studies

568A AASLD ABSTRACTS HEPATOLOGY, October, 2015
Shu-Pang Huang - Employment: Bristol-Myers Squibb Company; Stock Shareholder:
Bristol-Myers Squibb Company
Yash Gandhi - Employment: Bristol-Myers Squibb
Brenda Cirincione - Employment: BMS
Frank LaCreta - Employment: Bristol-Myers Squibb; Management Position: Bristol-Myers
Squibb; Stock Shareholder: Bristol-Myers Squibb
Tushar Garimella - Employment: Bristol Myers-Squibb; Stock Shareholder: Abbvie,
Bristol Myers-Squibb
The following authors have nothing to disclose: Reena Wang
721
Pharmacokinetics of Narlaprevir an NS3/4A Protease
Inhibitor with or without Ritonavir Following Single
Dose Use in Patients with Compensated Cirrhosis and
Healthy Volunteers
Dmitry Koloda 1 , Natalia Tikhonova 1 , Irina Malaya 2 , Miroslav
Ryska 3 , Mikhail Samsonov 1 , Vasily Isakov 4 ; 1 Medical Department,
R-Pharm, Moscow, Russian Federation; 2 Ascent Clinical Research
Solutions, Moscow, Russian Federation; 3 Quinta Analytica,
Prague, Czech Republic; 4 Department of gastroenterology & hepatology,
Institute of Nutrition, Moscow, Russian Federation
Background and Aims: Narlaprevir (NVR), a potent ritonavir-boosted
inhibitor of HCV NS3 protease, is currently being
developed for therapy of chronic HCV genotype 1 infection
in Russia and CIS countries. The purpose of this study was to
evaluate the pharmacokinetics (PK) after a single oral dose of
NVR alone and in combination with ritonavir (RTV) in healthy
controls and in patients with compensated cirrhosis. Methods:
This was a two-part, open-label, parallel group, single-dose
phase I study in patients with compensated cirrhosis Child-Pugh
class A (CPA) (n=16), and matched healthy subjects (n=16),
all Caucasians. In Part 1 of the study 8 healthy adult subjects
and 8 patients with CPA received single dose of NVR 200
mg under fed condition. In Part 2 of the study 8 healthy subjects
and 8 CPA patients received NVR 100 mg (dose was
decreased based on the Part 1 results) in combination with RTV
100 mg. Noncompartmental model was used for PK analysis of
NVR in plasma and urine. Simulation of PK parameters for NVR
at steady state was performed. Geometric least square means
(GMEAN) and 90% confidence intervals were calculated.
Results: In Part I GMEAN C max,
and AUC (0-inf)
were 1.6 and 2.7
times higher in CPA patients vs. healthy subjects, respectively
(Table 1). Simulated steady-state (tau=24 h) GMEAN C max,
and
AUC tau,
in patients with CPA were 167% and 237% vs. healthy
subjects respectively (Table 2). Increased NVR exposure in
patients with CPA was well tolerated and not associated with
increased adverse events rate. There were no significant difference
in plasma NVR exposure in CPA patients and healthy subjects
after single dose NVR 100 mg in combination with 100
mg RTV and after steady-state simulation (tau=24 h): GMEAN
C max,
and AUC tau,
were 107% and 105% in patients with CPA
vs. healthy subjects, respectively (Table 2). Conclusions: NVR
exposure after a single dose 200 mg was higher in patients
with CPA than in healthy subjects. No significant effect on
NVR exposure in CPA subjects compared to healthy subjects
was found when NRV 100 mg was co-administered with RTV
100 mg.
Disclosures:
Dmitry Koloda - Employment: R-Pharm
Natalia Tikhonova - Employment: R-Pharm
Mikhail Samsonov - Employment: RPharm
Vasily Isakov - Advisory Committees or Review Panels: Abbvie, Bristol-Myers
Squibb, Gilead, Janssen, Merck, Vertex, R-Pharm; Consulting: Bristol-Myers
Squibb, Merck; Speaking and Teaching: Bristol-Myers Squibb, Janssen, Merck
The following authors have nothing to disclose: Irina Malaya, Miroslav Ryska
722
Ombitasvir/Paritaprevir/r and Dasabuvir with Ribavirin
for HCV Genotype 1 Patients with Decompensated Cirrhosis
Parvez S. Mantry 1 , John Hanson 2 , Roger Trinh 3 , Alnoor Ramji 4 ,
Linda Fredrick 3 , Manal Abunimeh 3 , Leticia Canizaro 3 , Li Liu 3 ,
Nancy Shulman 3 , Stuart C. Gordon 5 ; 1 The Liver Institute at Methodist
Dallas, Dallas, TX; 2 Charlotte Gastroenterology and Hepatology,
PLLC, Charlotte, NC; 3 AbbVie, Inc., North Chicago, IL;
4 University of British Columbia, Vancouver, BC, Canada; 5 Henry
Ford Health System, Detroit, MI
Objective: Patients with HCV and decompensated cirrhosis are
at greatest risk for life-threatening complications leading to
liver transplantation. The 3 direct-acting antiviral (3D) regimen
of ombitasvir (OBV) co-formulated with paritaprevir/ritonavir
(PTV/r, identified by AbbVie and Enanta) and dasabuvir (DSV)
with ribavirin (RBV) has high efficacy in HCV genotype (GT)
1-infected patients with compensated cirrhosis. We assessed
the safety, pharmacokinetics, and efficacy of the 3D + RBV
regimen in an initial cohort of HCV GT1-infected patients with
decompensated cirrhosis. Methods: Patients with decompensated
cirrhosis (Child-Pugh score 7 – 9) and the following laboratory
parameters at the time of screening were enrolled:
platelet count ≥25 x 10 9 /L, serum albumin ≥2.8 g/dL, MELD
score ≤18. Those with GT1b or GT1a infection received standard
dosing of OBV/PTV/r (25/150/100 mg/day) and DSV
(250 mg twice daily) plus weight-based RBV (1000 – 1200
mg/day) for 12 or 24 weeks, respectively. A data review
was planned once the initial cohort reached week 12 of treatment,
prior to enrollment of a larger cohort. Results: Baseline
characteristics of the 11 patients enrolled are detailed in the
Table. Suppression of HCV RNA below the level of quantitation
occurred in 7/11 (64%) patients by treatment week 2 and in
all patients by week 6. At treatment week 12, all 11 patients
remained HCV RNA suppressed below the level of detection.
Sustained virologic response at post-treatment week 12 will