Single- and multiple-ascending dose studies to evaluate the safety, tolerability, and pharmacokinetics of daclatasvir and asunaprevir in healthy male Japanese subjects.
OBJECTIVE
Assess the safety, tolerability, and pharmacokinetic (PK) profiles of daclatasvir (DCV) and asunaprevir (ASV) in healthy male Japanese subjects.


METHODS
AI444-007 and AI447-005 were phase I, double-blind, placebo-controlled, sequential, single-ascending dose (SAD), and multiple-ascending dose (MAD) studies assessing DCV or ASV, respectively. Eight subjects per panel were randomized to study drug or placebo (3 : 1). In the SAD part of each study, subjects received single oral dose DCV 1/10/50/100/200 mg or ASV 200/400/600/900/1,200 mg. In MAD, subjects received 14-day oral multiple dose DCV 1/10/100 mg once-daily or ASV 200/400/600 mg every 12 hours. Serial PK blood sampling occurred from predose to 72-hours postdose or post-last-dose. Safety and tolerability was assessed throughout.


RESULTS
64 (SAD, n = 40; MAD, n = 24) and 65 (SAD, n = 40; MAD, n = 25) subjects were enrolled in AI444-007 and AI447-005, respectively. DCV and ASV were generally well tolerated, with no serious adverse events or clinicallyrelevant changes in vital signs or ECG parameters. Baseline demographic characteristics were comparable across treatment groups in both studies. DCV was readily absorbed, with median tmax of ~ 1 - 2 hours postdose and concentrations declining in a multi-phasic manner. Exposure generally increased dose-proportionally within dose-range studied. Steady-state was achieved between days 4 and 5 of multiple dosing. ASV was readily absorbed, with median tmax of ~ 2 - 4 hours postdose and concentrations declining in a biphasic manner. Exposure generally increased dose-proportionally within dose-range studied. Steady-state appeared to be achieved between days 3 - 5 of multiple dosing.


CONCLUSIONS
Results suggest no clinically significant short-term safety signals with DCV and ASV at single or multiple doses in this population.
Tomomi
T
Shiozaki
Takayo
T
Ueno
Hirotaka
H
Nagashima
Naomi
N
Yamahira
Masaki
M
Hiraoka
Tim
T
Eley
Marc
M
Bifano
Richard J
RJ
Bertz
D000284:Administration, Oral; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D044466:Asian People; D002219:Carbamates; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D064368:Healthy Volunteers; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D007546:Isoquinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011759:Pyrrolidines; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D014633:Valine / Q000031:analogs & derivatives; D055815:Young Adult
D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D007546:Isoquinolines; D011759:Pyrrolidines; D013449:Sulfonamides; D014633:Valine; C549273:daclatasvir; C571889:asunaprevir