.
T. Garimella, Bristol-Myers Squibb: Employee, Salary R. Adamczyk, Bristol-Myers Squibb:
Employee and Shareholder, Salary M. Stonier, Bristol-Myers Squibb: Employee, Salary
H. Kandoussi, Bristol-Myers Squibb: Employee, Salary M. Hesney, Bristol-Myers Squibb:
Employee, Salary E. Colston, Bristol-Myers Squibb: Employee, Salary T. Eley, Bristol-Myers
Squibb: Employee and Shareholder, Salary M. Bifano, Bristol-Myers Squibb: Employee,
Salary