- Email: [email protected]
intolerant patients with advanced chronic hepatitis C genotype 1 infection
POSTERS LDV/SOF+RBV group, 18/23 (78%) reported a TEAE. All were mild to moderate in severity and most were considered related to study drug. The most common AE in both arms was nasopharyngitis. In the LDV/SOF+RBV arm, RBV-related AEs such as anemia, nausea and rash were also reported. There were no Grade 3 or 4 AEs nor discontinuations due to AE in either arm. Conclusions: LDV/SOF FDC±RBV for 12 weeks achieved SVR12 in 100% of Japanese patients who had previously failed PI+ PegIFNa+RBV. LDV/SOF FDC for 12 weeks provides a highly effective, well-tolerated, IFN- and RBV-free treatment for Japanese patients with chronic HCV GT1 infection. P0787 COMPARISON OF SOFOSBUVIR +/− SIMEPREVIR IN HETEROGENEOUS, REAL-WORLD POPULATIONS OF HCV PATIENTS OVER 70 YEARS OF AGE VS YOUNGER HCV PATIENTS; DATA FROM THE TRIO NETWORK N. Tsai1 , K. Kowdley2 , B. Bacon3 , S. Flamm4 , E. Lawitz5 , S. Milligan6 , Z. Younossi7 , D. Dieterich8 . 1 Queen’s Medical Center, University of Hawaii, Honolulu, 2 Liver Care Network, Swedish Medical Center, Seattle, 3 School of Medicine, St. Louis University, St. Louis, 4 Feinberg School of Medicine, Northwestern University, Chicago, 5 The Texas Liver Institute, University of Texas Health Science Center, San Antonio, 6 Trio Health Analytics, Newton, 7 Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, Falls Church, 8 Icahn School of Medicine, Mount Sinai, New York, United States E-mail: [email protected] Background and Aims: Clinical trials often exclude significant numbers of patients over the age of 65 years and data on treatment of older patients with HCV is lacking. Trio Health is a disease management company that works in partnership with academic medical centres, community physicians and specialty pharmacies in the US to optimize care for Hepatitis C. Data obtained through the Trio Health program were used to evaluate efficacy and tolerability of regimens containing sofosbuvir or simeprevir in HCV patients over 70 years of age in comparison to HCV patients 70 years or younger. Methods: Data were collected from Rx records through the Trio Platform in partnership with specialty pharmacies. Analyses were limited to 955 patients who initiated treatment with 12 week regimens between December 2013 and March 2014. Patients were treated in 142 clinics, 30 of which were academic-based. 55 of the 955 patients were over 70 years of age. Table 1. Patient demographics and clinical characteristics at baseline
Age, mean (range) Male, no. (%) Black, no. (%) Platelets <100K/ul, no. (%) Treatment experienced, no. (%) Cirrhosis, no. (%) Genotype, no. (%) 1 1a 1b 2 3 4–6 mixed Initial viral load, no. (%) ≤800,000 IU/ml >6MM IU/ml Regimen, no. (%) a PEG + RBV + SOF RBV + SOF SMV + SOF +/− RBV a
Results: Patient demographics and baseline clinical measures are provided in Table 1. In the over 70 years old group, the discontinuation rate was 7% and SVR12 rates were 79% and 95% for the Intent to Treat (ITT) and Per Protocol (PP) populations, respectively, with results pending for 8 patients. In comparison and without balancing for disease, treatment and/or patient characteristics, outcomes for ≤70 year old patients (n = 900) from the same time period were 4% discontinuation, 80% SVR12 (ITT) and 87% SVR12 (PP), with results pending for 119 patients. None of the rates were significantly different between the age groups, though the SVR12 PP rate difference approached significance at p = 0.056. Conclusions: All oral DAA therapy is well tolerated in patients over 70 years old with SVR rates >80% similar to that seen in younger populations. P0788 ESTIMATING THE COST-EFFECTIVENESS OF DACLATASVIR PLUS SOFOSBUVIR IN TREATMENT-NA¨IVE, TREATMENT-EXPERIENCED AND INTERFERON-INELIGIBLE/INTOLERANT PATIENTS WITH ADVANCED CHRONIC HEPATITIS C GENOTYPE 1 INFECTION P. McEwan1,2 , S. Webster1 , T. Ward1 , A. Kalsekar3 , Y. Yuan3 , M. Brenner4 . 1 HEOR, HEOR Ltd, Monmouth, 2 School of Human & Health Sciences, Swansea University, Swansea, United Kingdom; 3 World Wide Health Economics and Outcomes Research, Bristol-Myers Squibb Pharmaceuticals Ltd, Princeton, United States; 4 UK HEOR, Bristol-Myers Squibb Pharmaceuticals Ltd, Uxbridge, United Kingdom E-mail: [email protected] Background and Aims: The availability of effective treatment for chronic hepatitis C patients with advanced disease has been considered an area of unmet medical need due to the limited efficacy and sub-optimal safety of historical treatments. However, the treatment landscape for chronic hepatitis C is rapidly evolving. Presented herein is a cost-effectiveness analysis of licensed regimens for treatment-naïve, treatment-experienced and interferon-ineligible/intolerant patients infected with hepatitis C virus (HCV) genotype 1 with advanced disease (METAVIR score ≥F3). Methods: A published Markov model was used to estimate the relative cost-effectiveness of chronic hepatitis C treatments over a lifetime horizon in a cohort that had a mean age of 50 years and were 67% male. Patients progress through disease stages using published transition rates. Patients were distributed across fibrosis stages F3 and F4 at therapy initiation according to UK data (78.62% and 21.38%, respectively). Disease state costs were obtained from 2013 UK data and discounting was set to 3.5%. Weekly treatment costs were as follows: daclatasvir (DCV): £2,083.13; sofosbuvir (SOF): £2,915.24; simeprevir (SMV): £1,866.50; telaprevir (TVR): £1,866.50; boceprevir (BOC): £700.00; ribavirin (RBV): £66.95;
Age ≤70 years, N = 900 (94%)
Age >70 years, N = 55 (6%)
56 (17–70) 535 (59%) 141 (16%) 122 (16%) 392 (44%) 268 (30%)
74 (71–86) 30 (55%) 10 (18%) 10 (20%) 15 (27%) 23 (42%)
61 (7%) 448 (50%) 159 (18%) 194 (22%) 7 (1%) 24 (3%) 7 (1%)
1 (2%) 14 (25%) 20 (36%) 18 (33%) 0 (0%) 1 (2%) 1 (2%)
283 (31%) 169 (19%)
26 (47%) 9 (16%)
Interferon-ineligible/intolerant
377 (42%) 207 (23%) 292 (32%)
7 (13%) 20 (36%) 28 (51%)
a
Population
Regimen
SVR (%)
Naive
DCV+SOF TVR+PR BOC+PR SOF+PR SMV+PR PR No treatment DCV+SOF No treatment DCV+SOF SOF+RBV SMV+SOF No treatment
100 66 41 80 68 41 0 100 0 100 36 93 0
Experienced
24 patients received other therapies.
ICER (£) versus DCV+SOF 7,851 1,346 14,240 12,265 8,861 4,263 − 4,263 − Dominant a Dominant a 4,263
DCV+SOF is associated with improved quality of life and reduced total cost.
Journal of Hepatology 2015 vol. 62 | S263–S864
S627
POSTERS pegylated interferon-alfa+ribavirin (PR): £191.35. Clinical inputs were obtained from pivotal studies for all treatment regimens, as reported in respective Summaries of Product Characteristics (SPCs) or published articles. Results: Predicted incremental cost-effectiveness results are presented in Table 1. Conclusions: Treatment with DCV+SOF is likely to be cost-effective (at the £20,000/QALY threshold) and associated with improved quality of life against all available comparators in treatmentnaïve, treatment-experienced and interferon-ineligible/intolerant HCV genotype 1 patients with advanced disease; further, DCV+SOF is expected to be associated with reduced total medical costs in interferon-ineligible/intolerant patients versus active comparators. P0789 EFFECTIVENESS, SAFETY AND COST PER SVR IN GT4 HEPATITIS C PATIENTS TREATED WITH SOFOSBUVIR-BASED THERAPIES IN REAL CLINICAL PRACTICE: A FRANCO-GERMAN EXPERIENCE (SOFEX-4) R. Pais1 , P. Buggisch2 , J. Moussalli1 , Y. Benhamou1 , H. Wedemeyer3 , T. Asselah4 , M. Bec5 , J. Schwarzbard5 , V. Ratziu1 , J. Petersen2 . 1 Hepatogastroenterology, La Piti´e-Salpˆetri`ere Hospital, Paris, France; 2 Hepatology, Asklepios Klinik St Georg, Hamburg, 3 Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; 4 Hepatology, Beaujon Hospital, Clichy, France; 5 Amaris, London, United Kingdom E-mail: [email protected] Background and Aims: Sofosbuvir (SOF) is approved for treatment of chronic hepatitis C (CHC) patients genotypes (GT) 1–6 but clinical trial data with SOF regimens in GT4 is limited. In the real-world (RW) setting, very limited clinical data was recently presented (Buggisch et al. AASLD 2014 n = 18, TRIO AASLD 2014 n = 16), and no study to date has simultaneously evaluated the clinical and economic outcomes of SOF-based therapies in GT4 patients in Europe. The aim of this study was to estimate the total costs, RW effectiveness, safety and cost per SVR of CHC patients treated with SOF-based therapies in a Franco-German collaboration. Methods: This is a retrospective multicentre cohort study including 160 GT4 patients treated in 5 centers (3 in France and 2 in Germany). All patients who received at least 1 week of SOF from January 17th 2014 (date of SOF approval by EMA) to October 31st 2014, are included. SVR rates (ITT), overall and by subgroup, along with incidence of adverse events (AE) requiring intervention, were estimated. Total cost incurred from therapy initiation to 12 weeks after treatment was estimated by summing drug costs, lab costs, patient care costs including AE (treatment related only) management costs. Cost per SVR was calculated as median cost divided by the SVR rate. Subgroup analysis included treatment experience and fibrosis stage. Results: Complete results will be available at the time of presentation. Recruitment is on-going and preliminary results are based on 51 patients with 49% receiving SOF+PR, 33% SOF+SIM, 10% SOF+R and 8% SOF+DCV. Mean age was 54 years, and 88% were male. At study entry, 57% of patients were cirrhotic and 73% had received at least one prior therapy (from the 31 patients with data available, 61% did not respond to prior therapy and 29% relapsed). Overall the SVR rate was 92% with 86% in treatment-naïve patients and 94% in treatment-experienced patients. A total of 11 patients (22%) experienced AEs (7 patients on SOF+PR). One patient discontinued due to AE. Cost per SVR results, overall and per subgroup will be estimated once patients have completed treatment and SVR12 is available. Conclusions: Preliminary data indicates high levels of SVR in this difficult to treat mostly cirrhotic and experienced GT4 patients.
S628
P0790 THE EFFECT OF RENAL IMPAIRMENT ON MULTIPLE-DOSE PHARMACOKINETICS OF THE FIXED-DOSE COMBINATION OF DACLATASVIR/ASUNAPREVIR/BECLABUVIR R. Adamczyk1 , K. Sims1 , M. Hesney1 , M. Wind-Rotolo1 , M. Stonier1 , R. Penn2 , L. Reynolds2 , F. LaCreta1 , M. AbuTarif1 . 1 Bristol-Myers Squibb Research and Development, Princeton, 2 ICON, Development Solutions, Hanover, United States E-mail: [email protected] Background and Aims: Daclatasvir (DCV; NS5A inhibitor), asunaprevir (ASV; NS3 inhibitor), and beclabuvir (BCV [BMS791325]; nonnucleoside NS5B inhibitor) are in phase 3 evaluation for chronic hepatitis C as a fixed-dose combination (FDC) of DCV/ASV/BCV (30/200/75 mg BID). As a subset of HCV patients have some degree of renal impairment due to age and comorbidities, this open-label, multiple-dose study (AI443–110) assessed the pharmacokinetics (PK) and safety of DCV/ASV/BCV FDC in HCV-uninfected subjects with normal renal function and renal impairment (RI) of varying degree. Methods: All subjects were scheduled to receive DCV/ASV/BCV FDC + additional 75 mg BCV (to adjust for higher BCV exposures in HCVinfected patients) BID with food. Subjects were grouped based on renal function: normal renal function (creatinine clearance [CrCl] by Cockcroft-Gault of ≥90 mL/min), mild RI (CrCl 60 to <90 mL/min), moderate RI (CrCl 30 to <60 mL/min), severe RI (CrCl <30 mL/min) and end-stage renal dysfunction (ESRD) on hemodialysis (HD). All subjects received the regimen for 9 days with a single morning dose on Day 10. Noncompartmental PK parameters were derived and linear regression was used to estimate the relationship between Cmax (ng/mL) and AUCTAU (ng·.h/mL) and CrCl. Predicted values for each PK parameter and associated 90% CIs were presented for CrCl equal to 15, 30, 60, and 90 mL/min. Safety was assessed and reported. Results: A total of 41 subjects received study drug across normal renal function (n = 8), mild RI (n = 9), moderate RI (n = 8), severe RI (n = 8), and ESRD on HD (n = 8) groups. Values of PK parameters relative to the normal renal function group predicted from the regression analysis of CrCl are shown in the table. Regression analysis indicated that Cmax and AUCTAU increased with decreasing CrCl for all 3 drugs. For subjects with ESRD on HD, exposures were similar to subjects with normal renal function. Multiple doses of study drug were generally well tolerated in all subjects. There were no deaths or SAEs. There was 1 discontinuation due to an AE (in moderate RI group) due to increased blood uric acid in a subject with baseline abnormalities, which was assessed as moderate and study drug-related. Conclusions: No dose adjustment is recommended for renal impairment except for severe RI subjects that are not on HD, where QD dosing of the FDC is recommended instead of BID dosing. Group
Adjusted Geometric Mean Ratio (90% CI) (vs Normal) DCV
Mild a
ESRD b
Dose adjustment
BCV
Cmax
AUCTAU
Cmax
AUCTAU
Cmax
AUCTAU
1.16
1.22
1.29
1.33
1.15
1.28
(1.03, 1.31)
(1.09, 1.37)
(0.98, 1.69) (1.12, 1.59)
(1.02, 1.29)
(1.14, 1.45)
Moderate a 1.35 Severe a
ASV
1.50
1.65
1.76
1.32
1.65
(1.19, 1.52)
(1.33, 1.68)
(1.26, 2.17)
(1.47, 2.11)
(1.17, 1.49)
(1.45, 1.86)
1.45
1.65
1.88
2.03
1.42
1.86
(1.29, 1.63)
(1.47, 1.86)
(1.43, 2.47)
(1.69, 2.43) (1.26, 1.60)
(1.65, 2.11)
0.95
1.00
0.89
0.84
1.03
(0.72, 1.25) (0.76, 1.33)
a Estimated by linear regression analysis. b Estimated by categorical analysis.
Journal of Hepatology 2015 vol. 62 | S263–S864
0.93
(0.45, 1.73) (0.52, 1.35) (0.70, 1.23) (0.75, 1.40)
No No QD instead of BID No
Age, mean (range) Male, no. (%) Black, no. (%) Platelets <100K/ul, no. (%) Treatment experienced, no. (%) Cirrhosis, no. (%) Genotype, no. (%) 1 1a 1b 2 3 4–6 mixed Initial viral load, no. (%) ≤800,000 IU/ml >6MM IU/ml Regimen, no. (%) a PEG + RBV + SOF RBV + SOF SMV + SOF +/− RBV a
Results: Patient demographics and baseline clinical measures are provided in Table 1. In the over 70 years old group, the discontinuation rate was 7% and SVR12 rates were 79% and 95% for the Intent to Treat (ITT) and Per Protocol (PP) populations, respectively, with results pending for 8 patients. In comparison and without balancing for disease, treatment and/or patient characteristics, outcomes for ≤70 year old patients (n = 900) from the same time period were 4% discontinuation, 80% SVR12 (ITT) and 87% SVR12 (PP), with results pending for 119 patients. None of the rates were significantly different between the age groups, though the SVR12 PP rate difference approached significance at p = 0.056. Conclusions: All oral DAA therapy is well tolerated in patients over 70 years old with SVR rates >80% similar to that seen in younger populations. P0788 ESTIMATING THE COST-EFFECTIVENESS OF DACLATASVIR PLUS SOFOSBUVIR IN TREATMENT-NA¨IVE, TREATMENT-EXPERIENCED AND INTERFERON-INELIGIBLE/INTOLERANT PATIENTS WITH ADVANCED CHRONIC HEPATITIS C GENOTYPE 1 INFECTION P. McEwan1,2 , S. Webster1 , T. Ward1 , A. Kalsekar3 , Y. Yuan3 , M. Brenner4 . 1 HEOR, HEOR Ltd, Monmouth, 2 School of Human & Health Sciences, Swansea University, Swansea, United Kingdom; 3 World Wide Health Economics and Outcomes Research, Bristol-Myers Squibb Pharmaceuticals Ltd, Princeton, United States; 4 UK HEOR, Bristol-Myers Squibb Pharmaceuticals Ltd, Uxbridge, United Kingdom E-mail: [email protected] Background and Aims: The availability of effective treatment for chronic hepatitis C patients with advanced disease has been considered an area of unmet medical need due to the limited efficacy and sub-optimal safety of historical treatments. However, the treatment landscape for chronic hepatitis C is rapidly evolving. Presented herein is a cost-effectiveness analysis of licensed regimens for treatment-naïve, treatment-experienced and interferon-ineligible/intolerant patients infected with hepatitis C virus (HCV) genotype 1 with advanced disease (METAVIR score ≥F3). Methods: A published Markov model was used to estimate the relative cost-effectiveness of chronic hepatitis C treatments over a lifetime horizon in a cohort that had a mean age of 50 years and were 67% male. Patients progress through disease stages using published transition rates. Patients were distributed across fibrosis stages F3 and F4 at therapy initiation according to UK data (78.62% and 21.38%, respectively). Disease state costs were obtained from 2013 UK data and discounting was set to 3.5%. Weekly treatment costs were as follows: daclatasvir (DCV): £2,083.13; sofosbuvir (SOF): £2,915.24; simeprevir (SMV): £1,866.50; telaprevir (TVR): £1,866.50; boceprevir (BOC): £700.00; ribavirin (RBV): £66.95;
Age ≤70 years, N = 900 (94%)
Age >70 years, N = 55 (6%)
56 (17–70) 535 (59%) 141 (16%) 122 (16%) 392 (44%) 268 (30%)
74 (71–86) 30 (55%) 10 (18%) 10 (20%) 15 (27%) 23 (42%)
61 (7%) 448 (50%) 159 (18%) 194 (22%) 7 (1%) 24 (3%) 7 (1%)
1 (2%) 14 (25%) 20 (36%) 18 (33%) 0 (0%) 1 (2%) 1 (2%)
283 (31%) 169 (19%)
26 (47%) 9 (16%)
Interferon-ineligible/intolerant
377 (42%) 207 (23%) 292 (32%)
7 (13%) 20 (36%) 28 (51%)
a
Population
Regimen
SVR (%)
Naive
DCV+SOF TVR+PR BOC+PR SOF+PR SMV+PR PR No treatment DCV+SOF No treatment DCV+SOF SOF+RBV SMV+SOF No treatment
100 66 41 80 68 41 0 100 0 100 36 93 0
Experienced
24 patients received other therapies.
ICER (£) versus DCV+SOF 7,851 1,346 14,240 12,265 8,861 4,263 − 4,263 − Dominant a Dominant a 4,263
DCV+SOF is associated with improved quality of life and reduced total cost.
Journal of Hepatology 2015 vol. 62 | S263–S864
S627
POSTERS pegylated interferon-alfa+ribavirin (PR): £191.35. Clinical inputs were obtained from pivotal studies for all treatment regimens, as reported in respective Summaries of Product Characteristics (SPCs) or published articles. Results: Predicted incremental cost-effectiveness results are presented in Table 1. Conclusions: Treatment with DCV+SOF is likely to be cost-effective (at the £20,000/QALY threshold) and associated with improved quality of life against all available comparators in treatmentnaïve, treatment-experienced and interferon-ineligible/intolerant HCV genotype 1 patients with advanced disease; further, DCV+SOF is expected to be associated with reduced total medical costs in interferon-ineligible/intolerant patients versus active comparators. P0789 EFFECTIVENESS, SAFETY AND COST PER SVR IN GT4 HEPATITIS C PATIENTS TREATED WITH SOFOSBUVIR-BASED THERAPIES IN REAL CLINICAL PRACTICE: A FRANCO-GERMAN EXPERIENCE (SOFEX-4) R. Pais1 , P. Buggisch2 , J. Moussalli1 , Y. Benhamou1 , H. Wedemeyer3 , T. Asselah4 , M. Bec5 , J. Schwarzbard5 , V. Ratziu1 , J. Petersen2 . 1 Hepatogastroenterology, La Piti´e-Salpˆetri`ere Hospital, Paris, France; 2 Hepatology, Asklepios Klinik St Georg, Hamburg, 3 Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; 4 Hepatology, Beaujon Hospital, Clichy, France; 5 Amaris, London, United Kingdom E-mail: [email protected] Background and Aims: Sofosbuvir (SOF) is approved for treatment of chronic hepatitis C (CHC) patients genotypes (GT) 1–6 but clinical trial data with SOF regimens in GT4 is limited. In the real-world (RW) setting, very limited clinical data was recently presented (Buggisch et al. AASLD 2014 n = 18, TRIO AASLD 2014 n = 16), and no study to date has simultaneously evaluated the clinical and economic outcomes of SOF-based therapies in GT4 patients in Europe. The aim of this study was to estimate the total costs, RW effectiveness, safety and cost per SVR of CHC patients treated with SOF-based therapies in a Franco-German collaboration. Methods: This is a retrospective multicentre cohort study including 160 GT4 patients treated in 5 centers (3 in France and 2 in Germany). All patients who received at least 1 week of SOF from January 17th 2014 (date of SOF approval by EMA) to October 31st 2014, are included. SVR rates (ITT), overall and by subgroup, along with incidence of adverse events (AE) requiring intervention, were estimated. Total cost incurred from therapy initiation to 12 weeks after treatment was estimated by summing drug costs, lab costs, patient care costs including AE (treatment related only) management costs. Cost per SVR was calculated as median cost divided by the SVR rate. Subgroup analysis included treatment experience and fibrosis stage. Results: Complete results will be available at the time of presentation. Recruitment is on-going and preliminary results are based on 51 patients with 49% receiving SOF+PR, 33% SOF+SIM, 10% SOF+R and 8% SOF+DCV. Mean age was 54 years, and 88% were male. At study entry, 57% of patients were cirrhotic and 73% had received at least one prior therapy (from the 31 patients with data available, 61% did not respond to prior therapy and 29% relapsed). Overall the SVR rate was 92% with 86% in treatment-naïve patients and 94% in treatment-experienced patients. A total of 11 patients (22%) experienced AEs (7 patients on SOF+PR). One patient discontinued due to AE. Cost per SVR results, overall and per subgroup will be estimated once patients have completed treatment and SVR12 is available. Conclusions: Preliminary data indicates high levels of SVR in this difficult to treat mostly cirrhotic and experienced GT4 patients.
S628
P0790 THE EFFECT OF RENAL IMPAIRMENT ON MULTIPLE-DOSE PHARMACOKINETICS OF THE FIXED-DOSE COMBINATION OF DACLATASVIR/ASUNAPREVIR/BECLABUVIR R. Adamczyk1 , K. Sims1 , M. Hesney1 , M. Wind-Rotolo1 , M. Stonier1 , R. Penn2 , L. Reynolds2 , F. LaCreta1 , M. AbuTarif1 . 1 Bristol-Myers Squibb Research and Development, Princeton, 2 ICON, Development Solutions, Hanover, United States E-mail: [email protected] Background and Aims: Daclatasvir (DCV; NS5A inhibitor), asunaprevir (ASV; NS3 inhibitor), and beclabuvir (BCV [BMS791325]; nonnucleoside NS5B inhibitor) are in phase 3 evaluation for chronic hepatitis C as a fixed-dose combination (FDC) of DCV/ASV/BCV (30/200/75 mg BID). As a subset of HCV patients have some degree of renal impairment due to age and comorbidities, this open-label, multiple-dose study (AI443–110) assessed the pharmacokinetics (PK) and safety of DCV/ASV/BCV FDC in HCV-uninfected subjects with normal renal function and renal impairment (RI) of varying degree. Methods: All subjects were scheduled to receive DCV/ASV/BCV FDC + additional 75 mg BCV (to adjust for higher BCV exposures in HCVinfected patients) BID with food. Subjects were grouped based on renal function: normal renal function (creatinine clearance [CrCl] by Cockcroft-Gault of ≥90 mL/min), mild RI (CrCl 60 to <90 mL/min), moderate RI (CrCl 30 to <60 mL/min), severe RI (CrCl <30 mL/min) and end-stage renal dysfunction (ESRD) on hemodialysis (HD). All subjects received the regimen for 9 days with a single morning dose on Day 10. Noncompartmental PK parameters were derived and linear regression was used to estimate the relationship between Cmax (ng/mL) and AUCTAU (ng·.h/mL) and CrCl. Predicted values for each PK parameter and associated 90% CIs were presented for CrCl equal to 15, 30, 60, and 90 mL/min. Safety was assessed and reported. Results: A total of 41 subjects received study drug across normal renal function (n = 8), mild RI (n = 9), moderate RI (n = 8), severe RI (n = 8), and ESRD on HD (n = 8) groups. Values of PK parameters relative to the normal renal function group predicted from the regression analysis of CrCl are shown in the table. Regression analysis indicated that Cmax and AUCTAU increased with decreasing CrCl for all 3 drugs. For subjects with ESRD on HD, exposures were similar to subjects with normal renal function. Multiple doses of study drug were generally well tolerated in all subjects. There were no deaths or SAEs. There was 1 discontinuation due to an AE (in moderate RI group) due to increased blood uric acid in a subject with baseline abnormalities, which was assessed as moderate and study drug-related. Conclusions: No dose adjustment is recommended for renal impairment except for severe RI subjects that are not on HD, where QD dosing of the FDC is recommended instead of BID dosing. Group
Adjusted Geometric Mean Ratio (90% CI) (vs Normal) DCV
Mild a
ESRD b
Dose adjustment
BCV
Cmax
AUCTAU
Cmax
AUCTAU
Cmax
AUCTAU
1.16
1.22
1.29
1.33
1.15
1.28
(1.03, 1.31)
(1.09, 1.37)
(0.98, 1.69) (1.12, 1.59)
(1.02, 1.29)
(1.14, 1.45)
Moderate a 1.35 Severe a
ASV
1.50
1.65
1.76
1.32
1.65
(1.19, 1.52)
(1.33, 1.68)
(1.26, 2.17)
(1.47, 2.11)
(1.17, 1.49)
(1.45, 1.86)
1.45
1.65
1.88
2.03
1.42
1.86
(1.29, 1.63)
(1.47, 1.86)
(1.43, 2.47)
(1.69, 2.43) (1.26, 1.60)
(1.65, 2.11)
0.95
1.00
0.89
0.84
1.03
(0.72, 1.25) (0.76, 1.33)
a Estimated by linear regression analysis. b Estimated by categorical analysis.
Journal of Hepatology 2015 vol. 62 | S263–S864
0.93
(0.45, 1.73) (0.52, 1.35) (0.70, 1.23) (0.75, 1.40)
No No QD instead of BID No