POSTERS

P738

NO CLINICALLY RELEVANT DRUG–DRUG INTERACTIONS

BETWEEN FALDAPREVIR AND PEGYLATED INTERFERON a-2aPLUS RIBAVIRIN IN HCV-INFECTED PATIENTS:

PHARMACOKINETIC ANALYSES FROM TWO PHASE II STUDIES

M. Bourliere1, M. Sulkowski2, M.P. Manns3, T. Asselah4, P. Ferenci5,

S. Pol6, T. Berg7, J. Lalezari8, A.-M. Quinson9, Y. Datsenko10,

J. Scherer9, C.-L. Yong9, F. Huang9. 1Hopital Saint Joseph, Marseille,

France; 2Johns Hopkins University School of Medicine, Baltimore, MD,

United States; 3Hannover Medical School, Hannover, Germany;4Hopital Beaujon, APHP, University Paris-Diderot and INSERM CRB 3,

Clichy, France; 5Medical University of Vienna, Vienna, Austria; 6Hopital

Cochin, Paris, France; 7Universitatsklinikum Leipzig AoR, Leipzig,

Germany; 8Quest Clinical Research and University of California-San

Francisco, San Francisco, CA, 9Boehringer Ingelheim Pharmaceuticals,

Inc., Ridgefield, CT, United States; 10Boehringer Ingelheim Pharma

GmbH & Co KG, Biberach, Germany

E-mail: mbourliere@hopital-saint-joseph.fr

Background and Aims: Faldaprevir is a potent HCV NS3/4A

protease inhibitor in development for the treatment of chronic HCV

infection in combination with ribavirin and pegylated interferon

a-2a (PegIFN), and in interferon-free combinations. Here we report

the pharmacokinetic (PK) interactions between faldaprevir and

ribavirin and PegIFN.

Methods: PK interactions were measured in two Phase Ib-II studies.

In study 1, treatment-naïve patients (N=26) received 14 days

(D) faldaprevir followed by 14D faldaprevir plus PegIFN/ribavirin.

The effect of PegIFN/ribavirin on steady-state (SS) faldaprevir was

assessed by comparing PK profiles on D28 with D14. In study

2, the effect of 120 and 240mg faldaprevir on ribavirin PK was

assessed versus placebo in a substudy (N=49) at week (W) 10 of

24W treatment; the effect on PegIFN was evaluated by comparison

of faldaprevir trough values (PegIFN/ribavirin + faldaprevir vs

PegIFN/ribavirin + placebo) at W12 and W24.

Results: The geometric mean ratio (GMR) (90%CI) of faldaprevir

plus PegIFN/ribavirin versus faldaprevir alone was 107.4 (96.9–

119.1), 110.5 (96.5–126.4) and 106.8 (94.5–120.6) for AUCt,ss, Cmax,ss

and Cmin,ss, respectively. The GMR of ribavirin/faldaprevir versus

ribavirin/placebo for ribavirin AUCt,ss was 0.81 and 0.82 for 1000mg

and 1200mg ribavirin, respectively (for the faldaprevir 120mg

regimen), and 1.06 and 0.83, respectively (for the faldaprevir 240mg

regimen). The trough PegIFN concentration GMR was within ±10%

for faldaprevir vs placebo at W12 and W24.

Conclusions: These data indicate that faldaprevir has no clinically

relevant effect on exposure of ribavirin or PegIFN, and PegIFN or

ribavirin have no effect on the PK of faldaprevir.

P739

RISK FACTORS AND TREATMENT OUTCOMES IN GENOTYPE 1

AND GENOTYPE 4 HEPATITIS C INFECTED PATIENTS FROM A

REAL WORLD DATA ANALYSIS IN EUROPE

C. Moreno1, Y. Horsmans2, R. Flisiak3, H. Van Vlierberghe4,

E. Trepo1, P. Starkel2, J. Jaroszewicz3, A. Geerts4, M. Pisini5,

L. Lantican6, D. Koletzki6. 1Erasme University Hospital, 2Saint

Luc University Hospital, Brussels, Belgium; 3Medical University of

Bialystok, Bialystok, Poland; 4University Hospital Ghent, Ghent,5Janssen Pharmaceutica NV, 6Janssen Diagnostics BVBA, Beerse,

Belgium

E-mail: dkoletzk@its.jnj.com

Background and Aims: Despite improvement in treatment of

chronic hepatitis C (CHC), there seems to be an unmet need

for patients infected with other genotypes (G) than G1 in real

world settings. This was assessed by comparing clinical outcomes

of patients with G1 and G4.

Methods: Routine clinical practice data were collected from

Belgium and Poland using a web-based registry. Univariate

statistical data analysis was performed.

Results: Demographics: N=293 G1 patients mainly consisting of

Caucasians (91%) and n=75 G4 patients mainly consisting of Black-

Africans (54%) and Caucasians (42%) were studied. Nosocomial

virus transmission was equally observed in both genotypes (57%).

Injecting-drug-use-related transmission was higher in G1 (22%)

than G4 (13%), whereas sexual transmission was lower in G1 (5%)

than G4 (13%). HIV co-infection was observed in 6% of G1 versus

15% of G4 patients.

Risk factors: A higher percentage of patients with baseline

BMI >25 was seen in G4 (53%) and differences were observed for

comorbidities with higher frequencies for hypertension, diabetes

and hypercholesterolemia and higher prescription frequencies of

certain concomitant medication potentially interacting with CHC

treatment in G4 compared to G1 (table).

Treatment and treatment response: PegIFN+RBV-based regimen

contributed with 76% to treatments. In terms of ultimate treatment

response per patient, the G4 cohort showed a higher percentage of

treatment failure (65%) than the G1 cohort (52%).

Table: Potential risk factors for lower treatment success

Observed risk factors G1 (n =293) G4 (n =75)

BMI >25 a 42% 53%HIV Co-infection 6% 15%Having ≥1 concurrent illness b 46% 60%Leading concurrent illnesses b

Hypertension 18% 32%Diabetes 7% 17%Hypercholesterolemia 3% 5%Renal failure 1% 5%

Leading concomitant medication b

Antihypertensives 20% 30%Calcium channel blockers 5% 18%HIV-Antivirals 7% 17%Beta blockers 6% 12%Statins 3% 3%

a Total number of records with available information (G1 n=158; G4 n=45).b Total number of treated patients (G1 n=234; G4 n=60).

Conclusions: The data suggest that G4 patients had a higher

prevalence of risk factors with potential negative impact on

treatment response, thus highlighting the need to identify disease

management strategies to improve treatment outcomes.

P740

PHARMACOKINETICS OF FALDAPREVIR IN HEALTHY SUBJECTS

FOLLOWING CO-ADMINISTRATION WITH ITRACONAZOLE

K. Marzin1, R. Koenen1, N. Strelkowa1, K.-P. Kammerer1, M. Elgadi2,

F. Huang3. 1Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim,

Germany; 2Boehringer Ingelheim Canada Ltd/Ltee., Burlington, ON,

Canada; 3Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT,

United States

E-mail: kristell.marzin@boehringer-ingelheim.com

Background and Aims: Faldaprevir is a potent inhibitor of HCV

NS3/4A protease in Phase III development for the treatment

of chronic HCV infection. Since faldaprevir is a CYP3A4/P-

glycoprotein substrate, we investigated the extent to which the

pharmacokinetics of faldaprevir is influenced by co-administration

of itraconazole, a strong CYP3A4/P-glycoprotein inhibitor.

Methods: This was an open-label, fixed-sequence study with intra-

subject comparison to evaluate the effect of itraconazole 200mg QD

on the pharmacokinetics of faldaprevir. Faldaprevir 120mg BID was

administered on Day 1 and then 120mg QD from Day 2 until end of

study (total 10 days); after 6 days of faldaprevir, itraconazole 200mg

QD (except 200mg BID on first day) was added to faldaprevir for

an additional 4 days. Intensive PK sampling was performed after

6 days of faldaprevir treatment and after 4 days of faldaprevir +

itraconazole treatment.

S316 Journal of Hepatology 2014 vol. 60 | S215–S359

POSTERS

Table (abstract P740): Faldaprevir PK parameters: adjusted geometric mean ratios

Pharmacokinetic parameter Adjusted gMean Intra-individual gCV, %

Faldaprevir + itraconazole(test) (N =17)

Faldaprevir alone(reference) (N=17)

Ratio of test to reference treatment,% (LL, UL) (N=17)

AUCt,ss [ng·h/mL] 59,454.33 29,944.19 198.55 (182.43, 216.09) 14.2Cmax,ss [ng/mL] 5,027.05 2,783.02 180.63 (165.68, 196.93) 14.5

Results: Eighteen subjects received trial medication and 17

completed the trial. The table shows steady-state pharmacokinetic

parameters along with geometric mean ratio of faldaprevir with vs.

without itraconazole.

Conclusions: Co-administration of faldaprevir with itraconazole

resulted in an approximately 2-fold increase in faldaprevir

steady-state exposure. Administration of faldaprevir alone or

in combination with itraconazole was generally safe and well

tolerated. No dose adjustment is required when faldaprevir is co-

administered with itraconazole.

P741

PHASE ANGLE IS ASSOCIATED WITH ADVANCED FIBROSIS IN

HCV PATIENTS

M.S. Dorna, N.A. Costa, L.F. Campos, F.G. Romeiro, L.Y. Sassaki,

S.A.R. Paiva, M.F. Minicucci, G.F. Silva. Internal Medicine, State

University of Sao Paulo, Botucatu, Brazil

E-mail: giovanni@fmb.unesp.br

Background and Aims: Hepatitis C is the major cause of chronic

liver disease worldwide. It is also known to silently evolve to

liver cirrhosis and hepatocellular carcinoma. For more than 20

years Bioelectrical Impedance has been used to assess nutritional

status. More recently, Phase Angle (PhA) derived from bioelectrical

impedance has been used as a predictor tool in different clinical

situations, including liver diseases.

Objective: Our aim was to associate PhA and advanced fibrosis in

patients with hepatitis C virus (HCV).

Methods: Study conducted in a reference treatment centre in Brazil.

Written informed consent was obtained from all patients. Inclusion

criteria were the confirmed diagnosis for HCV and a previous liver

biopsy for fibrosis staging. Exclusion criteria were ascites and age

<18 years. A single frequency bioelectrical impedance analysis was

performed in all patients. Liver fibrosis was classified according to

Metavir score. For statistical analysis multiple logistic regression

and the receiver operator characteristics (ROC) curves were used,

and statistical significance was set at p < 0.05.

Results: We assessed 135 subjects, 60% male, over 40 years old and

73.3% had HCV genotype 1. In multiple logistic regression, PhA was

predictor of advanced liver fibrosis, adjusted by age and gender

(OR: 0.448; 95%CI: 0.237–0.847; p: 0.013). The best PhA’s cut-offs

were 6.43 (AUC: 0.701; 95%CI: 0.608–0.793; p < 0.001) for general

data, 6.72 (AUC: 0.747; 95%CI: 95%; p =0.0001) for male and 5.94

(AUC: 0.698; CI:95%; p < 0.013) for female.

Conclusions: According to our data low PhA is associated with

advanced liver fibrosis in HCV patients.

P742

THE PHARMACOKINETICS OF GS-5816, A PAN-GENOTYPIC

HCV NS5A INHIBITOR, IN HCV-UNINFECTED SUBJECTS WITH

MODERATE AND SEVERE HEPATIC IMPAIRMENT

E. Mogalian1, A. Mathias1, D. Brainard1, J. McNally1, L. Moorehead1,

M. Hernandez1, R. Perry2, C. Curtis3, E. Lawitz4, K. Lasseter5,

T. Marbury6. 1Gilead Sciences, Inc., Foster City, CA, 2Elite Research

Institute, Miami, FL, 3Compass Research, Orlando, CA, 4Texas Liver

Institute, University of Texas Health Science Center, San Antonio, TX,5Clinical Pharmacology of Miami, Miami, 6Orlando Clinical Research

Center, Orlando, FL, United States

E-mail: erik.mogalian@gilead.com

Background and Aims: GS-5816 is an NS5A inhibitor with activity

against a broad range of HCV genotypes and is in clinical

development for the treatment of chronic HCV infection. This

study evaluated short-term safety and PK of GS-5816 in subjects

with moderate or severe hepatic impairment (HI) versus subjects

with normal hepatic function (NF) to inform GS-5816 dosing

recommendations in patients with HI.

Methods: Subjects with stable moderate or severe HI (CPT

Classification B or C), and subjects with NF, matched for age,

gender, and BMI, received a single dose of GS-5816 100mg followed

by intensive PK sampling over 120 hours. Safety assessments were

performed throughout the study. Comparative statistics for GS-5816

AUC and Cmax were calculated with an exposure increase >100%

being considered clinically relevant. Since HI may alter protein

binding, GS-5816 free fraction (%) was also determined.

Results: All subjects completed the study; no subject discontinued

due to an AE. All treatment-emergent AEs were Grade 1 (mild),

except for one Grade 2 (moderate, ascites: severe HI subject). Total

plasma exposures (AUC) were similar in subjects with moderate

or severe HI compared to NF. Cmax was lower in subjects with HI

but was not considered clinically impactful as overall exposure to

GS-5816 was unaltered. GS-5816 free fraction increased with HI

and unbound clearance decreased with HI.

Table: GS-5816 PK parameter comparison

GS-5816 PK parameter GMR% (90%CI)

Moderate HI:NF(N=10:10)

Severe HI:NF(N=10:10)

AUCinf 83.0 (57.5, 120) 114 (74.7, 173)AUClast 82.0 (56.8, 118) 105 (68.7, 160)Cmax 59.4 (37.8, 88.7) 47.2 (29.3, 76.0)

Conclusions: No clinically relevant changes in GS-5816 exposures

were observed in subjects with HI compared to those with NF.

GS-5816 may be administered without dose adjustment to patients

with mild, moderate, or severe hepatic impairment.

Journal of Hepatology 2014 vol. 60 | S215–S359 S317