studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 567A
Hadas Dvory-Sobol - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Jenny C. Yang - Employment: Gilead Sciences, Inc
Luisa M. Stamm - Employment: Gilead Sciences
James Taylor - Employment: Gilead Sciences
Diana M. Brainard - Employment: Gilead Sciences; Stock Shareholder: Gilead
Sciences
Michael D. Miller - Employment: Gilead Sciences, Inc.; Stock Shareholder: Gilead
Sciences, Inc.
Hongmei Mo - Employment: Gilead Science Inc
Maribel Rodriguez-Torres - Advisory Committees or Review Panels: Bristol-Myers
Squibb, Janssen R&D Ireland; Consulting: Glaxo Smith Kline, Janssen R&D Ireland,
Theravance; Grant/Research Support: Merck, Bristol-Myers Squibb, Merck,
Pfizer, Gilead, Johnson & Johnson, Beckman Coulter, Theravance
719
Pharmacokinetics of Coadministration of Pan-Genotypic,
Direct Acting Antiviral Agents, ABT-493 and ABT-
530, with or without Ribavirin for 12 weeks in HCV
Infected Subjects without Cirrhosis
Chih-Wei Lin, Wei Liu, Armen Asatryan, Stanley Wang, Federico
J. Mensa, Jens Kort, Sandeep Dutta; Abbvie, North Chicago, IL
Purpose: A direct acting antiviral agent (DAA) combination of
ABT-493 (NS3/4A protease inhibitor discovered by AbbVie
and Enanta) and ABT-530 (NS5A inhibitor) is being developed
for the treatment of chronic hepatitis C (HCV) genotype
(GT) 1-6 infection. In two Phase 2 studies (SURVEYOR-1 and
-2), the ABT-493 and ABT-530 combination has demonstrated
high sustained virologic response rates in GT1-, GT2- and
GT3-infected subjects without cirrhosis following 12-weeks of
treatment. Pharmacokinetics of ABT-493 and ABT-530 with or
without ribavirin (RBV) were evaluated in these studies. Methods:
Two open-label, multicenter studies, SURVEYOR-1 and
-2, were conducted evaluate the efficacy, safety, and pharmacokinetics
of co-administration of ABT-493 (200 or 300
mg QD) and ABT-530 (40 or 120 mg QD) with or without
RBV in GT1-, GT2- or GT3-infected subjects. Blood samples for
pharmacokinetic analysis were collected throughout the study
treatment period. ABT-493 and ABT-530 pharmacokinetics following
a single dose (Day 1) and at steady state (Week 4)
were assessed by non-compartmental methods. Results: A total
of 274 subjects received ABT-493 and ABT-530 with or without
RBV. Both ABT-493 and ABT-530 showed rapid absorption
with Tmax ranging from 2 to 4 hours. Steady state ABT-493
exposure (area under the curve from 0 to 4 hour) following
300 mg was 2570 ng.h/mL, approximately 3.7-fold of the
exposure following 200 mg administration. Coadministration
of either 40 mg or 120 mg ABT-530 each with 200 mg ABT-
493 resulted in ABT-530 exposure of 157 or 372 ng.h/mL,
respectively. ABT-493 300 mg increased 120 mg ABT-530
exposure by an additional 20% to 30%. Minimal accumulation
in ABT-493 or ABT-530 exposure was observed at Week 4
compared to Day 1. ABT-530 had minimal impact on ABT-493
exposures, however, ABT-493 200 mg and 300 mg increased
120 mg ABT-530 exposures to 3- to 4-fold of ABT-530 exposures
when administered alone. HCV genotype and RBV coadministration
had no impact on ABT-493 or ABT-530 exposures.
Conclusions: ABT-493 exhibited non-linear pharmacokinetics
with more than dose-proportional increase in exposures with
increasing doses, while ABT-530 exposures increased in an
approximately dose-proportional manner when coadministered
with ABT-493. ABT-530 had minimal impact on ABT-
493, while ABT-493 increased ABT-530 exposures, with the
increase in ABT-530 exposure being dependent on ABT-493
dose. ABT-493 or ABT-530 had minimal accumulation in exposures
following multiple dosing in HCV-infected subjects.
Disclosures:
Chih-Wei Lin - Employment: Abbvie
Wei Liu - Employment: AbbVie
Armen Asatryan - Employment: AbbVie
Stanley Wang - Employment: AbbVie
Federico J. Mensa - Employment: Abbvie Inc.; Stock Shareholder: Abbvie Inc.
Jens Kort - Employment: AbbVie Inc.; Stock Shareholder: AbbVie Inc.
Sandeep Dutta - Employment: AbbVie; Stock Shareholder: AbbVie
720
Daclatasvir exposure does not explain lower sustained
virologic response rates in cirrhotic patients with HCV
genotype 3 following 12 weeks of daclatasvir plus
sofosbuvir treatment
Timothy Eley, Reena Wang, Shu-Pang Huang, Yash Gandhi,
Brenda Cirincione, Frank LaCreta, Tushar Garimella; Bristol-Myers
Squibb, Princeton, NJ
Background: The ALLY-3 study evaluated daclatasvir (DCV; 60
mg daily) plus sofosbuvir (SOF; 400 mg daily) for 12 weeks in
treatment-naive and -experienced patients with HCV genotype
3 (GT 3) infection. Sustained virologic response at posttreatment
week 12 (SVR12) was lower in patients with compensated
cirrhosis than in those without (63% [20/32] vs 96%
[105/109]), mostly due to posttreatment relapse. Pharmacokinetic
(PK) exposure to DCV in ALLY-3 was evaluated in patients
with and without cirrhosis to explore this observation. Methods:
Systemic exposure to total (protein-bound + unbound) DCV on
dosing Day 1 was evaluated in a prespecified 24-hour intensive
PK substudy of cirrhotic GT 3 patients in ALLY-3 (N=10)
using noncompartmental methods. DCV exposure parameters
were compared to those of non-cirrhotic ALLY-3 patients derived
from population PK (PopPK) modeling, and against historical
single-dose DCV data in HCV-uninfected subjects with hepatic
impairment. Model-predicted steady-state average DCV concentrations
across the dosing interval (C avgss
) for cirrhotic and
non-cirrhotic ALLY-3 patients with and without SVR12 were
compared visually in an exploratory exposure-response assessment.
Results: Taking into account the historical DCV accumulation
ratio in HCV-infected patients (1.2–1.4), median observed
Day 1 AUC 0-24h
in cirrhotic GT 3 patients in ALLY-3 (6210
[range 3141–10895] ng.h/mL) was comparable to PopPK
model estimates of median steady-state AUC 0-24h
in both cirrhotic
patients (7980 [3744–17856] ng.h/mL) and non-cirrhotic
patients (9192 [3696–19776] ng.h/mL). Similarly, after
considering the accumulation, the median observed Day 1
AUC 0-24h
in cirrhotic patients was comparable to historical single-dose
median AUC inf
for DCV 30 mg in HCV-uninfected
subjects with Child-Pugh class A, B or C hepatic impairment
normalized to 60 mg (9638–11398 ng.h/mL). Calculated
median C avgss
exposures were similar in cirrhotic and non-cirrhotic
ALLY-3 patients in the PopPK model (non-cirrhotic: 358
ng/mL without SVR12 [n=4], 408 ng/mL with SVR12 [n=105];
cirrhotic 283 ng/mL without SVR12 [n=12], 382 ng/mL with
SVR12 [n=20]). Despite a weak trend towards lower C avgss
in
patients without SVR12 there was substantial overlap between
those who did and those who did not achieve SVR12 in both
groups, though numbers were small. Conclusions: The data
indicate that higher relapse rates among GT 3-infected cirrhotic
patients in ALLY-3 cannot be explained by DCV exposure
alone. These data suggest that cirrhotic patients with HCV GT 3
may require longer (>12 weeks) treatment duration with DCV+-
SOF or the addition of ribavirin.
Disclosures:
Timothy Eley - Employment: Bristol-Myers Squibb; Stock Shareholder: Bristol-Myers
Squibb