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794 THE EFFECT OF COADMINISTRATION OF THE PROTON-PUMP INHIBITOR OMEPRAZOLE ON THE PHARMACOKINETICS OF DACLATASVIR IN HEALTHY SUBJECTS
POSTERS 793 REAL-LIFE DATA OF TELAPREVIR-BASED TRIPLE-THERAPY IN PATIENTS WITH CHRONIC HEPATITIS C GT1 IN GERMANY – AN INTERIM ANALYSIS T. Berg1 , P. Buggisch2 , D. Hueppe3 , H. Wedemeyer4 , M. Schuier5 , S. Decker-Burgard5 , S. Mauss6 , TEPs Study Group. 1 Universitaetsklinik, Leipzig, 2 Ifi-Institut, Hamburg, 3 Gastroenterologische Gemeinschaftspraxis, Herne, 4 Medizinische Hochschule, Hannover, 5 Janssen-Cilag GmbH, Neuss, 6 Praxis, D¨ usseldorf, Germany E-mail: [email protected] Background and Aims: Telaprevir (TVR)-based triple therapy in patients (pts) with chronic Hepatitis C (HCV) in daily practice in Germany is investigated in this non-interventional study to evaluate the implementation of futility rules, response-guided therapy, safety and efficiency. Methods: Prospective study, investigating TVR-based therapy in therapy-naive and pretreated pts with chronic HCV GT 1. Data from the first 400 pts starting treatment (50% of the planned total) at 67 sites, followed up for a maximum of 24 weeks (W) of treatment. Results: 70.3% of pts were pretreated (41.3% prior relapser, 32.7% non-responder) and 16% of pts reported cirrhosis at baseline (BL). 42.0% of pts had HCV RNA levels <800.000 IU/ml (BL). 78.9%* of pts (79.4% therapy-naïve; 78.3% pretreated) showed rapid virological response (RVR). Adherence to futility rules (stop if HCV-RNA >1000 IU/ml at W4) was found in 5 of 7 pts; two pts continued treatment until W12. At W12, 90.6%* of pts had undetectable HCV RNA. 73.3%* of therapy-naive pts and 76.0%* of pretreated pts were HCV-RNA negative at both W4 and W12. 12 pts (3.0%) with RVR at W4 suffered a breakthrough. Most pts (86.8%) had adverse events (AE) during the first 12W, 11.5% serious adverse events (SAE). AEs were mostly mild (62.0%) or moderate (35.1%), including rash (32.2%, mostly rated as mild or moderate) and anemia (30.1%). Hb decrease <12 g/dl (female) or <13 g/dl (male) was reported in 88.5% of pts. Mean Hb levels decreased from 14.3 g/dl at BL to 10.4 g/dl at W12; Hb levels <8.5 g/dl within the first 24W of treatment were present in 19.6% of anemia cases and 8.4% required transfusion. 14 pts (3.5%) received erythropoeitin. 14 (3.8%) anemia cases and 13 (15.3%) rash cases were considered as SAE. Conclusions: This interim analysis confirms the antiviral efficiency of TVR-based triple-therapy in GT1 HCV in a real life setting showing eRVR rates of more than 70% in treatment naïve and pre-treated patients. Adherence to futility rules was confirmed in most patients. As observed in clinical trials, adverse events were reported frequently. * % based on number of pts with HCV-RNA measurements 794 THE EFFECT OF COADMINISTRATION OF THE PROTON-PUMP INHIBITOR OMEPRAZOLE ON THE PHARMACOKINETICS OF DACLATASVIR IN HEALTHY SUBJECTS M. Bifano1 , S. Connolly2 , C. Hwang1 , H. Sevinsky1 , R.J. Bertz1 . Clinical Research and Development, Bristol-Myers Squibb, Hopewell, 2 Celerion Inc, Neptune, NJ, USA E-mail: [email protected] 1
Background: Daclatasvir (DCV; BMS-790052) is a highly selective, first-in-class, HCV NS5A replication complex inhibitor. DCV exhibits pH-dependent solubility, which decreases from 20 mg/mL at pH2 to 0.015 mg/mL at pH7. Since it is anticipated that DCV will be coadministered with acid-suppressing medications potentially reducing DCV exposure, this study aimed to assess the effect of the proton-pump inhibitor omeprazole on the pharmacokinetics of DCV. Methods: This was a randomized, open-label study in healthy subjects (N = 24). Subjects received a single dose of DCV 20 mg or 60 mg on Day 1 (Treatments A/B) followed by a 48h washout period. S324
These DCV doses were selected since they represented the lowest and highest doses undergoing clinical evaluation when this study was conducted, and it was expected that DCV exposures would vary across this dose range. Omeprazole 40 mg QD was administered from Days 3–9 (Treatment C), with a concomitant single dose of DCV 20 mg or 60 mg on Day 8 (Treatments D/E). Subjects received the same DCV dose on both days. DCV pharmacokinetics were assessed for 48h post-dose on Days 1 and 8. Adjusted ratios of geometric means and 90% confidence intervals (CI) were estimated. Results: Adjusted ratios of geometric means and 90% CIs are presented in the table. Coadministration of DCV 20 mg with omeprazole did not affect overall DCV exposures. AUC(INF) and C24 were reduced by approximately 16% and 8%, respectively, when DCV 60 mg was coadministered with omeprazole. Both doses of DCV with/without omeprazole were well tolerated. Table 1 Adjusted geometric mean ratio (90% CI)
DCV 20 mg (Treatment D vs A) DCV 60 mg (Treatment E vs B)
Cmax
AUC(0-T)
AUC(INF)
C24
0.800 (0.633, 1.102) 0.643 (0.536, 0.771)
1.004 (0.869, 1.161) 0.821 (0.716, 0.941)
1.021 (0.888, 1.175) 0.840 (0.732, 0.963)
1.113 (0.989, 1.254) 0.915 (0.795, 1.054)
Conclusions: Coadministration of DCV with omeprazole resulted in reduced bioavailability of DCV; a 16% reduction in AUC(INF) was observed at the 60 mg dose selected for phase 3 evaluation. However, this reduction in DCV exposure was not clinically significant and dose adjustment is not required when DCV is coadministered with omeprazole. These findings are comparable to those observed when DCV is coadministered with the H2-receptor agonist famotidine. 795 REAL WORLD COSTS OF TELAPREVIR-BASED TRIPLE THERAPY, INCLUDING COSTS OF MANAGING ADVERSE EVENTS, AT THE MOUNT SINAI MEDICAL CENTER, NY: $147,000 PER EOT K. Bichoupan, V. Martel-Laferriere, M. Ng, E.A. Schonfeld, A. Pappas, J. Crismale, A. Stivala, V. Khaitova, D. Gardenier, P. Perumalswami, T.D. Schiano, J.A. Odin, L. Liu, D.T. Dieterich, A.D. Branch. Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY, USA E-mail: [email protected] Aims: The addition of telaprevir to IFN/RBV improved SVR rates for genotype 1 HCV, but also increased adverse events (AEs) and costs. We estimated the total management cost of triple therapy in a real-world setting. Methods: Pre-treatment, on-treatment, and post-treatment costs were calculated using 2010 US estimates from Medicare, Agency for Healthcare Research and Quality (AHRQ), and Red Book WAC, adjusting for inflation. Resource utilization was based on standard practices and data on 134 patients who initiated telaprevir use at Mount Sinai Medical Center (5/2011–12/2011). End-of-treatment (EOT) data were available; SVR data are pending. FIB-4 scores ≥3.25 indicated advanced fibrosis/cirrhosis. Results: Median age of the 134 patients was 57 years (IQR=51–61), 91 were male, 23 were black, 16 had HCV/HIV co-infection, 48 had advanced fibrosis/cirrhosis; 75 (56%) had an EOT. Median cost of standard triple therapy (telaprevir, IFN/RBV and routine care) was $77,020 ($66,045-$92,980) per patient. Median total cost of treatment (triple therapy plus AE management) was significantly higher: $82,500 ($67,967-$98,138), p = 0.02. On an intention-to-treat basis, median total cost per EOT was $147,321 ($121,321-$175,176). Seventy-seven patients (57%) had AE-attributable costs; 49% received epoetin-a and 12% had a treatment-related hospitalization. For the 58 patients who completed 48 weeks of treatment, the
Journal of Hepatology 2013 vol. 58 | S229–S407
Background: Daclatasvir (DCV; BMS-790052) is a highly selective, first-in-class, HCV NS5A replication complex inhibitor. DCV exhibits pH-dependent solubility, which decreases from 20 mg/mL at pH2 to 0.015 mg/mL at pH7. Since it is anticipated that DCV will be coadministered with acid-suppressing medications potentially reducing DCV exposure, this study aimed to assess the effect of the proton-pump inhibitor omeprazole on the pharmacokinetics of DCV. Methods: This was a randomized, open-label study in healthy subjects (N = 24). Subjects received a single dose of DCV 20 mg or 60 mg on Day 1 (Treatments A/B) followed by a 48h washout period. S324
These DCV doses were selected since they represented the lowest and highest doses undergoing clinical evaluation when this study was conducted, and it was expected that DCV exposures would vary across this dose range. Omeprazole 40 mg QD was administered from Days 3–9 (Treatment C), with a concomitant single dose of DCV 20 mg or 60 mg on Day 8 (Treatments D/E). Subjects received the same DCV dose on both days. DCV pharmacokinetics were assessed for 48h post-dose on Days 1 and 8. Adjusted ratios of geometric means and 90% confidence intervals (CI) were estimated. Results: Adjusted ratios of geometric means and 90% CIs are presented in the table. Coadministration of DCV 20 mg with omeprazole did not affect overall DCV exposures. AUC(INF) and C24 were reduced by approximately 16% and 8%, respectively, when DCV 60 mg was coadministered with omeprazole. Both doses of DCV with/without omeprazole were well tolerated. Table 1 Adjusted geometric mean ratio (90% CI)
DCV 20 mg (Treatment D vs A) DCV 60 mg (Treatment E vs B)
Cmax
AUC(0-T)
AUC(INF)
C24
0.800 (0.633, 1.102) 0.643 (0.536, 0.771)
1.004 (0.869, 1.161) 0.821 (0.716, 0.941)
1.021 (0.888, 1.175) 0.840 (0.732, 0.963)
1.113 (0.989, 1.254) 0.915 (0.795, 1.054)
Conclusions: Coadministration of DCV with omeprazole resulted in reduced bioavailability of DCV; a 16% reduction in AUC(INF) was observed at the 60 mg dose selected for phase 3 evaluation. However, this reduction in DCV exposure was not clinically significant and dose adjustment is not required when DCV is coadministered with omeprazole. These findings are comparable to those observed when DCV is coadministered with the H2-receptor agonist famotidine. 795 REAL WORLD COSTS OF TELAPREVIR-BASED TRIPLE THERAPY, INCLUDING COSTS OF MANAGING ADVERSE EVENTS, AT THE MOUNT SINAI MEDICAL CENTER, NY: $147,000 PER EOT K. Bichoupan, V. Martel-Laferriere, M. Ng, E.A. Schonfeld, A. Pappas, J. Crismale, A. Stivala, V. Khaitova, D. Gardenier, P. Perumalswami, T.D. Schiano, J.A. Odin, L. Liu, D.T. Dieterich, A.D. Branch. Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY, USA E-mail: [email protected] Aims: The addition of telaprevir to IFN/RBV improved SVR rates for genotype 1 HCV, but also increased adverse events (AEs) and costs. We estimated the total management cost of triple therapy in a real-world setting. Methods: Pre-treatment, on-treatment, and post-treatment costs were calculated using 2010 US estimates from Medicare, Agency for Healthcare Research and Quality (AHRQ), and Red Book WAC, adjusting for inflation. Resource utilization was based on standard practices and data on 134 patients who initiated telaprevir use at Mount Sinai Medical Center (5/2011–12/2011). End-of-treatment (EOT) data were available; SVR data are pending. FIB-4 scores ≥3.25 indicated advanced fibrosis/cirrhosis. Results: Median age of the 134 patients was 57 years (IQR=51–61), 91 were male, 23 were black, 16 had HCV/HIV co-infection, 48 had advanced fibrosis/cirrhosis; 75 (56%) had an EOT. Median cost of standard triple therapy (telaprevir, IFN/RBV and routine care) was $77,020 ($66,045-$92,980) per patient. Median total cost of treatment (triple therapy plus AE management) was significantly higher: $82,500 ($67,967-$98,138), p = 0.02. On an intention-to-treat basis, median total cost per EOT was $147,321 ($121,321-$175,176). Seventy-seven patients (57%) had AE-attributable costs; 49% received epoetin-a and 12% had a treatment-related hospitalization. For the 58 patients who completed 48 weeks of treatment, the
Journal of Hepatology 2013 vol. 58 | S229–S407