The Experts below are selected from a list of 1395 Experts worldwide ranked by ideXlab platform
Yoshiyuki Suzuki - One of the best experts on this subject based on the ideXlab platform.
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Real-world virological efficacy and safety of daclatasvir/Asunaprevir/beclabuvir in patients with chronic hepatitis C virus genotype 1 infection in Japan.
Journal of Gastroenterology, 2019Co-Authors: Koichi Takaguchi, Yoshiyuki Suzuki, Michio Imamura, Hidenori Toyoda, Akemi Tsutsui, Makoto Nakamuta, Tomonori Senoh, Takuya Nagano, Toshifumi Tada, Yoshihiko TachiAbstract:Background The virological efficacy and safety of the direct-acting antiviral (DAA) regimen consisting of daclatasvir, Asunaprevir, and beclabuvir (DCV/ASV/BCV) for patients chronically infected with hepatitis C virus (HCV) genotype 1 have not been previously evaluated in Japanese real-world settings.
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favorable efficacy of daclatasvir plus Asunaprevir in treatment of elderly japanese patients infected with hcv genotype 1b aged 70 and older
Journal of Medical Virology, 2017Co-Authors: Norio Akuta, Tetsuya Hosaka, Yusuke Kawamura, Hitomi Sezaki, Satoshi Saitoh, Masahiro Kobayashi, Mariko Kobayashi, Fumitaka Suzuki, Yoshiyuki Suzuki, Yasuji AraseAbstract:The combination of daclatasvir and Asunaprevir is efficacious in the treatment of hepatitis C virus (HCV) infection, but its efficacy and predictors of efficacy in the elderly (≥70 years) remain unclear. In this study, 844 patients with chronic HCV genotype 1b infection, were treated with daclatasvir (60 mg once daily) plus Asunaprevir (100 mg twice daily) for 24 weeks. Using the intention-to-treat analysis, the sustained virological response (SVR) rates were 87% and 88% for all 844 patients and 411 elderly (>70 years of age), respectively. In both groups, multivariate analysis identified NS5A-Y93H mutation (<20%), pretreatment (failure of treatment except for triple therapy with simeprevir, or treatment naive), and level of viremia (<6.0 log IU/ml) as independent predictors of SVR. Direct sequencing showed a significantly higher rate of NS3-D168 mutation at baseline in non-responders to triple therapy with simeprevir (44%) than others (2%). Alfa-fetoprotein (AFP) level and liver stiffness were significantly lower after end of treatment than at baseline, in both the SVR and non-SVR groups. In conclusion, daclatasvir-Asunaprevir combination achieved high SVR in HCV genotype 1b patients, including elderly patients. Viral factors negatively influenced the response to treatment. Treatment improved AFP level and liver stiffness (surrogate markers of hepatocellular carcinoma), regardless of treatment efficacy. J. Med. Virol. 89:91-98, 2017. © 2016 Wiley Periodicals, Inc.
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Retreatment efficacy and predictors of ledipasvir plus sofosbuvir to HCV genotype 1 in Japan
Journal of medical virology, 2016Co-Authors: Norio Akuta, Shunichiro Fujiyama, Tetsuya Hosaka, Yusuke Kawamura, Hitomi Sezaki, Satoshi Saitoh, Masahiro Kobayashi, Mariko Kobayashi, Fumitaka Suzuki, Yoshiyuki SuzukiAbstract:Predictors of treatment efficacy with ledipasvir plus sofosbuvir as direct-acting antiviral (DAA) regimen for HCV infection are still unclear. Retreatment efficacy of ledipasvir plus sofosbuvir for failures to prior DAA regimens, including NS5A inhibitors, are also unknown because resistance-associated variants (RAVs) in NS5A have been shown to persist up to the long-term of post-treatment. One hundred seventy-five patients with chronic HCV genotype 1 infection, without decompensated liver cirrhosis and hepatocellular carcinoma, were evaluated SVR12 by ledipasvir 90 mg plus sofosbuvir 400 mg once-daily for 12 weeks. Overall, SVR12 were 92%, based on intention to treat analysis. In failures to daclatasvir plus Asunaprevir, SVR12 were 71%. The study using ultra-deep sequencing showed that ledipasvir plus sofosbuvir was effective to one case of failures to daclatasvir plus Asunaprevir with multidrug RAVs (triple mutation in NS3-D168/NS5A-L31/NS5A-Y93). Multivariate analysis identified FIB4 index (
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Favorable efficacy of daclatasvir plus Asunaprevir in treatment of elderly Japanese patients infected with HCV genotype 1b aged 70 and older
Journal of medical virology, 2016Co-Authors: Norio Akuta, Tetsuya Hosaka, Yusuke Kawamura, Hitomi Sezaki, Satoshi Saitoh, Masahiro Kobayashi, Mariko Kobayashi, Fumitaka Suzuki, Yoshiyuki Suzuki, Yasuji AraseAbstract:The combination of daclatasvir and Asunaprevir is efficacious in the treatment of hepatitis C virus (HCV) infection, but its efficacy and predictors of efficacy in the elderly (≥70 years) remain unclear. In this study, 844 patients with chronic HCV genotype 1b infection, were treated with daclatasvir (60 mg once daily) plus Asunaprevir (100 mg twice daily) for 24 weeks. Using the intention-to-treat analysis, the sustained virological response (SVR) rates were 87% and 88% for all 844 patients and 411 elderly (>70 years of age), respectively. In both groups, multivariate analysis identified NS5A-Y93H mutation (
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relationships between serum Asunaprevir concentration and alanine aminotransferase elevation during daclatasvir plus Asunaprevir for chronic hcv genotype 1b infection
Journal of Medical Virology, 2016Co-Authors: Norio Akuta, Tetsuya Hosaka, Yusuke Kawamura, Hitomi Sezaki, Satoshi Saitoh, Masahiro Kobayashi, Mariko Kobayashi, Fumitaka Suzuki, Yoshiyuki Suzuki, Yasuji AraseAbstract:Alanine aminotransferase (ALT) elevations were the most frequent adverse events during all-oral combinations with daclatasvir and Asunaprevir for patients with hepatitis C virus (HCV) infection, but the underline mechanisms are unclear. Seventy patients with chronic HCV genotype 1b infection, who were introduced daclatasvir 60 mg once daily plus Asunaprevir 100 mg twice daily for 24 weeks, were measured serum Asunaprevir concentrations at the one point or more of 2, 4, and 8 weeks after the start of treatment. In 4 and 8 weeks after the start of treatment, Asunaprevir concentrations in patients with albumin levels <3.6 g/dl at baseline were significantly higher than those in patients with albumin levels ≥3.6 g/dl. The baseline factors did not affect to ALT severe elevations (≥300 IU/l). At 2 weeks after the start of treatment, ALT severe elevations with Asunaprevir concentrations of ≥800 ng/ml (54.5%) tended to indicate the higher rates than those of <800 ng/ml (17.6%). Furthermore, the discontinuation or reduction of Asunaprevir improved ALT levels, regardless the significant decrease of serum Asunaprevir concentrations. In conclusion, serum albumin levels affected to serum Asunaprevir concentrations, and serum Asunaprevir concentrations might partly affect to ALT severe elevations. Further large-scale prospective studies are needed to investigate the impact of the discontinuation or reduction of Asunaprevir to help in the design of more effective therapeutic regimens.
Yoshiiku Kawakami - One of the best experts on this subject based on the ideXlab platform.
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safety and efficacy of dual therapy with daclatasvir and Asunaprevir for older patients with chronic hepatitis c
Journal of Gastroenterology, 2017Co-Authors: Reona Morio, Yoshiiku Kawakami, Michio Imamura, Kei Morio, Tomoki Kobayashi, Satoe Yokoyama, Yuko Nagaoki, Tomokazu Kawaoka, Yuki Kimura, Masataka TsugeAbstract:Daclatasvir and Asunaprevir combination therapy has shown a high virological response for chronic genotype 1 hepatitis C virus (HCV)-infected patients. However, the safety and efficacy of the therapy for older patients are unknown. One hundred seventy patients younger than 75 years and 139 patients aged 75 years or older with genotype 1 HCV infection were treated for 24 weeks with daclatasvir plus Asunaprevir. Pretreatment drug-resistance-associated variants at NS5A-L31 and NS5A-Y93 were determined by the Invader assay. Virological response and adverse events according to age were analyzed. The sustained virological response (SVR) rate for older patients was similar to that for younger patients (97.1 and 92.4 % respectively). In multivariate regression analysis, prior simeprevir treatment (odds ratio 56.6 for absence; P < 0.001) was identified as a significant independent predictor of SVR. The SVR rate for patients with pretreatment resistance-associated variants (RAVs) at a low population frequency (less than 25 %) was similar to that for patients with no detectable RAVs. The frequency of adverse events was similar between younger and older patients. All 19 very elderly patients (85 years or older) completed the 24 weeks of treatment and achieved SVR. Older patients have a virological response and tolerance of daclatasvir plus Asunaprevir therapy similar to those of younger patients. Even though RAVs were detected, virological response similar to that for patients with no detectable RAVs may still be expected for patients with RAVs as long as the population frequency is low.
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efficacy and safety of daclatasvir plus Asunaprevir therapy for chronic hepatitis c patients with renal dysfunction
Journal of Medical Virology, 2017Co-Authors: Yuki Nakamura, Yoshiiku Kawakami, Michio Imamura, Kei Morio, Tomoki Kobayashi, Kana Daijo, Yuji Teraoka, Fumi Honda, Takashi Nakahara, Yuko NagaokiAbstract:Chronic hepatitis C virus (HCV) infection is associated with renal dysfunction. Daclatasvir and Asunaprevir combination therapy showed a high virological response for genotype 1 chronic HCV-infected patients with renal dysfunction on hemodialysis. However, the safety and efficacy of the therapy for patients with renal dysfunction who are not on hemodialysis are not well-known. In total, 147 patients with chronic HCV genotype 1 infection were treated with 24 weeks of daclatasvir plus Asunaprevir therapy. Among these patients, 126 had normal renal function (estimated glomerular filtration rate [eGFR] ≥ 50 ml/min/1.73 m2) and 21 had renal dysfunction (eGFR < 50 ml/min/1.73 m2). Plasma concentrations of daclatasvir and Asunaprevir after 5 days of treatment were the same in the normal renal function and renal dysfunction groups. Early virological response (4, 8, 48, 96, and 168 hr after the start of the therapy) was similar between the two groups. End-of-treatment response was achieved in 122 (96.8%) and 20 (95.2%) patients with normal renal function and with renal dysfunction, respectively, and sustained virological response was achieved in 119 (94.4%) and 20 (95.2%) patients. The frequency of adverse events was also comparable between the two groups. Treatment discontinuation due to adverse events was required for only one patient in each group. Renal function did not change either during or after treatment in both groups. In conclusion, renal function is unlikely to have a significant impact on blood kinetics of daclatasvir and Asunaprevir. This combination therapy was effective and safe for patients without hemodialysis. J. Med. Virol. 89:665–671, 2017. © 2016 Wiley Periodicals, Inc.
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Real-world efficacy and safety of daclatasvir and Asunaprevir therapy for hepatitis C virus-infected cirrhosis patients.
Journal of Gastroenterology and Hepatology, 2017Co-Authors: Kei Morio, Yoshiiku Kawakami, Michio Imamura, Masataka Tsuge, Reona Morio, Tomoki Kobayashi, Satoe Yokoyama, Yuko Nagaoki, Tomokazu Kawaoka, Akira HiramatsuAbstract:Background and Aims Daclatasvir and Asunaprevir combination therapy has shown a high virological response for chronic genotype 1 hepatitis C virus (HCV) infected-patients. However, the real-world efficacy and safety of the therapy for patients with cirrhosis are unknown. Methods A total of 252 patients with genotype 1 HCV infection (158 with chronic hepatitis and 94 with compensated liver cirrhosis) were treated with 24 weeks of daclatasvir and Asunaprevir combination therapy. Plasma concentrations of daclatasvir and Asunaprevir at day 5 of treatment, end-of-treatment response, sustained virological response (SVR), and the frequencies of adverse events were analyzed. Result Plasma Asunaprevir concentration was significantly higher, and daclatasvir concentration tended to be higher, in cirrhosis patients compared with chronic hepatitis patients. End-of-treatment response was achieved in 95.6% and 94.7% of chronic hepatitis and cirrhosis patients, respectively, and SVR was achieved in 94.3% and 92.6%. Although pre-treatment NS5A drug resistant-associated variants were detected, a high SVR rate was achieved when the population frequency of the variant was low. The frequencies of treatment-related adverse events in cirrhosis patients were similar to those in chronic hepatitis patients. Treatment discontinuation due to adverse events occurred in three and two patients in chronic hepatitis and cirrhosis groups, respectively; however, four out of five patients with treatment discontinuation nonetheless achieved SVR. Conclusion Patients with compensated liver cirrhosis have similar virological response and tolerance for daclatasvir plus Asunaprevir therapy to patients with chronic hepatitis. This combination therapy might offer a safe and effective treatment for chronic HCV infected-patients with compensated cirrhosis.
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Efficacy and safety of daclatasvir plus Asunaprevir therapy for chronic hepatitis C patients with renal dysfunction
Journal of Medical Virology, 2016Co-Authors: Yuki Nakamura, Yoshiiku Kawakami, Michio Imamura, Kei Morio, Tomoki Kobayashi, Kana Daijo, Yuji Teraoka, Fumi Honda, Takashi Nakahara, Yuko NagaokiAbstract:Chronic hepatitis C virus (HCV) infection is associated with renal dysfunction. Daclatasvir and Asunaprevir combination therapy showed a high virological response for genotype 1 chronic HCV-infected patients with renal dysfunction on hemodialysis. However, the safety and efficacy of the therapy for patients with renal dysfunction who are not on hemodialysis are not well-known. In total, 147 patients with chronic HCV genotype 1 infection were treated with 24 weeks of daclatasvir plus Asunaprevir therapy. Among these patients, 126 had normal renal function (estimated glomerular filtration rate [eGFR] ≥ 50 ml/min/1.73 m2) and 21 had renal dysfunction (eGFR
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Safety and efficacy of dual therapy with daclatasvir and Asunaprevir for older patients with chronic hepatitis C
Journal of Gastroenterology, 2016Co-Authors: Reona Morio, Yoshiiku Kawakami, Michio Imamura, Kei Morio, Tomoki Kobayashi, Satoe Yokoyama, Yuko Nagaoki, Tomokazu Kawaoka, Yuki Kimura, Masataka TsugeAbstract:Daclatasvir and Asunaprevir combination therapy has shown a high virological response for chronic genotype 1 hepatitis C virus (HCV)-infected patients. However, the safety and efficacy of the therapy for older patients are unknown. One hundred seventy patients younger than 75 years and 139 patients aged 75 years or older with genotype 1 HCV infection were treated for 24 weeks with daclatasvir plus Asunaprevir. Pretreatment drug-resistance-associated variants at NS5A-L31 and NS5A-Y93 were determined by the Invader assay. Virological response and adverse events according to age were analyzed. The sustained virological response (SVR) rate for older patients was similar to that for younger patients (97.1 and 92.4 % respectively). In multivariate regression analysis, prior simeprevir treatment (odds ratio 56.6 for absence; P
Fumitaka Suzuki - One of the best experts on this subject based on the ideXlab platform.
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daclatasvir Asunaprevir beclabuvir fixed dose combination in japanese patients with hcv genotype 1 infection
Journal of Gastroenterology, 2017Co-Authors: Joji Toyota, Fumitaka Suzuki, Yoshiyasu Karino, Fusao Ikeda, Akio Ido, Katsuaki Tanaka, Koichi Takaguchi, Atsushi Naganuma, Eiichi Tomita, Kazuaki ChayamaAbstract:Background DCV-TRIO, a fixed-dose combination of daclatasvir (pangenotypic NS5A inhibitor), Asunaprevir (NS3/4A protease inhibitor), and beclabuvir (non-nucleoside NS5B inhibitor), has achieved high rates of sustained virologic response at post-treatment Week 12 (SVR12) in phase 3 studies.
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favorable efficacy of daclatasvir plus Asunaprevir in treatment of elderly japanese patients infected with hcv genotype 1b aged 70 and older
Journal of Medical Virology, 2017Co-Authors: Norio Akuta, Tetsuya Hosaka, Yusuke Kawamura, Hitomi Sezaki, Satoshi Saitoh, Masahiro Kobayashi, Mariko Kobayashi, Fumitaka Suzuki, Yoshiyuki Suzuki, Yasuji AraseAbstract:The combination of daclatasvir and Asunaprevir is efficacious in the treatment of hepatitis C virus (HCV) infection, but its efficacy and predictors of efficacy in the elderly (≥70 years) remain unclear. In this study, 844 patients with chronic HCV genotype 1b infection, were treated with daclatasvir (60 mg once daily) plus Asunaprevir (100 mg twice daily) for 24 weeks. Using the intention-to-treat analysis, the sustained virological response (SVR) rates were 87% and 88% for all 844 patients and 411 elderly (>70 years of age), respectively. In both groups, multivariate analysis identified NS5A-Y93H mutation (<20%), pretreatment (failure of treatment except for triple therapy with simeprevir, or treatment naive), and level of viremia (<6.0 log IU/ml) as independent predictors of SVR. Direct sequencing showed a significantly higher rate of NS3-D168 mutation at baseline in non-responders to triple therapy with simeprevir (44%) than others (2%). Alfa-fetoprotein (AFP) level and liver stiffness were significantly lower after end of treatment than at baseline, in both the SVR and non-SVR groups. In conclusion, daclatasvir-Asunaprevir combination achieved high SVR in HCV genotype 1b patients, including elderly patients. Viral factors negatively influenced the response to treatment. Treatment improved AFP level and liver stiffness (surrogate markers of hepatocellular carcinoma), regardless of treatment efficacy. J. Med. Virol. 89:91-98, 2017. © 2016 Wiley Periodicals, Inc.
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Daclatasvir/Asunaprevir/beclabuvir fixed-dose combination in Japanese patients with HCV genotype 1 infection
Journal of gastroenterology, 2016Co-Authors: Joji Toyota, Fumitaka Suzuki, Yoshiyasu Karino, Fusao Ikeda, Akio Ido, Katsuaki Tanaka, Koichi Takaguchi, Atsushi Naganuma, Eiichi Tomita, Kazuaki ChayamaAbstract:Background DCV-TRIO, a fixed-dose combination of daclatasvir (pangenotypic NS5A inhibitor), Asunaprevir (NS3/4A protease inhibitor), and beclabuvir (non-nucleoside NS5B inhibitor), has achieved high rates of sustained virologic response at post-treatment Week 12 (SVR12) in phase 3 studies.
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Retreatment efficacy and predictors of ledipasvir plus sofosbuvir to HCV genotype 1 in Japan
Journal of medical virology, 2016Co-Authors: Norio Akuta, Shunichiro Fujiyama, Tetsuya Hosaka, Yusuke Kawamura, Hitomi Sezaki, Satoshi Saitoh, Masahiro Kobayashi, Mariko Kobayashi, Fumitaka Suzuki, Yoshiyuki SuzukiAbstract:Predictors of treatment efficacy with ledipasvir plus sofosbuvir as direct-acting antiviral (DAA) regimen for HCV infection are still unclear. Retreatment efficacy of ledipasvir plus sofosbuvir for failures to prior DAA regimens, including NS5A inhibitors, are also unknown because resistance-associated variants (RAVs) in NS5A have been shown to persist up to the long-term of post-treatment. One hundred seventy-five patients with chronic HCV genotype 1 infection, without decompensated liver cirrhosis and hepatocellular carcinoma, were evaluated SVR12 by ledipasvir 90 mg plus sofosbuvir 400 mg once-daily for 12 weeks. Overall, SVR12 were 92%, based on intention to treat analysis. In failures to daclatasvir plus Asunaprevir, SVR12 were 71%. The study using ultra-deep sequencing showed that ledipasvir plus sofosbuvir was effective to one case of failures to daclatasvir plus Asunaprevir with multidrug RAVs (triple mutation in NS3-D168/NS5A-L31/NS5A-Y93). Multivariate analysis identified FIB4 index (
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Favorable efficacy of daclatasvir plus Asunaprevir in treatment of elderly Japanese patients infected with HCV genotype 1b aged 70 and older
Journal of medical virology, 2016Co-Authors: Norio Akuta, Tetsuya Hosaka, Yusuke Kawamura, Hitomi Sezaki, Satoshi Saitoh, Masahiro Kobayashi, Mariko Kobayashi, Fumitaka Suzuki, Yoshiyuki Suzuki, Yasuji AraseAbstract:The combination of daclatasvir and Asunaprevir is efficacious in the treatment of hepatitis C virus (HCV) infection, but its efficacy and predictors of efficacy in the elderly (≥70 years) remain unclear. In this study, 844 patients with chronic HCV genotype 1b infection, were treated with daclatasvir (60 mg once daily) plus Asunaprevir (100 mg twice daily) for 24 weeks. Using the intention-to-treat analysis, the sustained virological response (SVR) rates were 87% and 88% for all 844 patients and 411 elderly (>70 years of age), respectively. In both groups, multivariate analysis identified NS5A-Y93H mutation (
Timothy Eley - One of the best experts on this subject based on the ideXlab platform.
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Population Pharmacokinetic Analysis of Asunaprevir in Subjects with Hepatitis C Virus Infection
Infectious diseases and therapy, 2018Co-Authors: Li Zhu, Timothy Eley, Mayu Osawa, Takayo Ueno, Phyllis Chan, Yash Gandhi, Marc Bifano, Eric Hughes, Malaz AbutarifAbstract:Introduction Asunaprevir (ASV) is a potent, pangenotypic, twice-daily hepatitis C virus (HCV) NS3 inhibitor indicated for the treatment of chronic HCV infection.
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Effects of a Fixed-Dose Co-Formulation of Daclatasvir, Asunaprevir, and Beclabuvir on the Pharmacokinetics of a Cocktail of Cytochrome P450 and Drug Transporter Substrates in Healthy Subjects
Drugs in R&D, 2017Co-Authors: Tushar Garimella, Timothy Eley, Xiaolu Tao, K. Sims, Yi-ting Chang, Jignasa Rana, Elsa Myers, Megan Wind-rotolo, Rahul Bhatnagar, Frank LacretaAbstract:Background A fixed-dose combination of daclatasvir (DCV; hepatitis C virus NS5A inhibitor), Asunaprevir (ASV; non-structural protein 3 inhibitor), and beclabuvir (BCV; non-structural protein 5B inhibitor) is approved in Japan for hepatitis C virus genotype 1.
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Asunaprevir: An HCV Protease Inhibitor With Preferential Liver Distribution.
Clinical pharmacology in drug development, 2017Co-Authors: Timothy Eley, Tushar Garimella, Richard BertzAbstract:Asunaprevir is an inhibitor of the hepatitis C virus (HCV) NS3/4A protease, demonstrating efficacy in clinical studies in patients infected with HCV genotype 1 or 4, with either peginterferon/ribavirin or combinations of direct-acting antivirals. Because of preferential distribution of Asunaprevir to the liver via organic anion-transporting polypeptide (OATP)-mediated transport, Asunaprevir demonstrates high apparent oral clearance and very low plasma concentrations. Asunaprevir plasma concentrations are markedly increased by single-dose rifampin (an OATP inhibitor) and in subjects with moderate to severe hepatic impairment. In addition, modestly higher plasma concentrations of Asunaprevir have been noted in subjects infected with HCV relative to healthy subjects and in Asian subjects relative to whites. At the marketed dose, infrequent hepatic transaminase abnormalities were poorly predicted by plasma concentrations. For a compound with these characteristics, hepatic concentrations may have provided an improved understanding of the in vivo pharmacokinetic and pharmacodynamic data to support decision making during development.
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Asunaprevir: A Review of Preclinical and Clinical Pharmacokinetics and Drug–Drug Interactions
Clinical Pharmacokinetics, 2015Co-Authors: Timothy Eley, Tushar Garimella, Richard J. BertzAbstract:Asunaprevir is a tripeptidic acylsulfonamide inhibitor of the hepatitis C virus (HCV) NS3/4A protease. Asunaprevir undergoes rapid absorption, with a time to reach maximum plasma concentration ( T _max) of 2–4 h and an elimination half-life ( t _½) of ≈15–20 h observed in single-ascending dose studies. Steady state was achieved by day 7 in multiple-ascending dose studies. The large food effect observed with earlier formulations was mitigated by the soft-gel capsule. Asunaprevir demonstrates high apparent oral clearance and minimal renal elimination, and is eliminated primarily via cytochrome P450 (CYP) 3A4–mediated hepatic oxidative metabolism and faecal excretion. Highly preferential distribution of Asunaprevir to the liver occurs via organic anion–transporting polypeptide (OATP)–mediated transport and results in low plasma concentrations. The condition of the liver affects disposition, as higher Asunaprevir plasma exposures are observed in patients infected with HCV and/or hepatic impairment. Japanese patients also have higher exposure relative to North American/European patients, but comparable safety at the registrational dose. Asunaprevir has a low potential to perpetrate drug–drug interactions via CYP3A4, P-glycoprotein and OATP, but is a moderate CYP2D6 inhibitor; concomitant drugs that are substrates of CYP2D6 or P-glycoprotein and have a narrow therapeutic index should be used with care. Asunaprevir plasma exposure is strongly affected by inhibitors of OATP transport. No clinically significant interactions were observed between Asunaprevir and daclatasvir or daclatasvir/beclabuvir. Asunaprevir has a complex pharmacokinetic profile and forms part of potent and well-tolerated all-oral regimens for the treatment of chronic HCV infection.
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A highly sensitive and selective LC–MS/MS method to quantify Asunaprevir, an HCV NS3 protease inhibitor, in human plasma in support of pharmacokinetic studies
Journal of pharmaceutical and biomedical analysis, 2015Co-Authors: Hamza Kandoussi, Timothy Eley, Tushar Garimella, Hao Jiang, Jianing Zeng, Roger Demers, Pathanjali Kadiyala, Naiyu Zheng, Laura CojocaruAbstract:Asunaprevir (BMS-650032) is a selective hepatitis C virus (HCV) NS3 protease inhibitor with potent activity against HCV genotypes 1, 4, 5 and 6. It has been developed in conjunction with direct-acting antiviral agents, in interferon- and ribavirin-free regimen, to improve existing therapies for HCV infection. To support the pharmacokinetic analyses in Asunaprevir clinical studies, we have developed and validated a highly sensitive and robust LC-MS/MS method to quantify Asunaprevir in human EDTA plasma with an LLOQ of 0.05ng/mL, which was a 20-fold sensitivity improvement over a previously reported assay for Asunaprevir. A deuterated labeled [D9]-Asunaprevir was used as the internal standard (IS). The analyte and the IS were extracted using a semi-automated liquid-liquid extraction (LLE) at pH 7 with methyl-t-butyl ether (MTBE) in a 96-well plate containing 10μL of 10% CHAPS as the surfactant to prevent non-specific binding issue. Chromatographic separation was achieved on a Genesis C8 column (2.1×50mm, 4μm) with a gradient elution using 0.1% formic acid in water as mobile phase A and a mixture of methanol: acetone: formic acid (95:5:0.1; v/v/v) as the mobile phase B. Positive electrospray ionization was performed using multiple reaction monitoring (MRM) with transitions of m/z 748→648 for Asunaprevir and m/z 757→649 for [D9]-Asunaprevir,and a collision energy of 30 electron Volts (eV). The assay was validated over a standard curve range from 0.05 to 50ng/mL for Asunaprevir in human plasma. The intra- and inter assay precisions were within 7.1% CV, and the % deviation was within 5.5% of their nominal concentrations. This assay has been successfully applied to multiple clinical studies with excellent assay ruggedness and reproducibility.
Fiona Mcphee - One of the best experts on this subject based on the ideXlab platform.
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BRIEF REPORT In Vitro Assessment of Re-treatment Options for Patients with Hepatitis C Virus Genotype 1b Infection Resistant to Daclatasvir Plus Asunaprevir
2016Co-Authors: Jacques Friborg, Nannan Zhou, Zhou Han, Xiaoyan Yang, Paul Falk, Patricia Mendez, Fiona McpheeAbstract:The Author(s) 2014. This article is published with open access at Springerlink.com Introduction: Daclatasvir is a non-structural protein 5A (NS5A) inhibitor with activity against hepatitis C virus (HCV) genotypes 1–6 in vitro, and Asunaprevir is a non-structural protein 3 (NS3) protease inhibitor with activit
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Case report: successful retreatment of hepatitis C genotype 1b infection with sofosbuvir + simeprevir in a patient with cirrhosis who had prior virologic relapse after treatment with daclatasvir and Asunaprevir.
Clinical case reports, 2016Co-Authors: Rifaat Safadi, Stephanie Noviello, Navdeep Boparai, Fiona McpheeAbstract:There is currently minimal clinical experience regarding retreatment options for patients failing direct-acting antiviral combination regimens. Here, we report the outcomes of a HCV genotype 1b-infected patient with virologic failure following treatment with daclatasvir and Asunaprevir, who was successfully retreated with sofosbuvir plus simeprevir.
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case report successful retreatment of hepatitis c genotype 1b infection with sofosbuvir simeprevir in a patient with cirrhosis who had prior virologic relapse after treatment with daclatasvir and Asunaprevir
Clinical Case Reports, 2016Co-Authors: Rifaat Safadi, Stephanie Noviello, Navdeep Boparai, Fiona McpheeAbstract:There is currently minimal clinical experience regarding retreatment options for patients failing direct-acting antiviral combination regimens. Here, we report the outcomes of a HCV genotype 1b-infected patient with virologic failure following treatment with daclatasvir and Asunaprevir, who was successfully retreated with sofosbuvir plus simeprevir.
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In Vitro Assessment of Re-treatment Options for Patients with Hepatitis C Virus Genotype 1b Infection Resistant to Daclatasvir Plus Asunaprevir
Infectious Diseases and Therapy, 2014Co-Authors: Jacques Friborg, Nannan Zhou, Zhou Han, Xiaoyan Yang, Paul Falk, Patricia Mendez, Fiona McpheeAbstract:Introduction Daclatasvir is a non-structural protein 5A (NS5A) inhibitor with activity against hepatitis C virus (HCV) genotypes 1–6 in vitro, and Asunaprevir is a non-structural protein 3 (NS3) protease inhibitor with activity against genotypes 1, 4, 5, and 6. This study evaluates potential options for the re-treatment of HCV genotype 1b-infected patients who have failed combination therapy with daclatasvir plus Asunaprevir.
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Resistance analysis of hepatitis C virus genotype 1 prior treatment null responders receiving daclatasvir and Asunaprevir.
Hepatology, 2013Co-Authors: Fiona Mcphee, Joseph Ueland, Dennis Hernandez, Paul Falk, Aaron Monikowski, Arlene Carifa, Timothy EleyAbstract:In a sentinel cohort, hepatitis C virus (HCV) patients (primarily genotype [GT] 1a) were treated with daclatasvir (NS5A inhibitor) and Asunaprevir (NS3 protease inhibitor). Preexistence, emergence, and persistence of resistance variants in patients who failed this treatment are described. HCV-infected null responders received daclatasvir (60 mg once daily) and Asunaprevir (600 mg twice daily) alone (Group A, 11 patients) or with peginterferon alfa-2a and ribavirin (Group B, 10 patients) for 24 weeks. Resistance testing was performed on baseline samples and samples with HCV RNA ≥1,000 IU/mL at Week 1 through posttreatment Week 48. Resistance substitution susceptibility to inhibition by Asunaprevir and daclatasvir was assessed using HCV replicon assays. In Group A, six GT1a patients experiencing viral breakthrough and one GT1a patient who relapsed had detectable NS5A (Q30E/R, L31V/M, Y93C/N) and NS3 (R155K, D168A/E/V/Y) resistance-associated variants at failure. Two of six viral breakthrough patients achieved SVR48 after treatment intensification with peginterferon alfa-2a and ribavirin. For 2/4 viral breakthrough patients not responding to treatment intensification, NS3 resistance variants changed (D168Y to D168T; R155K to V36M-R155K). At posttreatment Week 48, daclatasvir-resistant variants persisted while Asunaprevir-resistant variants were generally replaced by wild-type sequences. The NS3 sequence remained unchanged in the one patient with NS3-R155K at baseline, relapse, and posttreatment Week 48. In Group B, no viral breakthrough was observed. Conclusion: The treatment failure of daclatasvir and Asunaprevir in HCV GT1a patients was associated with both NS5A and NS3 resistance variants in prior null responders. NS5A resistance variants persisted while NS3 resistance variants generally decayed, suggesting a higher relative fitness of NS5A variants. (Hepatology 2013;53:902–911)
