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Diana M. Brainard - One of the best experts on this subject based on the ideXlab platform.
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Drug–Drug Interaction Profile of the Fixed-Dose Combination Tablet Regimen Ledipasvir/Sofosbuvir
Clinical Pharmacokinetics, 2018Co-Authors: Polina German, Anita Mathias, Diana M. Brainard, Brian P. KearneyAbstract:Ledipasvir/sofosbuvir (Harvoni^®), a fixed-dose combination tablet of an NS5A inhibitor Ledipasvir and an NS5B polymerase inhibitor sofosbuvir, is approved for the treatment of chronic hepatitis C virus infection. Ledipasvir/sofosbuvir exhibits a favorable drug–drug interaction profile and can be administered with various medications that may be used by hepatitis C virus-infected patients, including patients with comorbidities, such as co-infection with human immunodeficiency virus or immunosuppression following liver transplantation. Ledipasvir/sofosbuvir is not expected to act as a victim or perpetrator of cytochrome P450- or UDP-glucuronosyltransferase 1A1-mediated drug–drug interactions. With the exception of strong inducers of P-glycoprotein, such as rifampin, Ledipasvir/sofosbuvir is not expected to act as a victim of clinically relevant drug–drug interactions. As a perpetrator of pharmacokinetic drug–drug interactions via P-glycoprotein/BCRP, Ledipasvir/sofosbuvir should not be used with rosuvastatin and elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate, whereas its co-administration with amiodarone is not recommended because of a pharmacodynamic interaction. This review summarizes a number of drug interaction studies conducted in support of the clinical development of Ledipasvir/sofosbuvir.
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Drug-Drug Interaction Profile of the Fixed-Dose Combination Tablet Regimen Ledipasvir/Sofosbuvir.
Clinical pharmacokinetics, 2018Co-Authors: Polina German, Anita Mathias, Diana M. Brainard, Brian P. KearneyAbstract:Ledipasvir/sofosbuvir (Harvoni®), a fixed-dose combination tablet of an NS5A inhibitor Ledipasvir and an NS5B polymerase inhibitor sofosbuvir, is approved for the treatment of chronic hepatitis C virus infection. Ledipasvir/sofosbuvir exhibits a favorable drug-drug interaction profile and can be administered with various medications that may be used by hepatitis C virus-infected patients, including patients with comorbidities, such as co-infection with human immunodeficiency virus or immunosuppression following liver transplantation. Ledipasvir/sofosbuvir is not expected to act as a victim or perpetrator of cytochrome P450- or UDP-glucuronosyltransferase 1A1-mediated drug-drug interactions. With the exception of strong inducers of P-glycoprotein, such as rifampin, Ledipasvir/sofosbuvir is not expected to act as a victim of clinically relevant drug-drug interactions. As a perpetrator of pharmacokinetic drug-drug interactions via P-glycoprotein/BCRP, Ledipasvir/sofosbuvir should not be used with rosuvastatin and elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate, whereas its co-administration with amiodarone is not recommended because of a pharmacodynamic interaction. This review summarizes a number of drug interaction studies conducted in support of the clinical development of Ledipasvir/sofosbuvir.
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A Thorough QT Study to Evaluate the Effects of Supratherapeutic Doses of Ledipasvir on the QTc Interval in Healthy Subjects
Clinical pharmacology in drug development, 2017Co-Authors: Polina German, Anita Mathias, Diana M. Brainard, Qinghua Song, John Ling, Brian P. KearneyAbstract:This study evaluated the effect of supratherapeutic exposure of the anti-HCV drug Ledipasvir on the QTc interval in healthy subjects. Sixty healthy volunteers were randomized to receive twice-daily blinded Ledipasvir (120 mg) or placebo, administered for 10 days each, or single doses of open-label moxifloxacin (400 mg). Serial plasma samples for Ledipasvir concentration analysis were collected after each treatment. Triplicate time-matched electrocardiograms were collected at baseline and after each treatment. Change from baseline in the QTc for Ledipasvir or moxifloxacin versus placebo was determined using several correction formulas (primary: QTcF [Fridericia's]; secondary: QTcN [population] and QTcI [individual]). Pharmacokinetics and exposure-QTc relationships were evaluated. Ledipasvir AUC0-24 and Cmax achieved approximately 3.7-fold and 4.2-fold, respectively, above exposures observed following administration of Ledipasvir/sofosbuvir (90/400 mg) to HCV-infected patients. There was a lack of effect of supratherapeutic Ledipasvir on QTc intervals using all correction methods (upper bound of the 2-sided 90%CIs for the mean difference in time-matched baseline-corrected QTc between Ledipasvir versus placebo 5 milliseconds, thereby establishing assay sensitivity. Categorical analyses did not demonstrate clinically relevant effects of Ledipasvir on QTc intervals or other electrocardiogram parameters. No relationships between Ledipasvir plasma concentration and QTc interval were observed. Ledipasvir does not prolong QTc interval. Based on these results and a previous TQT evaluation for sofosbuvir, the fixed-dose combination regimen of Ledipasvir/sofosbuvir is not expected to prolong the QTc interval.
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post treatment resistance analysis of hepatitis c virus from phase ii and iii clinical trials of Ledipasvir sofosbuvir
Journal of Hepatology, 2017Co-Authors: David L Wyles, Hadas Dvorysobol, Evguenia S. Svarovskaia, Brian P. Doehle, Nezam H. Afdhal, Kris V Kowdley, Diana M. Brainard, Ross Martin, E Lawitz, Michael D MillerAbstract:Background & Aims Ledipasvir/sofosbuvir combination treatment in phase III clinical trials resulted in sustained viral suppression in 94–99% of patients. This study characterized drug resistance in treatment failures, which may help to inform retreatment options. Methods We performed NS5A and NS5B deep sequencing of hepatitis C virus (HCV) from patients infected with genotype (GT) 1 who participated in Ledipasvir/sofosbuvir phase II and III clinical trials. Results Fifty-one of 2144 (2.4%) (42 GT1a and 9 GT1b) treated patients met the criteria for resistance analysis due to virologic failure following the end of treatment. The majority of patients with virologic failure (38 of 51; 74.5%) had detectable Ledipasvir-specific resistance-associated substitutions (RASs) at the time of virologic failure (1% deep sequencing cut-off). The percent of patients with NS5A RASs at virologic failure were 37.5%, 66.7%, 94.7% and 100% in patients treated for 6, 8, 12 and 24weeks, respectively. The common substitutions detected at failure were Q30R/H, and/or Y93H/N in GT1a and Y93H in GT1b. At failure, 35.3% (18/51) of virologic failure patients' viruses had two or more NS5A RASs and the majority of patients harbored NS5A RASs conferring a 100–1000-fold (n=10) or >1000-fold (n=23) reduced susceptibility to Ledipasvir. One patient in a phase II study with a known Ledipasvir RAS at baseline (L31M) developed the S282T sofosbuvir (NS5B) RAS at failure. Conclusions In GT1 HCV-infected patients treated with Ledipasvir/sofosbuvir±ribavirin, virologic failure was rare. Ledipasvir resistance in NS5A was selected or enhanced in most patients with virologic failure, one of whom also developed resistance to sofosbuvir. Lay summary Clinical studies have shown that combination treatment with Ledipasvir/sofosbuvir efficiently cures most patients with genotype 1 hepatitis C infection. For the few patients failing treatment, we show that resistance to Ledipasvir was observed in most patients, whereas resistance to sofosbuvir was less common. This has important implications for the selection of optimal retreatment strategies for these patients.
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Efficacy of Ledipasvir Plus Sofosbuvir for 8 or 12 Weeks in Patients With Hepatitis C Virus Genotype 2 Infection.
Gastroenterology, 2017Co-Authors: Edward Gane, Evguenia S. Svarovskaia, Diana M. Brainard, Robert H Hyland, John G. Mchutchison, Yin Yang, Luisa M. Stamm, Catherine A M StedmanAbstract:Background & Aims Patients with chronic hepatitis C virus (HCV) genotype 2 have high rates of response to treatment with sofosbuvir and ribavirin. However, ribavirin is associated with hemolytic events and is poorly tolerated by some patients. We evaluated the effectiveness of sofosbuvir and Ledipasvir in treatment-naive and treatment-experienced patients with HCV genotype 2, comparing 12 versus 8 weeks of treatment. Methods This Phase 2, open-label study included 2 cohorts in New Zealand. The first received a fixed-dose combination tablet of Ledipasvir–sofosbuvir (90/400 mg) once daily for 12 weeks. If this cohort had a 90% rate of sustained virologic response (SVR) 4 weeks after treatment, a second cohort receiving 8 weeks of Ledipasvir–sofosbuvir was to be enrolled. The primary endpoint in both cohorts was the percentage of patients with HCV RNA Results SVR12 rates were 96% (25/26; 95% CI, 80%-100%) for 12 weeks and 74% (20/27; 95% CI, 54%-89%) for 8 weeks of Ledipasvir–sofosbuvir. The single patient receiving 12 weeks of Ledipasvir–sofosbuvir who did not reach SVR12 did not complete treatment because of withdrawing consent after receiving 1 dose of study drug. Six of the 7 patients who did not reach SVR12 after 8 weeks of treatment experienced virologic relapse after stopping therapy. The most common adverse events were headache (26% of patients), fatigue (21%), and nausea (17%). No patients discontinued treatment because of an adverse event. Conclusions For treatment-naive and -experienced patients, Ledipasvir–sofosbuvir for 12 weeks is highly effective for the treatment of HCV genotype 2 (ClinicalTrials.gov: NCT02202980).
Nezam H. Afdhal - One of the best experts on this subject based on the ideXlab platform.
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post treatment resistance analysis of hepatitis c virus from phase ii and iii clinical trials of Ledipasvir sofosbuvir
Journal of Hepatology, 2017Co-Authors: David L Wyles, Hadas Dvorysobol, Evguenia S. Svarovskaia, Brian P. Doehle, Nezam H. Afdhal, Kris V Kowdley, Diana M. Brainard, Ross Martin, E Lawitz, Michael D MillerAbstract:Background & Aims Ledipasvir/sofosbuvir combination treatment in phase III clinical trials resulted in sustained viral suppression in 94–99% of patients. This study characterized drug resistance in treatment failures, which may help to inform retreatment options. Methods We performed NS5A and NS5B deep sequencing of hepatitis C virus (HCV) from patients infected with genotype (GT) 1 who participated in Ledipasvir/sofosbuvir phase II and III clinical trials. Results Fifty-one of 2144 (2.4%) (42 GT1a and 9 GT1b) treated patients met the criteria for resistance analysis due to virologic failure following the end of treatment. The majority of patients with virologic failure (38 of 51; 74.5%) had detectable Ledipasvir-specific resistance-associated substitutions (RASs) at the time of virologic failure (1% deep sequencing cut-off). The percent of patients with NS5A RASs at virologic failure were 37.5%, 66.7%, 94.7% and 100% in patients treated for 6, 8, 12 and 24weeks, respectively. The common substitutions detected at failure were Q30R/H, and/or Y93H/N in GT1a and Y93H in GT1b. At failure, 35.3% (18/51) of virologic failure patients' viruses had two or more NS5A RASs and the majority of patients harbored NS5A RASs conferring a 100–1000-fold (n=10) or >1000-fold (n=23) reduced susceptibility to Ledipasvir. One patient in a phase II study with a known Ledipasvir RAS at baseline (L31M) developed the S282T sofosbuvir (NS5B) RAS at failure. Conclusions In GT1 HCV-infected patients treated with Ledipasvir/sofosbuvir±ribavirin, virologic failure was rare. Ledipasvir resistance in NS5A was selected or enhanced in most patients with virologic failure, one of whom also developed resistance to sofosbuvir. Lay summary Clinical studies have shown that combination treatment with Ledipasvir/sofosbuvir efficiently cures most patients with genotype 1 hepatitis C infection. For the few patients failing treatment, we show that resistance to Ledipasvir was observed in most patients, whereas resistance to sofosbuvir was less common. This has important implications for the selection of optimal retreatment strategies for these patients.
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Post-treatment resistance analysis of hepatitis C virus from phase II and III clinical trials of Ledipasvir/sofosbuvir.
Journal of hepatology, 2016Co-Authors: David L Wyles, Evguenia S. Svarovskaia, Brian P. Doehle, Nezam H. Afdhal, Kris V Kowdley, Diana M. Brainard, Eric Lawitz, Ross Martin, Hadas Dvory-sobol, Michael D MillerAbstract:Background & Aims Ledipasvir/sofosbuvir combination treatment in phase III clinical trials resulted in sustained viral suppression in 94–99% of patients. This study characterized drug resistance in treatment failures, which may help to inform retreatment options. Methods We performed NS5A and NS5B deep sequencing of hepatitis C virus (HCV) from patients infected with genotype (GT) 1 who participated in Ledipasvir/sofosbuvir phase II and III clinical trials. Results Fifty-one of 2144 (2.4%) (42 GT1a and 9 GT1b) treated patients met the criteria for resistance analysis due to virologic failure following the end of treatment. The majority of patients with virologic failure (38 of 51; 74.5%) had detectable Ledipasvir-specific resistance-associated substitutions (RASs) at the time of virologic failure (1% deep sequencing cut-off). The percent of patients with NS5A RASs at virologic failure were 37.5%, 66.7%, 94.7% and 100% in patients treated for 6, 8, 12 and 24weeks, respectively. The common substitutions detected at failure were Q30R/H, and/or Y93H/N in GT1a and Y93H in GT1b. At failure, 35.3% (18/51) of virologic failure patients' viruses had two or more NS5A RASs and the majority of patients harbored NS5A RASs conferring a 100–1000-fold (n=10) or >1000-fold (n=23) reduced susceptibility to Ledipasvir. One patient in a phase II study with a known Ledipasvir RAS at baseline (L31M) developed the S282T sofosbuvir (NS5B) RAS at failure. Conclusions In GT1 HCV-infected patients treated with Ledipasvir/sofosbuvir±ribavirin, virologic failure was rare. Ledipasvir resistance in NS5A was selected or enhanced in most patients with virologic failure, one of whom also developed resistance to sofosbuvir. Lay summary Clinical studies have shown that combination treatment with Ledipasvir/sofosbuvir efficiently cures most patients with genotype 1 hepatitis C infection. For the few patients failing treatment, we show that resistance to Ledipasvir was observed in most patients, whereas resistance to sofosbuvir was less common. This has important implications for the selection of optimal retreatment strategies for these patients.
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prevalence of resistance associated substitutions in hcv ns5a ns5b or ns3 and outcomes of treatment with Ledipasvir and sofosbuvir
Gastroenterology, 2016Co-Authors: Christoph Sarrazin, Hadas Dvorysobol, Evguenia S. Svarovskaia, Brian P. Doehle, Nezam H. Afdhal, Kris V Kowdley, Phillip S Pang, Shu Min Chuang, Xiao Ding, Edward GaneAbstract:Background & Aims We evaluated the effects of baseline hepatitis C virus (HCV) NS5A, NS5B, and NS3 resistance-associated substitutions (RASs) on response to the combination of Ledipasvir and sofosbuvir, with or without ribavirin, in patients with HCV genotype 1 infection. Methods We analyzed data from 2144 participants in phase 2 and 3 studies of patients with HCV genotype 1a or b infection who received the combination of Ledipasvir (90 mg) and sofosbuvir (400 mg) (Ledipasvir/sofosbuvir) once daily, with or without ribavirin twice daily. Population and/or deep sequence analyses of the HCV NS3, NS5A, and NS5B genes were performed on blood samples collected at baseline. Results Overall, 16.0% of patients had detectable baseline RASs in NS5A. Among patients with HCV genotype 1b infection, there was no significant effect of baseline RASs in NS5A on sustained viral response 12 weeks after the end of treatment (SVR12) with Ledipasvir/sofosbuvir and only a small effect in patients with HCV genotype 1a infection. RASs in NS5A that increased the half-maximal effective concentration to Ledipasvir by more than 100-fold reduced the rate of SVR12 in treatment-naive patients given Ledipasvir/sofosbuvir for 8 weeks ( P = .011), but not for 12 weeks. These same baseline NS5A RASs reduced the percentage of treatment-experienced patients who achieved an SVR12 to 12 weeks (but not 24 weeks) Ledipasvir/sofosbuvir ( P Conclusions Baseline RASs in NS5A have minimal effects on patient responses to Ledipasvir/sofosbuvir therapy. When these RASs do have effects, they could be largely overcome by extending treatment duration or through treatment intensification.
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improvement of health related quality of life and work productivity in chronic hepatitis c patients with early and advanced fibrosis treated with Ledipasvir and sofosbuvir
Journal of Hepatology, 2015Co-Authors: Nezam H. Afdhal, Zobair M Younossi, Maria Stepanova, Kris V Kowdley, S Zeuzem, Linda Henry, Sharon L Hunt, Patrick MarcellinAbstract:Background & Aims New interferon-free anti-HCV regimens are highly efficacious with a favorable safety profile. We assessed health-related quality of life (HRQL) and work productivity in patients with different stages of hepatic fibrosis treated with sofosbuvir+Ledipasvir. Methods Four questionnaires [Chronic Liver Disease Questionnaire-HCV (CLDQ-HCV), Short Form-36 (SF-36), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Work Productivity and Activity Index:Specific Health Problem (WPAI:SHP)] were administered at baseline, during, and after treatment with sofosbuvir+Ledipasvir+ribavirin or sofosbuvir+Ledipasvir (ION-1,2,3 clinical trials). Metavir fibrosis stage was determined from pre-treatment liver biopsies. Results There were 1005 patients included (stage F0: n=94; F1: n=311; F2: n=301; F3: n=197; F4: n=102). At baseline, patients with more advanced fibrosis had more HRQL impairments, predominantly related to physical functioning (stage 0 vs. stage 4 by up to 0.126 on a normalized 0–1 scale p p >0.05 across fibrosis stages). In multivariate analysis, advanced fibrosis was independently associated with impairment of HRQL and work productivity (beta up to −0.056 in comparison with none-to-mild fibrosis, p p >0.05). Conclusions Although advanced hepatic fibrosis is associated with HRQL and work productivity impairment, viral eradication with sofosbuvir+Ledipasvir leads to HRQL improvement regardless of fibrosis stage. HCV patients with early fibrosis experience similar improvement of patient reported outcomes as those with advanced fibrosis.
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Ledipasvir and Sofosbuvir for Untreated HCV Genotype 1 Infection
New England Journal of Medicine, 2014Co-Authors: Nezam H. Afdhal, Stefan Zeuzem, Paul Kwo, Mario Chojkier, Norman Gitlin, Massimo Puoti, Manuel Romero-gomez, Jean-pierre Zarski, Kosh Agarwal, Peter BuggischAbstract:Background In phase 2 studies, treatment with the all-oral combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor Ledipasvir resulted in high rates of sustained virologic response among previously untreated patients with hepatitis C virus (HCV) genotype 1 infection. Methods We conducted a phase 3, open-label study involving previously untreated patients with chronic HCV genotype 1 infection. Patients were randomly assigned in a 1:1:1:1 ratio to receive Ledipasvir and sofosbuvir in a fixed-dose combination tablet once daily for 12 weeks, Ledipasvir–sofosbuvir plus ribavirin for 12 weeks, Ledipasvir–sofosbuvir for 24 weeks, or Ledipasvir–sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. Results Of the 865 patients who underwent randomization and were treated, 16% had cirrhosis, 12% were black, and 67% had HCV genotype 1a infection. The rates of sustained virologic response were 99% (95% confidence interval [CI], 96 to 100) in the group that received 12 weeks of Ledipasvir–sofosbuvir; 97% (95% CI, 94 to 99) in the group that received 12 weeks of Ledipasvir–sofosbuvir plus ribavirin; 98% (95% CI, 95 to 99) in the group that received 24 weeks of Ledipasvir–sofosbuvir; and 99% (95% CI, 97 to 100) in the group that received 24 weeks of Ledipasvir–sofosbuvir plus ribavirin. No patient in either 12-week group discontinued Ledipasvir–sofosbuvir owing to an adverse event. The most common adverse events were fatigue, headache, insomnia, and nausea. Conclusions Once-daily Ledipasvir–sofosbuvir with or without ribavirin for 12 or 24 weeks was highly effective in previously untreated patients with HCV genotype 1 infection.
Polina German - One of the best experts on this subject based on the ideXlab platform.
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Drug–Drug Interaction Profile of the Fixed-Dose Combination Tablet Regimen Ledipasvir/Sofosbuvir
Clinical Pharmacokinetics, 2018Co-Authors: Polina German, Anita Mathias, Diana M. Brainard, Brian P. KearneyAbstract:Ledipasvir/sofosbuvir (Harvoni^®), a fixed-dose combination tablet of an NS5A inhibitor Ledipasvir and an NS5B polymerase inhibitor sofosbuvir, is approved for the treatment of chronic hepatitis C virus infection. Ledipasvir/sofosbuvir exhibits a favorable drug–drug interaction profile and can be administered with various medications that may be used by hepatitis C virus-infected patients, including patients with comorbidities, such as co-infection with human immunodeficiency virus or immunosuppression following liver transplantation. Ledipasvir/sofosbuvir is not expected to act as a victim or perpetrator of cytochrome P450- or UDP-glucuronosyltransferase 1A1-mediated drug–drug interactions. With the exception of strong inducers of P-glycoprotein, such as rifampin, Ledipasvir/sofosbuvir is not expected to act as a victim of clinically relevant drug–drug interactions. As a perpetrator of pharmacokinetic drug–drug interactions via P-glycoprotein/BCRP, Ledipasvir/sofosbuvir should not be used with rosuvastatin and elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate, whereas its co-administration with amiodarone is not recommended because of a pharmacodynamic interaction. This review summarizes a number of drug interaction studies conducted in support of the clinical development of Ledipasvir/sofosbuvir.
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Drug-Drug Interaction Profile of the Fixed-Dose Combination Tablet Regimen Ledipasvir/Sofosbuvir.
Clinical pharmacokinetics, 2018Co-Authors: Polina German, Anita Mathias, Diana M. Brainard, Brian P. KearneyAbstract:Ledipasvir/sofosbuvir (Harvoni®), a fixed-dose combination tablet of an NS5A inhibitor Ledipasvir and an NS5B polymerase inhibitor sofosbuvir, is approved for the treatment of chronic hepatitis C virus infection. Ledipasvir/sofosbuvir exhibits a favorable drug-drug interaction profile and can be administered with various medications that may be used by hepatitis C virus-infected patients, including patients with comorbidities, such as co-infection with human immunodeficiency virus or immunosuppression following liver transplantation. Ledipasvir/sofosbuvir is not expected to act as a victim or perpetrator of cytochrome P450- or UDP-glucuronosyltransferase 1A1-mediated drug-drug interactions. With the exception of strong inducers of P-glycoprotein, such as rifampin, Ledipasvir/sofosbuvir is not expected to act as a victim of clinically relevant drug-drug interactions. As a perpetrator of pharmacokinetic drug-drug interactions via P-glycoprotein/BCRP, Ledipasvir/sofosbuvir should not be used with rosuvastatin and elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate, whereas its co-administration with amiodarone is not recommended because of a pharmacodynamic interaction. This review summarizes a number of drug interaction studies conducted in support of the clinical development of Ledipasvir/sofosbuvir.
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A Thorough QT Study to Evaluate the Effects of Supratherapeutic Doses of Ledipasvir on the QTc Interval in Healthy Subjects
Clinical pharmacology in drug development, 2017Co-Authors: Polina German, Anita Mathias, Diana M. Brainard, Qinghua Song, John Ling, Brian P. KearneyAbstract:This study evaluated the effect of supratherapeutic exposure of the anti-HCV drug Ledipasvir on the QTc interval in healthy subjects. Sixty healthy volunteers were randomized to receive twice-daily blinded Ledipasvir (120 mg) or placebo, administered for 10 days each, or single doses of open-label moxifloxacin (400 mg). Serial plasma samples for Ledipasvir concentration analysis were collected after each treatment. Triplicate time-matched electrocardiograms were collected at baseline and after each treatment. Change from baseline in the QTc for Ledipasvir or moxifloxacin versus placebo was determined using several correction formulas (primary: QTcF [Fridericia's]; secondary: QTcN [population] and QTcI [individual]). Pharmacokinetics and exposure-QTc relationships were evaluated. Ledipasvir AUC0-24 and Cmax achieved approximately 3.7-fold and 4.2-fold, respectively, above exposures observed following administration of Ledipasvir/sofosbuvir (90/400 mg) to HCV-infected patients. There was a lack of effect of supratherapeutic Ledipasvir on QTc intervals using all correction methods (upper bound of the 2-sided 90%CIs for the mean difference in time-matched baseline-corrected QTc between Ledipasvir versus placebo 5 milliseconds, thereby establishing assay sensitivity. Categorical analyses did not demonstrate clinically relevant effects of Ledipasvir on QTc intervals or other electrocardiogram parameters. No relationships between Ledipasvir plasma concentration and QTc interval were observed. Ledipasvir does not prolong QTc interval. Based on these results and a previous TQT evaluation for sofosbuvir, the fixed-dose combination regimen of Ledipasvir/sofosbuvir is not expected to prolong the QTc interval.
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The safety and effectiveness of Ledipasvir-sofosbuvir in adolescents 12-17 years old with hepatitis C virus genotype 1 infection.
Hepatology (Baltimore Md.), 2017Co-Authors: William F. Balistreri, Kathryn Kersey, Karen F. Murray, Philip J. Rosenthal, Sanjay Bansal, Chuan Hao Lin, Benedetta Massetto, Yanni Zhu, Bittoo Kanwar, Polina GermanAbstract:No all-oral, direct-acting antiviral regimens have been approved for children with chronic hepatitis C virus (HCV) infection. We conducted a phase 2, multicenter, open-label study to evaluate the efficacy and safety of Ledipasvir–sofosbuvir in adolescents with chronic HCV genotype 1 infection. One hundred patients aged 12-17 years received a combination tablet of 90 mg Ledipasvir and 400 mg sofosbuvir once daily for 12 weeks. On the tenth day following initiation of dosing, 10 patients underwent an intensive pharmacokinetic evaluation of the concentrations of sofosbuvir, Ledipasvir, and the sofosbuvir metabolite GS-331007. The primary efficacy endpoint was the percentage of patients with a sustained virologic response at 12 weeks posttreatment. Median age of patients was 15 years (range 12-17). A majority (80%) were HCV treatment-naive, and 84% were infected through perinatal transmission. One patient had cirrhosis, and 42 did not; in 57 patients the degree of fibrosis was unknown. Overall, 98% (98/100; 95% confidence interval 93%-100%) of patients reached sustained virologic response at 12 weeks. No patient had virologic failure. The 2 patients who did not achieve sustained virologic response at 12 weeks were lost to follow-up either during or after treatment. The three most commonly reported adverse events were headache (27% of patients), diarrhea (14%), and fatigue (13%). No serious adverse events were reported. Area under the concentration-time curve (tau) and maximum concentration values for sofosbuvir, Ledipasvir, and GS-331007 were within the predefined pharmacokinetic equivalence boundaries of 50%-200% when compared with adults from phase 2 and 3 studies of Ledipasvir and sofosbuvir. Conclusion: Ledipasvir−sofosbuvir was highly effective at treating adolescents with chronic HCV genotype 1 infection; the dose of Ledipasvir−sofosbuvir currently used in adults was well tolerated in adolescents and had an appropriate pharmacokinetic profile. (Hepatology 2017;66:371–378).
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Clinical Pharmacokinetics and Pharmacodynamics of Ledipasvir/Sofosbuvir, a Fixed-Dose Combination Tablet for the Treatment of Hepatitis C
Clinical Pharmacokinetics, 2016Co-Authors: Polina German, Anita Mathias, Diana Brainard, Brian P. KearneyAbstract:Ledipasvir/sofosbuvir (Harvoni^®), a fixed-dose combination tablet of an NS5A inhibitor Ledipasvir and an NS5B polymerase inhibitor sofosbuvir, is approved in the US, European Union, Canada, and other regions for the treatment of chronic hepatitis C virus infection in adults. Following absorption, Ledipasvir reaches maximum plasma concentrations ( T _max) 4–4.5 h post-dose and is eliminated with a terminal half-life ( t _1/2) of 47 h. Sofosbuvir undergoes intracellular activation to an active triphosphate GS-461203 (not detected in plasma) and ultimately to GS-331007, a predominant circulating metabolite, which is the primary analyte of interest in clinical pharmacology studies. Sofosbuvir is rapidly absorbed and eliminated from plasma ( T _max: 0.8–1 h; t _1/2: 0.5 h). The peak plasma concentrations for GS-331007 are achieved between 3.5 and 4 h post-dose; the elimination t _1/2 for GS-331007 is 27 h. Ledipasvir/sofosbuvir exhibits a favorable clinical pharmacology profile; it can be administered once daily without regard to food and does not require dose modification in hepatitis C virus-infected patients with any degree of hepatic impairment or mild to moderate renal impairment. The pharmacokinetic profiles of Ledipasvir, sofosbuvir, and GS-331007 (predominant circulating metabolite of sofosbuvir) are not significantly affected by demographic variables; pharmacokinetic/pharmacodynamic analyses reveal no exposure-response relationships for efficacy or safety. The review summarizes the clinical pharmacokinetics, pharmacodynamics, and pharmacokinetic/pharmacodynamic analyses for Ledipasvir/sofosbuvir.
Evguenia S. Svarovskaia - One of the best experts on this subject based on the ideXlab platform.
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ns5a resistance associated substitutions in patients with genotype 1 hepatitis c virus prevalence and effect on treatment outcome
Journal of Hepatology, 2017Co-Authors: Stefan Zeuzem, Hadas Dvorysobol, Evguenia S. Svarovskaia, Brian P. Doehle, Masashi Mizokami, Stephen Pianko, Alessandra Mangia, Kwang Hyub Han, Ross Martin, Charlotte HedskogAbstract:Background & Aims The efficacy of NS5A inhibitors for the treatment of patients chronically infected with hepatitis C virus (HCV) can be affected by the presence of NS5A resistance-associated substitutions (RASs). We analyzed data from 35 phase I, II, and III studies in 22 countries to determine the pretreatment prevalence of various NS5A RASs, and their effect on outcomes of treatment with Ledipasvir-sofosbuvir in patients with genotype 1 HCV. Methods NS5A gene deep sequencing analysis was performed on samples from 5397 patients in Gilead clinical trials. The effect of baseline RASs on sustained virologic response (SVR) rates was assessed in the 1765 patients treated with regimens containing Ledipasvir-sofosbuvir. Results Using a 15% cut-off, pretreatment NS5A and Ledipasvir-specific RASs were detected in 13% and 8% of genotype 1a patients, respectively, and in 18% and 16% of patients with genotype 1b. Among genotype 1a treatment-naive patients, SVR rates were 91% (42/46) vs. 99% (539/546) for those with and without Ledipasvir-specific RASs, respectively. Among treatment-experienced genotype 1a patients, SVR rates were 76% (22/29) vs. 97% (409/420) for those with and without Ledipasvir-specific RASs, respectively. Among treatment-naive genotype 1b patients, SVR rates were 99% for both those with and without Ledipasvir-specific RASs (71/72 vs. 331/334), and among treatment-experienced genotype 1b patients, SVR rates were 89% (41/46) vs. 98% (267/272) for those with and without Ledipasvir-specific RASs, respectively. Conclusions Pretreatment Ledipasvir-specific RASs that were present in 8–16% of patients have an impact on treatment outcome in some patient groups, particularly treatment-experienced patients with genotype 1a HCV. Lay summary The efficacy of treatments using NS5A inhibitors for patients with chronic hepatitis C virus (HCV) infection can be affected by the presence of NS5A resistance-associated substitutions (RASs). We reviewed results from 35 clinical trials where patients with genotype 1 HCV infection received treatments that included Ledipasvir-sofosbuvir to determine how prevalent NS5A RASs are in patients at baseline, and found that Ledipasvir-specific RASs were present in 8–16% of patients prior to treatment and had a negative impact on treatment outcome in subset of patient groups, particularly treatment-experienced patients with genotype 1a HCV.
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post treatment resistance analysis of hepatitis c virus from phase ii and iii clinical trials of Ledipasvir sofosbuvir
Journal of Hepatology, 2017Co-Authors: David L Wyles, Hadas Dvorysobol, Evguenia S. Svarovskaia, Brian P. Doehle, Nezam H. Afdhal, Kris V Kowdley, Diana M. Brainard, Ross Martin, E Lawitz, Michael D MillerAbstract:Background & Aims Ledipasvir/sofosbuvir combination treatment in phase III clinical trials resulted in sustained viral suppression in 94–99% of patients. This study characterized drug resistance in treatment failures, which may help to inform retreatment options. Methods We performed NS5A and NS5B deep sequencing of hepatitis C virus (HCV) from patients infected with genotype (GT) 1 who participated in Ledipasvir/sofosbuvir phase II and III clinical trials. Results Fifty-one of 2144 (2.4%) (42 GT1a and 9 GT1b) treated patients met the criteria for resistance analysis due to virologic failure following the end of treatment. The majority of patients with virologic failure (38 of 51; 74.5%) had detectable Ledipasvir-specific resistance-associated substitutions (RASs) at the time of virologic failure (1% deep sequencing cut-off). The percent of patients with NS5A RASs at virologic failure were 37.5%, 66.7%, 94.7% and 100% in patients treated for 6, 8, 12 and 24weeks, respectively. The common substitutions detected at failure were Q30R/H, and/or Y93H/N in GT1a and Y93H in GT1b. At failure, 35.3% (18/51) of virologic failure patients' viruses had two or more NS5A RASs and the majority of patients harbored NS5A RASs conferring a 100–1000-fold (n=10) or >1000-fold (n=23) reduced susceptibility to Ledipasvir. One patient in a phase II study with a known Ledipasvir RAS at baseline (L31M) developed the S282T sofosbuvir (NS5B) RAS at failure. Conclusions In GT1 HCV-infected patients treated with Ledipasvir/sofosbuvir±ribavirin, virologic failure was rare. Ledipasvir resistance in NS5A was selected or enhanced in most patients with virologic failure, one of whom also developed resistance to sofosbuvir. Lay summary Clinical studies have shown that combination treatment with Ledipasvir/sofosbuvir efficiently cures most patients with genotype 1 hepatitis C infection. For the few patients failing treatment, we show that resistance to Ledipasvir was observed in most patients, whereas resistance to sofosbuvir was less common. This has important implications for the selection of optimal retreatment strategies for these patients.
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Efficacy of Ledipasvir Plus Sofosbuvir for 8 or 12 Weeks in Patients With Hepatitis C Virus Genotype 2 Infection.
Gastroenterology, 2017Co-Authors: Edward Gane, Evguenia S. Svarovskaia, Diana M. Brainard, Robert H Hyland, John G. Mchutchison, Yin Yang, Luisa M. Stamm, Catherine A M StedmanAbstract:Background & Aims Patients with chronic hepatitis C virus (HCV) genotype 2 have high rates of response to treatment with sofosbuvir and ribavirin. However, ribavirin is associated with hemolytic events and is poorly tolerated by some patients. We evaluated the effectiveness of sofosbuvir and Ledipasvir in treatment-naive and treatment-experienced patients with HCV genotype 2, comparing 12 versus 8 weeks of treatment. Methods This Phase 2, open-label study included 2 cohorts in New Zealand. The first received a fixed-dose combination tablet of Ledipasvir–sofosbuvir (90/400 mg) once daily for 12 weeks. If this cohort had a 90% rate of sustained virologic response (SVR) 4 weeks after treatment, a second cohort receiving 8 weeks of Ledipasvir–sofosbuvir was to be enrolled. The primary endpoint in both cohorts was the percentage of patients with HCV RNA Results SVR12 rates were 96% (25/26; 95% CI, 80%-100%) for 12 weeks and 74% (20/27; 95% CI, 54%-89%) for 8 weeks of Ledipasvir–sofosbuvir. The single patient receiving 12 weeks of Ledipasvir–sofosbuvir who did not reach SVR12 did not complete treatment because of withdrawing consent after receiving 1 dose of study drug. Six of the 7 patients who did not reach SVR12 after 8 weeks of treatment experienced virologic relapse after stopping therapy. The most common adverse events were headache (26% of patients), fatigue (21%), and nausea (17%). No patients discontinued treatment because of an adverse event. Conclusions For treatment-naive and -experienced patients, Ledipasvir–sofosbuvir for 12 weeks is highly effective for the treatment of HCV genotype 2 (ClinicalTrials.gov: NCT02202980).
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Post-treatment resistance analysis of hepatitis C virus from phase II and III clinical trials of Ledipasvir/sofosbuvir.
Journal of hepatology, 2016Co-Authors: David L Wyles, Evguenia S. Svarovskaia, Brian P. Doehle, Nezam H. Afdhal, Kris V Kowdley, Diana M. Brainard, Eric Lawitz, Ross Martin, Hadas Dvory-sobol, Michael D MillerAbstract:Background & Aims Ledipasvir/sofosbuvir combination treatment in phase III clinical trials resulted in sustained viral suppression in 94–99% of patients. This study characterized drug resistance in treatment failures, which may help to inform retreatment options. Methods We performed NS5A and NS5B deep sequencing of hepatitis C virus (HCV) from patients infected with genotype (GT) 1 who participated in Ledipasvir/sofosbuvir phase II and III clinical trials. Results Fifty-one of 2144 (2.4%) (42 GT1a and 9 GT1b) treated patients met the criteria for resistance analysis due to virologic failure following the end of treatment. The majority of patients with virologic failure (38 of 51; 74.5%) had detectable Ledipasvir-specific resistance-associated substitutions (RASs) at the time of virologic failure (1% deep sequencing cut-off). The percent of patients with NS5A RASs at virologic failure were 37.5%, 66.7%, 94.7% and 100% in patients treated for 6, 8, 12 and 24weeks, respectively. The common substitutions detected at failure were Q30R/H, and/or Y93H/N in GT1a and Y93H in GT1b. At failure, 35.3% (18/51) of virologic failure patients' viruses had two or more NS5A RASs and the majority of patients harbored NS5A RASs conferring a 100–1000-fold (n=10) or >1000-fold (n=23) reduced susceptibility to Ledipasvir. One patient in a phase II study with a known Ledipasvir RAS at baseline (L31M) developed the S282T sofosbuvir (NS5B) RAS at failure. Conclusions In GT1 HCV-infected patients treated with Ledipasvir/sofosbuvir±ribavirin, virologic failure was rare. Ledipasvir resistance in NS5A was selected or enhanced in most patients with virologic failure, one of whom also developed resistance to sofosbuvir. Lay summary Clinical studies have shown that combination treatment with Ledipasvir/sofosbuvir efficiently cures most patients with genotype 1 hepatitis C infection. For the few patients failing treatment, we show that resistance to Ledipasvir was observed in most patients, whereas resistance to sofosbuvir was less common. This has important implications for the selection of optimal retreatment strategies for these patients.
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prevalence of resistance associated substitutions in hcv ns5a ns5b or ns3 and outcomes of treatment with Ledipasvir and sofosbuvir
Gastroenterology, 2016Co-Authors: Christoph Sarrazin, Hadas Dvorysobol, Evguenia S. Svarovskaia, Brian P. Doehle, Nezam H. Afdhal, Kris V Kowdley, Phillip S Pang, Shu Min Chuang, Xiao Ding, Edward GaneAbstract:Background & Aims We evaluated the effects of baseline hepatitis C virus (HCV) NS5A, NS5B, and NS3 resistance-associated substitutions (RASs) on response to the combination of Ledipasvir and sofosbuvir, with or without ribavirin, in patients with HCV genotype 1 infection. Methods We analyzed data from 2144 participants in phase 2 and 3 studies of patients with HCV genotype 1a or b infection who received the combination of Ledipasvir (90 mg) and sofosbuvir (400 mg) (Ledipasvir/sofosbuvir) once daily, with or without ribavirin twice daily. Population and/or deep sequence analyses of the HCV NS3, NS5A, and NS5B genes were performed on blood samples collected at baseline. Results Overall, 16.0% of patients had detectable baseline RASs in NS5A. Among patients with HCV genotype 1b infection, there was no significant effect of baseline RASs in NS5A on sustained viral response 12 weeks after the end of treatment (SVR12) with Ledipasvir/sofosbuvir and only a small effect in patients with HCV genotype 1a infection. RASs in NS5A that increased the half-maximal effective concentration to Ledipasvir by more than 100-fold reduced the rate of SVR12 in treatment-naive patients given Ledipasvir/sofosbuvir for 8 weeks ( P = .011), but not for 12 weeks. These same baseline NS5A RASs reduced the percentage of treatment-experienced patients who achieved an SVR12 to 12 weeks (but not 24 weeks) Ledipasvir/sofosbuvir ( P Conclusions Baseline RASs in NS5A have minimal effects on patient responses to Ledipasvir/sofosbuvir therapy. When these RASs do have effects, they could be largely overcome by extending treatment duration or through treatment intensification.
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Drug–Drug Interaction Profile of the Fixed-Dose Combination Tablet Regimen Ledipasvir/Sofosbuvir
Clinical Pharmacokinetics, 2018Co-Authors: Polina German, Anita Mathias, Diana M. Brainard, Brian P. KearneyAbstract:Ledipasvir/sofosbuvir (Harvoni^®), a fixed-dose combination tablet of an NS5A inhibitor Ledipasvir and an NS5B polymerase inhibitor sofosbuvir, is approved for the treatment of chronic hepatitis C virus infection. Ledipasvir/sofosbuvir exhibits a favorable drug–drug interaction profile and can be administered with various medications that may be used by hepatitis C virus-infected patients, including patients with comorbidities, such as co-infection with human immunodeficiency virus or immunosuppression following liver transplantation. Ledipasvir/sofosbuvir is not expected to act as a victim or perpetrator of cytochrome P450- or UDP-glucuronosyltransferase 1A1-mediated drug–drug interactions. With the exception of strong inducers of P-glycoprotein, such as rifampin, Ledipasvir/sofosbuvir is not expected to act as a victim of clinically relevant drug–drug interactions. As a perpetrator of pharmacokinetic drug–drug interactions via P-glycoprotein/BCRP, Ledipasvir/sofosbuvir should not be used with rosuvastatin and elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate, whereas its co-administration with amiodarone is not recommended because of a pharmacodynamic interaction. This review summarizes a number of drug interaction studies conducted in support of the clinical development of Ledipasvir/sofosbuvir.
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Drug-Drug Interaction Profile of the Fixed-Dose Combination Tablet Regimen Ledipasvir/Sofosbuvir.
Clinical pharmacokinetics, 2018Co-Authors: Polina German, Anita Mathias, Diana M. Brainard, Brian P. KearneyAbstract:Ledipasvir/sofosbuvir (Harvoni®), a fixed-dose combination tablet of an NS5A inhibitor Ledipasvir and an NS5B polymerase inhibitor sofosbuvir, is approved for the treatment of chronic hepatitis C virus infection. Ledipasvir/sofosbuvir exhibits a favorable drug-drug interaction profile and can be administered with various medications that may be used by hepatitis C virus-infected patients, including patients with comorbidities, such as co-infection with human immunodeficiency virus or immunosuppression following liver transplantation. Ledipasvir/sofosbuvir is not expected to act as a victim or perpetrator of cytochrome P450- or UDP-glucuronosyltransferase 1A1-mediated drug-drug interactions. With the exception of strong inducers of P-glycoprotein, such as rifampin, Ledipasvir/sofosbuvir is not expected to act as a victim of clinically relevant drug-drug interactions. As a perpetrator of pharmacokinetic drug-drug interactions via P-glycoprotein/BCRP, Ledipasvir/sofosbuvir should not be used with rosuvastatin and elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate, whereas its co-administration with amiodarone is not recommended because of a pharmacodynamic interaction. This review summarizes a number of drug interaction studies conducted in support of the clinical development of Ledipasvir/sofosbuvir.
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A Thorough QT Study to Evaluate the Effects of Supratherapeutic Doses of Ledipasvir on the QTc Interval in Healthy Subjects
Clinical pharmacology in drug development, 2017Co-Authors: Polina German, Anita Mathias, Diana M. Brainard, Qinghua Song, John Ling, Brian P. KearneyAbstract:This study evaluated the effect of supratherapeutic exposure of the anti-HCV drug Ledipasvir on the QTc interval in healthy subjects. Sixty healthy volunteers were randomized to receive twice-daily blinded Ledipasvir (120 mg) or placebo, administered for 10 days each, or single doses of open-label moxifloxacin (400 mg). Serial plasma samples for Ledipasvir concentration analysis were collected after each treatment. Triplicate time-matched electrocardiograms were collected at baseline and after each treatment. Change from baseline in the QTc for Ledipasvir or moxifloxacin versus placebo was determined using several correction formulas (primary: QTcF [Fridericia's]; secondary: QTcN [population] and QTcI [individual]). Pharmacokinetics and exposure-QTc relationships were evaluated. Ledipasvir AUC0-24 and Cmax achieved approximately 3.7-fold and 4.2-fold, respectively, above exposures observed following administration of Ledipasvir/sofosbuvir (90/400 mg) to HCV-infected patients. There was a lack of effect of supratherapeutic Ledipasvir on QTc intervals using all correction methods (upper bound of the 2-sided 90%CIs for the mean difference in time-matched baseline-corrected QTc between Ledipasvir versus placebo 5 milliseconds, thereby establishing assay sensitivity. Categorical analyses did not demonstrate clinically relevant effects of Ledipasvir on QTc intervals or other electrocardiogram parameters. No relationships between Ledipasvir plasma concentration and QTc interval were observed. Ledipasvir does not prolong QTc interval. Based on these results and a previous TQT evaluation for sofosbuvir, the fixed-dose combination regimen of Ledipasvir/sofosbuvir is not expected to prolong the QTc interval.
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Lack of clinically important PK interaction between coformulated Ledipasvir/sofosbuvir and rilpivirine/emtricitabine/tenofovir alafenamide.
Pharmacology research & perspectives, 2017Co-Authors: Joseph M. Custodio, John Ling, Susan K. Chuck, Hoa Chu, Huyen Cao, John P. Flaherty, Brian P. KearneyAbstract:The drug-drug interaction (DDI) potential between the fixed-dose combinations of Ledipasvir/sofosbuvir 90/400 mg for hepatitis C virus and emtricitabine/rilpivirine/tenofovir alafenamide (TAF) 200/25/25 mg for HIV was evaluated in a randomized, open-label, single-center, multiple-dose, 3-way, 6-sequence, crossover Phase 1 study in 42 healthy subjects. Emtricitabine/rilpivirine/TAF had no relevant effect on the pharmacokinetic parameters of maximum concentration [Cmax ] and area under the concentration versus time curve over the dosing interval [AUCtau ] for Ledipasvir, sofosbuvir, and the metabolites GS-566500 and GS-331007. Ledipasvir/sofosbuvir had no effect on the Cmax and AUCtau for rilpivirine and emtricitabine. The Cmax and AUCtau of tenofovir, the major metabolite of TAF, were increased by 62% and 75%, respectively. However, the resulting absolute tenofovir exposures were markedly lower than the historical tenofovir exposures following tenofovir disoproxil fumarate (TDF) and, as such, were not considered to be clinically relevant. In contrast, additional adverse effect monitoring is recommended upon coadministration of Ledipasvir and TDF due to elevated tenofovir exposures resulting from the DDI. This difference is explained by the fact that TAF 25 mg results in markedly lower (~90%) plasma tenofovir exposure compared to TDF 300 mg. Ledipasvir/sofosbuvir and emtricitabine/rilpivirine/TAF were generally well tolerated when administered alone or in combination. HIV/hepatitis C virus-coinfected patients can coadminister Ledipasvir/sofosbuvir and emtricitabine/rilpivirine/TAF without dosage adjustments.
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Clinical Pharmacokinetics and Pharmacodynamics of Ledipasvir/Sofosbuvir, a Fixed-Dose Combination Tablet for the Treatment of Hepatitis C
Clinical Pharmacokinetics, 2016Co-Authors: Polina German, Anita Mathias, Diana Brainard, Brian P. KearneyAbstract:Ledipasvir/sofosbuvir (Harvoni^®), a fixed-dose combination tablet of an NS5A inhibitor Ledipasvir and an NS5B polymerase inhibitor sofosbuvir, is approved in the US, European Union, Canada, and other regions for the treatment of chronic hepatitis C virus infection in adults. Following absorption, Ledipasvir reaches maximum plasma concentrations ( T _max) 4–4.5 h post-dose and is eliminated with a terminal half-life ( t _1/2) of 47 h. Sofosbuvir undergoes intracellular activation to an active triphosphate GS-461203 (not detected in plasma) and ultimately to GS-331007, a predominant circulating metabolite, which is the primary analyte of interest in clinical pharmacology studies. Sofosbuvir is rapidly absorbed and eliminated from plasma ( T _max: 0.8–1 h; t _1/2: 0.5 h). The peak plasma concentrations for GS-331007 are achieved between 3.5 and 4 h post-dose; the elimination t _1/2 for GS-331007 is 27 h. Ledipasvir/sofosbuvir exhibits a favorable clinical pharmacology profile; it can be administered once daily without regard to food and does not require dose modification in hepatitis C virus-infected patients with any degree of hepatic impairment or mild to moderate renal impairment. The pharmacokinetic profiles of Ledipasvir, sofosbuvir, and GS-331007 (predominant circulating metabolite of sofosbuvir) are not significantly affected by demographic variables; pharmacokinetic/pharmacodynamic analyses reveal no exposure-response relationships for efficacy or safety. The review summarizes the clinical pharmacokinetics, pharmacodynamics, and pharmacokinetic/pharmacodynamic analyses for Ledipasvir/sofosbuvir.