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617 E1 therapeutic vaccination in patients with chronic HCV genotype 1 infection: Results of a 15-month, placebo-controlled trial
05G. Viral Hepatitis'
I
(g) Hepatitis' C
•
POPULATION PHARMACOKINETIC ANALYSIS OF RIBAVIRIN (COPEGUS | AFTER SINGLE AND MULTIPLE DOSE ADMINISTRATION IN ADULT CHRONIC HEPATITIS C (CHC) PATIENTS RECEIVING CONCURRENT PEGINTERFERON ALPHA-2a (40KD) (PEGASYS |
J.R. Wade 1, E. Snoeck 1, M. Lamb 2, F. Duff2, K. Jorga3. 1Exprimo NV, Lummen, Belgium," 2Roche, Nutle, NJ, USA," 3Roehe, Basel, Switzerland Baekgronnd: The combination of a pegylated interferon plus ribavirin is the treatment of choice for CHC. Ribavirin produces dose-related reductions in relapse rates during follow-up, but the use of higher doses of ribavirin is limited by dose-dependent haemolytic anaemia. A thorough understanding of the pharmacokinetics of drags with dose-dependent efficacy and toxicity is important to ensure optimal treatment outcomes. We analysed the population pharmacokinetics of ribavirin (COPEGUS | in patients with CHC, including those receiving concurrent peginterferon alpha-2a (40KD) (PEGASYS| Methods: Plasma concentration data from adults receiving ribavirin as a single 600mg dose in three phase I crossover studies, or 800, 1000 or 1200 mg/d in two randomised, multicentre, phase III studies were analysed. In multiple-dose studies, samples were collected at steady state (weeks 8 48). A population pharmacokinetic model was developed using nonlinear mixed effect modelling (NONMEM). Inter-occasion variability and food effects were included in the model. Resnlts (Table): 7025 ribavirin plasma measurements from 380 patients were analysed. Ribavirin pharmacokinetics were best described by a threecompartment model with a sequential zero/first order absorption process. The only covariate with a clinically significant influence on the pharmacokinetics of ribavirin was lean bodyweight (range 41 91 kg), influencing both clearance (15.3~3.9L/h over the lean bodyweight range) and the volume of the larger peripheral compartment (V2). Ribavirin clearance varied by <20% across the renal function range and between ethnic groups. Residual variability was very low for the final model (17%).
Parameter
Estimation
Std error (%)
Interindividual variability (%)
Std error (%)
Clearance Central Vd (V1) Peripheral Vd (V2) Peripheral Vd (V3) Residual error
19.8 L/h a 472L 4910 L a 871 L 17.0%
1.8 8.2 5.6 4.9 5.5
16 42 37 18
29 25 31 43
aFor a 67 kg (mean lean bodyweight) subject. Vd: volurne of distribution. Conclusion: The model provides a good description of ribavirin pharmacokinetics in CHC patients. Lean bodyweight was the only covariate that influenced clearance or volume of distribution. This modest effect supports the current recommendations that the dose of ribavirin be adjusted according to bodyweight to ensure adequate exposure in patients with genotype 1 infection.
I
Clinical therapy
•
E
$229
1
THERAPEUTIC VACCINATION IN PATIENTS WITH CHRONIC HCV GENOTYPE 1 INFECTION: RESULTS OF A 15-MONTH, PLACEBO-CONTROLLED TRIAL
H. Wedemeyer 1, H. Van Vlierberghe 2, H. Blum 3, F. Nevens4, M. Gschwantler5, S. Zeuzem6, T. Roskams7, V. Desmet7, S. Dincq 8, C. Vander Stichele 8, H. De Winter8, G. Maertens 8, Y. Horsmans9, T2S-916-HCV study group. 1Abteilung Gastroenterologie, Hepatologie
und Endokrinologie, Medizinisehe Hoehsehule Hannoveg Hannove~ Germany," 2Departement Gastroenterologie, Universitair Ziekenhuis Gent, Gent, Belgium," 3Abteilung Innere Medizin H Gastroenterologie, Hepatologie und Endokrinologie, Klinikum der Albert-LudwigsUniversitat Freiburg, Freiburg, Germany," 4Departement Hepatologie, Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium," 5Medizinisehe Abteilung mit Gastroenterologie und Hepatologie, Krankenanstalt Rudoljg'tiftung der Stadt Wien, Wien, Austria," 6Klinik fiir Innere Medizin II, Universitiitsklinikum des Saarlandes, Homburg/Saar, Germany," 7Departement Morfologie en Moleculaire Pathologie, Katholieke Universiteit Leuven, Leuven, Belgium," 8Innogenetics NV, Gent, Belgium," 9Service de Gastro-entdrology, Cliniques Universitaires St-Luc, Brussels', Belgium Baekgronnd and Alms: A pilot study in chronic HCV patients indicated that E1 vaccination could halt progression of liver fibrosis without pronounced effects on viral load. The aim was to confirm these findings in a larger placebo-controlled trial. Methods: 164 patients (9% naive) were randomized to either two courses of 8+6 injections of 20 gg El/alum or placebo/alum (82 in each group). Baseline and end-of-treatment liver biopsies (15 months apart) were assessed by blind and unpaired consensus scoring (Ishak) by two expert hepatopathologists. Resnlts: 151 patients completed the study; 2 biopsies were available for evaluation for 146 patients. In the E1 group, 30% of the patients improved by at least 1 point in Ishak fibrosis score, versus 27% in the placebo group. The mean change in Ishak fibrosis score was 0.01 [ 0.28;0.31] in the vaccine-treated group versus 0.12 [ 0.17;0.42] in the placebo group. Ishak inflammation and total Ishak scores improved by at least 2 points in 25% and 29% of E1 patients and in 18% and 23% of placebo patients, respectively. Mean Ishak inflammation and mean total Ishak score changes were 0.21 [ 0.35;0.76] and 0.22 [ 0.43;0.87] for E1 and 0.48 [ 0.04; 1.00] and 0.6 [ 0.09; 1.30] for the placebo group, respectively. Liver enzymes and viremia levels did not change markedly in either group. El-specific antibodies, T-cell proliferation, IFN-?, and IL-5 were significantly induced in the E1 group only. Of the 13 drop-outs, 5 patients discontinued because of an adverse event; 1 on E1 and 4 on placebo. The adverse event profile was similar in both groups. Conelnsions: This trial confirms earlier findings that E 1 vaccination has an excellent tolerability, induces significant immune responses, and may halt fibrosis in chronic HCV patients. This placebo-controlled trial showed that fibrosis progression in hepatitis C is slower than previously reported and thus, no significant difference between the treatment groups was evident after 15 months. An ongoing phase II trial of similar design was prolonged with 2 additional courses of E 1 vaccine or placebo to allow assessment of histological changes over 3 years. (HW and HVV contributed equally to the study.)
I
(g) Hepatitis' C
•
POPULATION PHARMACOKINETIC ANALYSIS OF RIBAVIRIN (COPEGUS | AFTER SINGLE AND MULTIPLE DOSE ADMINISTRATION IN ADULT CHRONIC HEPATITIS C (CHC) PATIENTS RECEIVING CONCURRENT PEGINTERFERON ALPHA-2a (40KD) (PEGASYS |
J.R. Wade 1, E. Snoeck 1, M. Lamb 2, F. Duff2, K. Jorga3. 1Exprimo NV, Lummen, Belgium," 2Roche, Nutle, NJ, USA," 3Roehe, Basel, Switzerland Baekgronnd: The combination of a pegylated interferon plus ribavirin is the treatment of choice for CHC. Ribavirin produces dose-related reductions in relapse rates during follow-up, but the use of higher doses of ribavirin is limited by dose-dependent haemolytic anaemia. A thorough understanding of the pharmacokinetics of drags with dose-dependent efficacy and toxicity is important to ensure optimal treatment outcomes. We analysed the population pharmacokinetics of ribavirin (COPEGUS | in patients with CHC, including those receiving concurrent peginterferon alpha-2a (40KD) (PEGASYS| Methods: Plasma concentration data from adults receiving ribavirin as a single 600mg dose in three phase I crossover studies, or 800, 1000 or 1200 mg/d in two randomised, multicentre, phase III studies were analysed. In multiple-dose studies, samples were collected at steady state (weeks 8 48). A population pharmacokinetic model was developed using nonlinear mixed effect modelling (NONMEM). Inter-occasion variability and food effects were included in the model. Resnlts (Table): 7025 ribavirin plasma measurements from 380 patients were analysed. Ribavirin pharmacokinetics were best described by a threecompartment model with a sequential zero/first order absorption process. The only covariate with a clinically significant influence on the pharmacokinetics of ribavirin was lean bodyweight (range 41 91 kg), influencing both clearance (15.3~3.9L/h over the lean bodyweight range) and the volume of the larger peripheral compartment (V2). Ribavirin clearance varied by <20% across the renal function range and between ethnic groups. Residual variability was very low for the final model (17%).
Parameter
Estimation
Std error (%)
Interindividual variability (%)
Std error (%)
Clearance Central Vd (V1) Peripheral Vd (V2) Peripheral Vd (V3) Residual error
19.8 L/h a 472L 4910 L a 871 L 17.0%
1.8 8.2 5.6 4.9 5.5
16 42 37 18
29 25 31 43
aFor a 67 kg (mean lean bodyweight) subject. Vd: volurne of distribution. Conclusion: The model provides a good description of ribavirin pharmacokinetics in CHC patients. Lean bodyweight was the only covariate that influenced clearance or volume of distribution. This modest effect supports the current recommendations that the dose of ribavirin be adjusted according to bodyweight to ensure adequate exposure in patients with genotype 1 infection.
I
Clinical therapy
•
E
$229
1
THERAPEUTIC VACCINATION IN PATIENTS WITH CHRONIC HCV GENOTYPE 1 INFECTION: RESULTS OF A 15-MONTH, PLACEBO-CONTROLLED TRIAL
H. Wedemeyer 1, H. Van Vlierberghe 2, H. Blum 3, F. Nevens4, M. Gschwantler5, S. Zeuzem6, T. Roskams7, V. Desmet7, S. Dincq 8, C. Vander Stichele 8, H. De Winter8, G. Maertens 8, Y. Horsmans9, T2S-916-HCV study group. 1Abteilung Gastroenterologie, Hepatologie
und Endokrinologie, Medizinisehe Hoehsehule Hannoveg Hannove~ Germany," 2Departement Gastroenterologie, Universitair Ziekenhuis Gent, Gent, Belgium," 3Abteilung Innere Medizin H Gastroenterologie, Hepatologie und Endokrinologie, Klinikum der Albert-LudwigsUniversitat Freiburg, Freiburg, Germany," 4Departement Hepatologie, Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium," 5Medizinisehe Abteilung mit Gastroenterologie und Hepatologie, Krankenanstalt Rudoljg'tiftung der Stadt Wien, Wien, Austria," 6Klinik fiir Innere Medizin II, Universitiitsklinikum des Saarlandes, Homburg/Saar, Germany," 7Departement Morfologie en Moleculaire Pathologie, Katholieke Universiteit Leuven, Leuven, Belgium," 8Innogenetics NV, Gent, Belgium," 9Service de Gastro-entdrology, Cliniques Universitaires St-Luc, Brussels', Belgium Baekgronnd and Alms: A pilot study in chronic HCV patients indicated that E1 vaccination could halt progression of liver fibrosis without pronounced effects on viral load. The aim was to confirm these findings in a larger placebo-controlled trial. Methods: 164 patients (9% naive) were randomized to either two courses of 8+6 injections of 20 gg El/alum or placebo/alum (82 in each group). Baseline and end-of-treatment liver biopsies (15 months apart) were assessed by blind and unpaired consensus scoring (Ishak) by two expert hepatopathologists. Resnlts: 151 patients completed the study; 2 biopsies were available for evaluation for 146 patients. In the E1 group, 30% of the patients improved by at least 1 point in Ishak fibrosis score, versus 27% in the placebo group. The mean change in Ishak fibrosis score was 0.01 [ 0.28;0.31] in the vaccine-treated group versus 0.12 [ 0.17;0.42] in the placebo group. Ishak inflammation and total Ishak scores improved by at least 2 points in 25% and 29% of E1 patients and in 18% and 23% of placebo patients, respectively. Mean Ishak inflammation and mean total Ishak score changes were 0.21 [ 0.35;0.76] and 0.22 [ 0.43;0.87] for E1 and 0.48 [ 0.04; 1.00] and 0.6 [ 0.09; 1.30] for the placebo group, respectively. Liver enzymes and viremia levels did not change markedly in either group. El-specific antibodies, T-cell proliferation, IFN-?, and IL-5 were significantly induced in the E1 group only. Of the 13 drop-outs, 5 patients discontinued because of an adverse event; 1 on E1 and 4 on placebo. The adverse event profile was similar in both groups. Conelnsions: This trial confirms earlier findings that E 1 vaccination has an excellent tolerability, induces significant immune responses, and may halt fibrosis in chronic HCV patients. This placebo-controlled trial showed that fibrosis progression in hepatitis C is slower than previously reported and thus, no significant difference between the treatment groups was evident after 15 months. An ongoing phase II trial of similar design was prolonged with 2 additional courses of E 1 vaccine or placebo to allow assessment of histological changes over 3 years. (HW and HVV contributed equally to the study.)