Littérature scientifique sur le sujet « Daclatasvir »

Abstract Background Current approaches of drug repurposing against COVID-19 have not proven overwhelmingly successful and the SARS-CoV-2 pandemic continues to cause major global mortality. SARS-CoV-2 nsp12, its RNA polymerase, shares homology in the nucleotide uptake channel with the HCV orthologue enzyme NS5B. Besides, HCV enzyme NS5A has pleiotropic activities, such as RNA binding, that are shared with various SARS-CoV-2 proteins. Thus, anti-HCV NS5B and NS5A inhibitors, like sofosbuvir and daclatasvir, respectively, could be endowed with anti-SARS-CoV-2 activity. Methods SARS-CoV-2-infected Vero cells, HuH-7 cells, Calu-3 cells, neural stem cells and monocytes were used to investigate the effects of daclatasvir and sofosbuvir. In silico and cell-free based assays were performed with SARS-CoV-2 RNA and nsp12 to better comprehend the mechanism of inhibition of the investigated compounds. A physiologically based pharmacokinetic model was generated to estimate daclatasvir’s dose and schedule to maximize the probability of success for COVID-19. Results Daclatasvir inhibited SARS-CoV-2 replication in Vero, HuH-7 and Calu-3 cells, with potencies of 0.8, 0.6 and 1.1 μM, respectively. Although less potent than daclatasvir, sofosbuvir alone and combined with daclatasvir inhibited replication in Calu-3 cells. Sofosbuvir and daclatasvir prevented virus-induced neuronal apoptosis and release of cytokine storm-related inflammatory mediators, respectively. Sofosbuvir inhibited RNA synthesis by chain termination and daclatasvir targeted the folding of secondary RNA structures in the SARS-CoV-2 genome. Concentrations required for partial daclatasvir in vitro activity are achieved in plasma at Cmax after administration of the approved dose to humans. Conclusions Daclatasvir, alone or in combination with sofosbuvir, at higher doses than used against HCV, may be further fostered as an anti-COVID-19 therapy.

The purpose of the review is to evaluate the efficacy and safety of using pangenotypic combination «of Sofosbuvir/Daclatasvir» — the direct action antiviral drugs in the treatment of chronic HCV infection at different stages of liver damage.Main provisions: Sofosbuvir is the antisense nucleotide, inhibiting RNA-dependent RNA-polymerase NS5B, this drug has earned a reputation as one of the strongest anti-replication drugs, including when there is interferon resistance. Daclatasvir is a powerful non-nucleotide inhibitor of NS5А protein, catalyzing formation of replicative complexes. Both components are proven to be effect against HCV genotypes 1-6. Their combination provides pangenotypic activity, and the mutual strengthening effect diminishes the risk of development of drug resistance. Indications for the administration of a combination «Sofosbuvir/Daclatasvi» are: treatment of HCV infection at the stage of acute hepatitis (for genotypes 1–6 of the virus), treatment for HCV infection at the stage of chronic hepatitis (for genotypes 1–6 of the virus), treatment of HCV infection in co-infection with HIV, treatment of HCV infection at the stage of liver cirrhosis, treatment of recurrent HCV infection after liver transplantation, treatment of HCV infection with immune manifestations.Conclusion: the combination «Sofosbuvir/Daclatasvir» is shown to be highly effective in the treatment of HCV infection of genotypes 1-6 with a frequency of SVR 93—97% at the stage of the hepatitis and 88—95% — at the stage of cirrhosis. Good tolerance and high efficiency has led to active use of this combination фе the stage of cirrhosis. This combination has been successfully used for the treatment of recurrence of HCV infection in the liver graft, including co-infection with HIV.

ABSTRACTObjective: The objective of the present work is to develop a simple, efficient, and reproducible spectrophotometric method for the quantitativeestimation of hepatitis-C drugs - Daclatasvir and Sofosbuvir in its active pharmaceutical ingredient (API) form.Methods: The developed ultraviolet spectrophotometric method for the quantitative estimation of hepatitis-C drugs - Daclatasvir and Sofosbuvir isbased on measurement of absorption at a wavelength maximum (λmax) of 317 and 261 nm using methanol as solvent.Results: The method was validated in terms of specificity, precision, linearity, accuracy, and robustness as per the ICH guidelines. The method wasfound to be linear in the range of 50-150% for Daclatasvir and in the range of 43-143% for Sofosbuvir. The percentage recovery values were in therange of 99.4-100.6% for Daclatasvir and in the range of 99.7-100.6% for Sofosbuvir at different concentration levels. Relative standard deviation forprecision and intermediate precision results were found to be <2%. The correlation coefficient value observed for Daclatasvir and Sofosbuvir drugsubstances was not <0.99, 0.99, respectively. Results obtained from the validation experiments prove that the developed method is quantified for theestimation of Daclatasvir and Sofosbuvir drug substances.Conclusion: The developed method can be successfully applied for routine analysis, quality control analysis, and also suitable for stability analysis ofDaclatasvir and Sofosbuvir in API form as per the regulatory requirements.Keywords: Daclatasvir, Sofosbuvir, Method development, Validation, Ultraviolet-visible spectrophotometry.

Direct acting fixed dose combination of sofosbuvir and daclatasvir to treat the viral hepatitis C disease is available in the market. So, a precise and robust stability indicating HPLC method for sofosbuvir and daclatasvir was developed. The SunQ C18 column (250 x 4.6 mm) was used for chromatographic separation with mobile phase consisting of 0.03 mM potassium dihydrogen phosphate buffer (pH 7): ACN (50: 50V/V). Optimised method satisfies the system suitability parameters with good resolution with 4.9 min Rt of sofosbuvir and 7.6 min Rt of daclatasvir. The method was validated as per ICH guidelines. Linearity was observed over range of 10-50 (µg mL-1) and 2.25-11.25 (µg mL-1) for sofosbuvir and daclatasvir, respectively. Both drugs were subjected to various stress conditions and high recovery values were found for daclatasvir on photolytic stress. The degradation was more on oxidative and hydrolytic stress for sofosbuvir. This optimised method offers new insight towards stability studies of both drugs.

A trouble-free, simple, specific and highly sensitive stability indicating phase HPLC method was developed for concurrent assessment of Daclatasvir and Sofosbuvir in pure and in their combined tablet formulation. An effectual separation was accomplished by using XDB Phenyl (250 x 4.6mm, 5µ,100 A0) column, mobile phase composition of Acetonitrile: buffer(0.1%v/v Trifluoroaceticacid in water) (50:50 v/v) and isocratic elution at a flow rate of 1ml/min and detection wavelength of 275nm. The extreme stress conditions like hydrolysis with acid and base, peroxide oxidation, thermal decomposition were used as per ICH specifications to assess the stability of the analytes in bulk and dosage forms. The retention times of Daclatasvir and Sofosbuvir were found at 2.8 and 3.7min respectively. The proposed method has linear response in the concentration ranges from 12 to 36µg/ml and 80 to 240 µg/ml for Daclatasvir and Sofosbuvir respectively. The detection and quantification limits calculated as 2.5μg/ml and 7.8μg/ml for DCL, 5.2μg/ml and 15.8μg/ml SOF respectively. All the method validation parameters were met the acceptance limits of Q2 specifications of ICH procedures. The degradation products produced by forced degradation studies were have good resolution from Daclatasir and Sofosbuvir peaks, which represents the methods stability. The proposed RP-HPLC method was highly sensitive, precise, stability indicating and economical. That’s why the method has the capacity to employ in the pharmaceutical manufacturing of Daclatasvir and Sofosbuvir and routine analysis in quality control department.

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A Hepatite C representa um grande impacto na saúde pública em todo o mundo. Interfere na vida dos portadores de HCV, na sociedade, no sistema de saúde e na economia. No Brasil, os medicamentos são de alto custo, apresentam terapias prolongadas e com efeitos colaterais nos tratamentos convencionais. Com evolução das novas tecnologias incorporadas ao SUS em 2015, há expectativa do aumento da resposta virológica e cura. Objetivos: Avaliar a eficácia e segurança do Daclatasvir e Sofosbuvir versus Alfapeginterferona 2A na Hepatite C Crônica. Método: Busca em dados eletrônicos: MedLine via PubMed, LILACS e Biblioteca Cochrane, com critérios: ensaios clínicos Randomizados (ECR) e Revisões Sistemáticas (RS) em Hepatite C Crônica. Resultados: Incluídos 01 ECR com a Daclatasvir e sofosbuvir com a ribavirina e 01 RS com Metanálise, somente ECR, que avaliou a terapia com interferon peguilado alfa 2A e alfa 2B associado a ribavirina, com ou sem inibidores de protease. Quanto à eficácia, o ECR identificou aqueles que contemplavam o Daclatasvir com o sofobusvir possuíam altos índices de resposta virológica sustentada. A eficácia reportada pela RS favorece ao uso da peginterferona alfa 2A. Conclusões: A segurança das intervenções foi analisada apenas no ECR na qual foi medida através do surgimento de eventos adversos durante e depois do tratamento. Como nos estudos relatam a eficácia das drogas de acordo com parâmetros diferentes, dificultando assim comparações mesmo que de forma indireta.
Introduction: Hepatitis C represents a major impact in public health worldwide.It Interferes in the lives of patients with HCV, in society, in the health system and the economy. In Brazil, medicaments are expensive and have length and side effects of conventional treatments therapies. With the evolution of new technologies incorporated into the SUS in 2015, there’s a expectation of a higher virologic response and healing. Objectives: To evaluate the efficacy and safety of Daclatasvir and sofosbuvir versus peginterferon alfa-2a in Chronic Hepatitis C. Method: Searching electronic data: Medline via PubMed, LILACS and Cochrane Library, with criteria: randomized clinical trials (RCTs) and Systematic Reviews (RS) in Chronic Hepatitis C. Results: Included with the ECR 01 and Daclatasvir sofosbuvir with ribavirin and RS 01 Metanalysis with only RCT, evaluating therapy with pegylated interferon alpha 2A and alpha-2B in combination with ribavirin, with or without protease inhibitors. As for effectiveness, the ECR identified those contemplated the Daclatasvir with sofobusvir had high rates of sustained virologic response. The efficacy reported by RS favors the use of peginterferon alfa 2a. Conclusions: The safety of interventions was only examined in the ECR in which was measured by the appearance of adverse events during and after treatment. As the studies report the effectiveness of drugs, according to different parameters, making comparisons difficult, even indirectly, about which interventions have better effectiveness.

Orientador : Prof. Dr. Roberto Pontarolo
Coorientadora : Drª. Inajara Rotta
Dissertação (mestrado) - Universidade Federal do Paraná, Setor de Ciências da Saúde, Programa de Pós-Graduação em Ciências Farmacêuticas. Defesa: Curitiba, 22/09/2017
Inclui referências : f. 83-93
Resumo: A hepatite viral C crônica é causada pelo vírus da hepatite C (VHC) e os indivíduos são considerados curados após atingir a resposta virológica sustentada (RVS). Porém, os elevados custos dificultam o acesso às terapias disponíveis. Dados os recursos limitados, a inserção de novas terapias deve ter sua viabilidade farmacoeconômica avaliada, para que a alocação de recursos seja eficiente. Portanto, o objetivo deste trabalho foi realizar análise de custo-efetividade das terapias preconizadas pelo Protocolo Clínico e Diretrizes Terapêuticas de 2015 no tratamento precoce de pacientes com hepatite C crônica sob a perspectiva do SUS. Esta análise utilizou um modelo de Markov para comparar o momento de inserção da terapia, comparando-se o tratamento a partir de F0, F1 ou F2 com o preconizado pelo PCDT de 2015, apenas F3 e F4. Como há diferentes genótipos (GT) do vírus e para alguns deles mais de uma terapia descrita, foram realizadas análises de subgrupos. O horizonte temporal foi a expectativa de vida do paciente, e a taxa de desconto foi determinada em 5%. A perspectiva do trabalho foi a do SUS, assim, foram mensurados apenas os custos diretos médicos. Como medida finalística foram utilizados os anos de vida ajustados por qualidade (AVAQ), estimados com base nas melhores evidências disponíveis. Os dados de eficácia foram empregados como probabilidade de transição entre os estágios de fibrose e a RVS e as demais probabilidades também foram estimadas com base na literatura. Foi assumido que apenas pacientes monoinfectados pelo VHC fariam parte do modelo, apenas os que atingissem a RVS a partir de F3 ou F4 poderiam continuar progredindo no modelo e após atingida a RVS eles não poderiam ser reinfectados. A análise demonstrou que a inserção precoce do tratamento é custo-efetiva, considerando limiar implícito sugerido para o Brasil para todas as terapias: sofosbuvir e daclatasvir para os genótipos 1, 3 e 4; sosfosbuvir e ribavirina para GT2; e sosfosbuvir, peguinterferona e ribavirina (PR) para GT3. E não é custo-efetiva para o tratamento a partir de F0, mas sim a partir de F1 ou F2 para as terapias sofosbuvir e simeprevir para GT1 e daclatasvir e PR para GT4. Porém com diferenças significativas entre as razões custo-efetividade incrementais (RCEI), variando de R$ 8.583/AVAQ a R$ 30.185/AVAQ. Para avaliar a robustez do modelo foram realizadas análises de sensibilidade. A análise determinística univariada demonstrou que as variáveis que mais afetam o modelo estão relacionadas à taxa de desconto dos resultados, ao custo dos medicamentos e aos dados de utilidade. A probabilística (PSA) permitiu quantificar as incertezas, fornecendo melhor evidência para o gestor. As 5000 iterações de cada subgrupo mantiveram-se no quadrante custo-efetivo do plano de custo-efetividade. Assim, pode-se afirmar que o tratamento precoce da hepatite C crônica é custo-efetivo, mas a alteração dos protocolos futuros depende de outras avaliações por parte dos gestores. Palavras-chave: hepatite C crônica, custo-efetividade, tratamento precoce, sofosbuvir, daclatasvir, simeprevir.
Abstratc: Chronic viral hepatitis C is caused by the hepatitis C virus (HCV) and is considered a curable disease, since individuals can achieve sustained virological response (SVR). However, access to the available therapies isn't universal, mainly due to high costs. As much as health resources are limited, pharmacoeconomic assessments that allow better allocation of resources are necessary. Therefore, the objective of this study is to perform a cost-effectiveness analysis of the therapies advocated by the Clinical Protocol and Therapeutic Guidelines of 2015 on early treatment of patients with chronic hepatitis C from the SUS perspective. This cost-effectiveness analysis used a Markov model to compare the moment of insertion of the therapy, comparing the treatment starts at F0, F1 or F2 with treatment according to the protocol, only F3 e F4. As there are different genotypes (GT) of the virus and for some of them more than one described therapy, subgroup analyses were performed. The model has a lifetime horizon, and the discount rate was defined in 5%. Considering the perspective of the work as the public health system, only direct medical costs were measured. As a final measure, quality adjusted life years (QALY) were estimated, based on the best available evidence. Efficacy data were used as a transition probability between the stages of fibrosis and SVR and the other probabilities were also estimated based on the literature. It was assumed that only HCV patients would be part of the model, just those who reached SVR from F3 or F4 could continue to progress in the model after reaching SVR and none of them could be reinfected. The analysis showed that the early insertion of the treatment is cost-effective, considering implicit limit suggested for Brazil for the therapies: sofosbuvir and daclatasvir for genotypes 1, 3 and 4; sosfosbuvir and ribavirina for GT2; sosfosbuvir; and peginterferon and ribavirin (PR) for GT3. And it isn't for treatment starting on F0, but it is when starting on F1 or F2 for the therapies sofosbuvir and simeprevir for GT1 and daclatasvir and PR for GT4. However, there were significant differences between the incremental cost-effectiveness ratios (ICER), ranging from R$ 8.583/AVAQ to R$ 30.185/AVAQ. To assess the robustness of the model, sensitivity analyses were performed. The univariate deterministic analyses showed that the variables that most affect the model are related to the discount rate of the results, the cost of medications and the utility data. The probabilistic (PSA) allowed to quantify the uncertainties, providing better evidence for the manager. The 5000 iterations of each subgroup remained in the cost-effective quadrant of the cost-effectiveness plan. Thus, it can be affirmed that the early treatment of chronic hepatitis C is cost-effective, but the change of future guidelines depends on other evaluations by the managers. Key-words: chronic hepatitis C, cost-effectiveness, early treatment, sofosbuvir, daclatasvir, simeprevir.

At the moment, several companies are studying the clinical potential of different all-oral combinations of direct-acting antivirals in ongoing studies. The most promising interferon-free combination therapies that are on the horizon include linear or cyclic NS3/4A protease inhibitors, nucleoside as well as non-nucleoside NS5B polymerase inhibitors , and NS5A inhibitors. DAAs that target NS3/4A (protease) and NS5B (RNA-dependent RNA polymerase) inhibit the enzymatic activity of these proteins. NS5A replication complex inhibitors will likely form a component of future interferon-free drug regimens but despite their remarkable potential to treat chronic hepatitis C, the detailed mechanism of action for this class of drug remains unclear. The goal of my work was to investigate the mechanism of action of different classes of antiviral agents believed to target the NS5A protein in the replication complex in order to improve the possibility to translate basic knowledge to a more meaningful clinical application. More specifically I focused my research on two classes of compounds, characterized by distinct resistance patterns in NS5A: a first class – with examples at the final stages of clinical development, represented by Daclatasvir (Lemm et al., 2011), and a second class - at earlier stages of development - represented by anilino-quinazolines such as A-831/AZD-2836 (Quinkert et al., 2008). I contributed to demonstrate that both of these inhibitor classes, by binding respectively to either HCV NS5A or to an NS5A-associated protein, PI4KIIIα, eventually interfere with the accumulation of PI4P 98 and cholesterol in the HCV replication membranous compartment, thus abrogating the ability of the virus form to replicate its RNA genome.

碩士
中山醫學大學
醫學研究所
104
Introduction: All-oral direct-acting agent dual therapy with Daclatasvir plus Asunaprevir (DCV+ASV) achieved high sustained virological responses (SVR) in genotype 1b (GT-1b) HCV patients in the HALLMARK-DUAL1 study and Phase 3 Japanese study2,3. DCV + ASV is approved in several countries including Taiwan in March, 2016, Japan, Korea, and Latin America, Eastern Europe. In this study, real-world experience of DCV+ASV dual therapy in HCV GT-1b patients was reported. Purpose: To evaluate the efficacy and safety of DCV+ASV therapy in GT-1b HCV infected Taiwanese patients in real-world. Method: Fifty GT-1b HCV infection patients received dual therapy were enrolled at two hospitals in central Taiwan. Five patients (10%) were excluded due to existence of baseline resistance-associated variants (RAVs). Outcomes from 27 patients, who had received 24 weeks dual therapy and been followed up for 24 weeks after end of treatment, were recorded and analyzed. Sustained virologic response at post-treatment week 12 and week 24(SVR12/SVR24) and safety profiles were evaluated. The results were compared with those from HALLMARK-DUAL study. Result: In the real-world group, the mean age was 57 years old ( male/female: 5/ 4); 63% (17/27) patients had advanced liver fibrosis or compensated cirrhosis; 56% patients were treatment-experienced. Virologic response(defined as HCV RNA < LLOQ )at week 4 was 89% (24/27) in the real-world group and74% (477/643) in phase 3 clinical trial group. SVR12 rate was higher than the phase 3 clinical trial group (93 % vs. 84%). SVR12 rates were100% (12/12), 89% (8/9) and 83% (5/6)in treatment-naive, ineligible/intolerant and non-responder patients, respectively. Patients with advanced liver disease or cirrhosis, experience of previous treatment, and higher baseline viral load (HCV RNA ≥ 800,000 IU/mL) had lower SVR 12. The results were similar to those from phase 3 study. Common adverse events included dizziness ( 3/27), pyrexia ( 1/27) and fatigue ( 1/27).There were neither SAE nor AE leading to treatment discontinuation occurred. Conclusion: Daclatasvir plus Asunaprevir were well-tolerated and resulted in a higher SVR rate in the Taiwanese real-world GT-1b HCV patients without baseline NS5A RAVs.

Review question / Objective: P: ("Hepatitis C"[Mesh] AND "Hepacivirus"[Mesh] AND "Hepatitis C, Chronic”[Mesh]) I: (direct acting antiviral OR asunaprevir OR boceprevir OR daclatasvir OR dasabuvir OR elbasvir OR glecaprevir OR grazoprevir OR ledipasvir OR ombitasvir OR paritaprevir OR pibrentasvir OR simeprevir OR sofosbuvir OR telaprevir OR velpatasvir OR voxilaprevir) C: placebo O: ( "Cholesterol, VLDL"[Mesh] OR "Cholesterol, LDL"[Mesh] OR "Cholesterol, HDL"[Mesh] OR "Dyslipidemias"[Mesh] OR "lipoprotein cholesterol ester, human" [Supplementary Concept] OR "lipoprotein cholesterol" [Supplementary Concept] ) OR ((lipoprotein cholesterol) OR ("lipidemia") OR (lipid metabolism) OR (lipid)). Information sources: We conducted a comprehensive literature search of PubMed, Cochrane Library, Embase, and Ovid MEDLINE electronic databases from their inception to May 20, 2022.