RESUMEN
Several purinergic receptors have been identified on platelets which are involved in hemostatic and thrombotic processes. The aim of the present study was to investigate the effects of uridine and its nucleotides on platelet aggregation and hemostasis in platelet-rich plasma (PRP) and whole blood. The effects of uridine, UMP, UDP, and UTP at different final concentrations (1 to 1000 µM) on platelet aggregation were studied using an aggregometer. In PRP samples, platelet aggregation was induced by ADP, collagen and epinephrine 3 min after addition of uridine, UMP, UDP, UTP and saline (as a control). All thromboelastogram experiments were performed at 1000 µM final concentrations of uridine and its nucleotides in whole blood. UDP and UTP were also tested in thromboelastogram with PRP. Our results showed that UDP, and especially UTP, inhibited ADP- and collagen-induced aggregation in a concentration-dependent manner. In whole blood thromboelastogram experiments, UDP stimulated clot formation while UTP suppressed clot formation. When thromboelastogram experiments were repeated with PRP, UTP's inhibitory effect on platelets was confirmed, while UDP's stimulated clot forming effect disappeared. Collectively, our data showed that UTP inhibited platelet aggregation in a concentration-dependent manner and suppressed clot formation. On the other hand, UDP exhibited distinct effects on whole blood or PRP in thromboelastogram. These data suggest that the difference on effects of UTP and UDP might have arisen from the different receptors that they stimulate and warrant further investigation with regard to their in vivo actions on platelet aggregation and hemostasis.
Asunto(s)
Adenosina Trifosfato , Nucleótidos , Humanos , Nucleótidos/farmacología , Uridina/farmacología , Uridina Trifosfato/farmacología , Adenosina Trifosfato/farmacología , Agregación Plaquetaria , Uridina Difosfato/farmacología , Colágeno/farmacología , Uridina Monofosfato/farmacologíaRESUMEN
Tuberculosis claims significantly more than one million lives each year. A feasible way to face the issue of drug resistance is the development of new antibiotics. Bacterial uridine 5'-monophosphate (UMP) kinase is a promising target for novel antibiotic discovery as it is essential for bacterial survival and has no counterpart in human cells. The UMP kinase from M. tuberculosis is also a model of particular interest for allosteric regulation with two effectors, GTP (positive) and UTP (negative). In this study, using X-ray crystallography and cryo-electron microscopy, we report for the first time a detailed description of the negative effector UTP-binding site of a typical Gram-positive behaving UMP kinase. Comparison between this snapshot of low affinity for Mg-ATP with our previous 3D-structure of the GTP-bound complex of high affinity for Mg-ATP led to a better understanding of the cooperative mechanism and the allosteric regulation of UMP kinase. Thermal shift assay and circular dichroism experiments corroborate our model of an inhibition by UTP linked to higher flexibility of the Mg-ATP-binding domain. These new structural insights provide valuable knowledge for future drug discovery strategies targeting bacterial UMP kinases.
Asunto(s)
Antibacterianos , Bacterias Grampositivas , Adenosina Trifosfato , Regulación Alostérica , Secuencia de Aminoácidos , Antibacterianos/farmacología , Microscopía por Crioelectrón , Guanosina Trifosfato/farmacología , Humanos , Nucleósido-Fosfato Quinasa , Uridina Monofosfato/farmacología , Uridina Trifosfato/farmacologíaRESUMEN
A 3'-protected route toward the synthesis of the diastereomers of clinically active ProTides, NUC-1031 and NUC-3373, is described. The in vitro cytotoxic activities of the individual diastereomers were found to be similar to their diastereomeric mixtures. In the KG1a cell line, NUC-1031 and NUC-3373 have preferential cytotoxic effects on leukemic stem cells (LSCs). These effects were not diastereomer-specific and were not observed with the parental nucleoside analogues gemcitabine and FUDR, respectively. In addition, NUC-1031 preferentially targeted LSCs in primary AML samples and cancer stem cells in the prostate cancer cell line, LNCaP. Although the mechanism for this remains incompletely resolved, NUC-1031-treated cells showed increased levels of triphosphate in both LSC and bulk tumor fractions. As ProTides are not dependent on nucleoside transporters, it seems possible that the LSC targeting observed with ProTides may be caused, at least in part, by preferential accumulation of metabolized nucleos(t)ide analogues.
Asunto(s)
Antineoplásicos/farmacología , Citidina Monofosfato/análogos & derivados , Células Madre Neoplásicas/efectos de los fármacos , Uridina Monofosfato/análogos & derivados , Uridina Monofosfato/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Línea Celular Tumoral , Citidina Monofosfato/síntesis química , Citidina Monofosfato/metabolismo , Citidina Monofosfato/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Estabilidad de Medicamentos , Hepatocitos/metabolismo , Humanos , Estereoisomerismo , Uridina Monofosfato/metabolismoRESUMEN
OBJECTIVE: The present study aimed to reveal the factors associated with virologic failure in sofosbuvir and ledipasvir (SOF/LDV)-treated patients, and identify baseline NS5A or NS5B resistance-associated substitutions (RASs). METHODS: Four hundred ninety-three patients with Hepatitis C Virus (HCV) genotype 1b infection were treated with SOF/LDV; 31 had a history of interferon (IFN)-free treatment with daclatasvir and asunaprevir. The effect of baseline RASs on the response to SOF/LDV therapy was analyzed. RESULTS: Overall, a sustained virologic response at 12 weeks (SVR12) was achieved in 476 patients (96.6%). The SVR12 rates in the patients with IFN-free treatment-naïve and retreatment were 97.6% and 80.6%, respectively. HCV elimination was not achieved in 17 patients, 11 (including 5 with IFN-free retreatment) of whom had virologic failure. Eight patients had coexisting NS5A RASs of Q24, L28 and/or R30, L31, or Y93 and one patient had coexisting NS5A RASs of P32L and A92K. Interestingly, 10 and 8 patients had NS5B A218S and C316N RAS respectively. According to a multivariate analysis, coexisting NS5A RASs, NS5A P32 RAS, NS5B A218 and/or C316 RASs, and γ-glutamyltranspeptidase were associated with virologic failure. In the naïve patients, all patients without NS5B A218 and/or C316 RAS achieved an SVR12. Notably, the SVR12 rates of patients with coexisting NS5A and NS5B RASs were significantly lower (83.3%). CONCLUSIONS: Although SOF/LDV therapy resulted in a high SVR12 rate, coexisting NS5A and NS5B RASs were associated with virologic failure. These results might indicate that the coexisting baseline RASs influence the therapeutic effects of SOF/LDV.
Asunto(s)
Bencimidazoles/farmacología , Farmacorresistencia Viral Múltiple/genética , Fluorenos/farmacología , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Uridina Monofosfato/análogos & derivados , Proteínas no Estructurales Virales/genética , Adulto , Anciano , Anciano de 80 o más Años , Bencimidazoles/uso terapéutico , Estudios de Cohortes , Femenino , Fluorenos/uso terapéutico , Genotipo , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/virología , Humanos , Masculino , Persona de Mediana Edad , Sofosbuvir , Respuesta Virológica Sostenida , Insuficiencia del Tratamiento , Uridina Monofosfato/farmacología , Uridina Monofosfato/uso terapéuticoRESUMEN
To identify a potent and selective nucleoside inhibitor of dengue virus RNA-dependent RNA polymerase, a series of 2'- and/or 4'-ribose sugar modified uridine nucleoside phosphoramidate prodrugs and their corresponding triphosphates were synthesized and evaluated. Replacement of 2'-OH with 2'-F led to be a poor substrate for both dengue virus and human mitochondrial RNA polymerases. Instead of 2'-fluorination, the introduction of fluorine at the ribose 4'-position was found not to affect the inhibition of the dengue virus polymerase with a reduction in uptake by mitochondrial RNA polymerase. 2'-C-ethynyl-4'-F-uridine phosphoramidate prodrug displayed potent anti-dengue virus activity in the primary human peripheral blood mononuclear cell-based assay with no significant cytotoxicity in human hepatocellular liver carcinoma cell lines and no mitochondrial toxicity in the cell-based assay using human prostate cancer cell lines.
Asunto(s)
Antivirales/farmacología , Inhibidores Enzimáticos/farmacología , Profármacos/farmacología , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Uridina Monofosfato/análogos & derivados , Uridina Monofosfato/farmacología , Antivirales/química , Antivirales/toxicidad , Virus del Dengue/enzimología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/toxicidad , Células Hep G2 , Humanos , Leucocitos Mononucleares/virología , Estructura Molecular , Sistema Mononuclear Fagocítico/virología , Profármacos/química , Profármacos/toxicidad , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Bencimidazoles/farmacología , Bencimidazoles/farmacocinética , Interacciones Farmacológicas , Fluorenos/farmacología , Fluorenos/farmacocinética , Uridina Monofosfato/análogos & derivados , Humanos , Sofosbuvir , Uridina Monofosfato/farmacocinética , Uridina Monofosfato/farmacologíaRESUMEN
HCV genotype 4 (GT4) has often been overlooked in drug development, even though it infects ~20 million people worldwide. Ledipasvir/sofosbuvir and sofosbuvir/velpatasvir were highly efficacious in GT4 HCV-infected patients from GS-US-337-1119 and GS-US-342-1138. Here, we characterize the resistance profile of ledipasvir (LDV) and velpatasvir (VEL) in patients with GT4 HCV infection. NS5A deep-sequencing was performed for 454 patients infected with HCV GT4 at baseline, including 44 patients enrolled in GS-US-337-1119 and 116 patients enrolled in GS-US-342-1138, and at relapse for patients with virologic failure. LDV and VEL susceptibilities of 56 patient isolates were determined. In GS-US-337-1119, SVR12 rates were 100% for all subtypes except 4b and 4r. Phenotypic assessment of 56 HCV NS5A patient isolates from various GT4 subtypes indicated that LDV had high potency for the common subtypes 4a/d, and subtypes 4c/f/k/l/m/n/o/p/r/t despite the presence of resistance-associated substitutions (RASs). For the rare GT4b, LDV median EC50 was higher, but with a broad range of individual values. Importantly, all GT4b isolates tested had 2-4 NS5A RASs, some including Y93H. Similarly, the 2 GT4r infected patients who had virologic relapse had rare triple RASs. Reversion of these substitutions to the consensus residue significantly increased LDV susceptibility. In GS-US-342-1138, all patients achieved SVR12, regardless of their subtype or presence of RASs. In vitro data confirmed that VEL is potent against all GT4 isolates tested. LDV and VEL are potent antiviral drugs, estimated to be effective against >95% and >99%, respectively, of GT4 HCV isolates.
Asunto(s)
Antivirales/farmacología , Bencimidazoles/farmacología , Carbamatos/farmacología , Farmacorresistencia Viral Múltiple/genética , Fluorenos/farmacología , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Uridina Monofosfato/análogos & derivados , Sustitución de Aminoácidos , Quimioterapia Combinada , Genotipo , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Análisis de Secuencia de ADN , Sofosbuvir , Respuesta Virológica Sostenida , Uridina Monofosfato/farmacología , Proteínas no Estructurales Virales/genéticaRESUMEN
Our objective was to identify drug interactions between ledipasvir (LDV) and sofosbuvir (SOF) against a genotype 1b replicon to determine optimal exposures for each agent that will maximize antiviral activity against susceptible and drug-resistant subpopulations. LDV and SOF were evaluated using a fully factorial experimental design in the BelloCell system. Replicon levels and drug-resistant variants were quantified at various times post-therapy for 14 days and a high-dimensional mathematical model was fit to the data. Mutations associated with SOF resistance were not detected; but LDV-resistant mutants were selected and mutant subpopulations increased as exposure intensity increased. Combination therapy was additive for the total replicon population and the LDV-resistant population, but a threshold concentration of 100 ng/ml of SOF must be attained to suppress LDV-resistant subpopulations. These novel findings hold important implications for not only improving therapeutic outcomes, but also maximizing the clinical utility of LDV and SOF combination regimens.
Asunto(s)
Bencimidazoles/farmacología , Bencimidazoles/uso terapéutico , Farmacorresistencia Viral/genética , Fluorenos/farmacología , Fluorenos/uso terapéutico , Uridina Monofosfato/análogos & derivados , Antivirales/uso terapéutico , Bencimidazoles/metabolismo , Línea Celular , Terapia Combinada , Interacciones Farmacológicas , Farmacorresistencia Viral/efectos de los fármacos , Quimioterapia Combinada , Fluorenos/metabolismo , Genotipo , Hepacivirus/efectos de los fármacos , Hepacivirus/patogenicidad , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Modelos Teóricos , Sofosbuvir/farmacología , Sofosbuvir/uso terapéutico , Uridina Monofosfato/metabolismo , Uridina Monofosfato/farmacología , Uridina Monofosfato/uso terapéuticoRESUMEN
BACKGROUND/AIMS: Direct-acting antiviral agents (DAAs) have increased the sustained viral response rate with minimal adverse effects and short treatment duration. In addition, recent data suggest the possibility that hepatitis C virus (HCV) clearance results in rapid improvement in metabolic pathways. The aim of the present study was to evaluate whether the DAA treatment without ribavirin lowers hemoglobin A1c (HbA1c) at 12 weeks after therapy completion. METHODS: We performed an observational study to assess the effect of sofosbuvir and ledipasvir (SOF/LED) treatment on glycemic control. We compared HbA1c levels before and after treatment with SOF/LED, considering that anemia is not a side effect of these drugs. RESULTS: In the 36 patients with HCV eradication, HbA1c levels decreased significantly after treatment (pre-treatment 5.85% vs. post-treatment 5.65%, p < 0.01). CONCLUSION: This pilot study shows the possibility that HCV eradication by SOF/LED was accompanied by an improvement of glucose metabolism in the population with or without diabetes, and suggests further investigation.
Asunto(s)
Antivirales/farmacología , Bencimidazoles/farmacología , Fluorenos/farmacología , Hemoglobina Glucada/efectos de los fármacos , Hepatitis C/sangre , Hepatitis C/tratamiento farmacológico , Uridina Monofosfato/análogos & derivados , Anciano , Femenino , Hepacivirus/efectos de los fármacos , Hepatitis C/virología , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Sofosbuvir , Respuesta Virológica Sostenida , Uridina Monofosfato/farmacologíaRESUMEN
High sustained virologic response (SVR) rates have been observed after 6 weeks of anti-HCV treatment using sofosbuvir, ledipasvir and a non-nucleoside polymerase-inhibitor (GS-9669) or a protease-inhibitor (GS-9451) and after 12 weeks with sofosbuvir + ledipasvir. Here we analyze the viral kinetics observed during these treatments to decipher the origin of the rapid cure and to evaluate the possibility of further reducing treatment duration. We found that viral kinetics were surprisingly slow in all treatment groups and could not reproduce the high SVR rates observed. Based on experimental results suggesting that NS5A- or protease-inhibitors can generate non-infectious virus, we incorporated this effect into a mathematical model. We found that to predict observed SVR rates it was necessary to assume that ledipasvir, GS-9669 and GS-9451 rapidly reduce virus infectivity. We predicted with this model that 4 weeks of triple therapy could be sufficient to achieve SVR in patients with undetectable viremia at week 1, but would be suboptimal in general. In conclusion, the rapid cure rate achieved with these combinations is largely disconnected from viral loads measured during treatment. A model assuming that rapid cure is due to a drug effect of generating non-infectious virus could be a basis for future response guided therapy.
Asunto(s)
Antivirales/uso terapéutico , Quimioterapia Combinada/métodos , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Sofosbuvir/uso terapéutico , Antivirales/farmacología , Bencimidazoles/farmacología , Bencimidazoles/uso terapéutico , Femenino , Fluorenos/farmacología , Fluorenos/uso terapéutico , Furanos/farmacología , Furanos/uso terapéutico , Hepatitis C Crónica/virología , Humanos , Cinética , Masculino , Modelos Teóricos , Quinolinas/farmacología , Quinolinas/uso terapéutico , Sofosbuvir/farmacología , Respuesta Virológica Sostenida , Tiofenos/farmacología , Tiofenos/uso terapéutico , Resultado del Tratamiento , Uridina Monofosfato/análogos & derivados , Uridina Monofosfato/farmacología , Uridina Monofosfato/uso terapéutico , Carga Viral/efectos de los fármacosRESUMEN
Herein we describe the discovery of IDX21437 35b, a novel RPd-aminoacid-based phosphoramidate prodrug of 2'-α-chloro-2'-ß-C-methyluridine monophosphate. Its corresponding triphosphate 6 is a potent inhibitor of the HCV NS5B RNA-dependent RNA polymerase (RdRp). Despite showing very weak activity in the in vitro Huh-7 cell based HCV replicon assay, 35b demonstrated high levels of active triphosphate 6 in mouse liver and human hepatocytes. A biochemical study revealed that the metabolism of 35b was mainly attributed to carboxyesterase 1 (CES1), an enzyme which is underexpressed in HCV Huh-7-derived replicon cells. Furthermore, due to its metabolic activation, 35b was efficiently processed in liver cells compared to other cell types, including human cardiomyocytes. The selected RP diastereoisomeric configuration of 35b was assigned by X-ray structural determination. 35b is currently in Phase II clinical trials for the treatment of HCV infection.
Asunto(s)
Antivirales/farmacología , ARN Polimerasas Dirigidas por ADN/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Hepacivirus/efectos de los fármacos , Uridina Monofosfato/análogos & derivados , Uridina/farmacología , Animales , Antivirales/síntesis química , Antivirales/química , ARN Polimerasas Dirigidas por ADN/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Hepacivirus/enzimología , Hepatocitos/efectos de los fármacos , Hepatocitos/virología , Humanos , Hígado/efectos de los fármacos , Hígado/virología , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad , Uridina/síntesis química , Uridina/química , Uridina Monofosfato/síntesis química , Uridina Monofosfato/química , Uridina Monofosfato/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/metabolismoRESUMEN
The increase in the number of bacterial strains resistant to known antibiotics is alarming. In this study we report the synthesis of novel compounds termed Lipophosphonoxins II (LPPO II). We show that LPPO II display excellent activities against Gram-positive and -negative bacteria, including pathogens and multiresistant strains. We describe their mechanism of action-plasmatic membrane pore-forming activity selective for bacteria. Importantly, LPPO II neither damage nor cross the eukaryotic plasmatic membrane at their bactericidal concentrations. Further, we demonstrate LPPO II have low propensity for resistance development, likely due to their rapid membrane-targeting mode of action. Finally, we reveal that LPPO II are not toxic to either eukaryotic cells or model animals when administered orally or topically. Collectively, these results suggest that LPPO II are highly promising compounds for development into pharmaceuticals.
Asunto(s)
Antibacterianos/química , Uridina Monofosfato/análogos & derivados , Animales , Antibacterianos/síntesis química , Antibacterianos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Membrana Celular/metabolismo , Supervivencia Celular/efectos de los fármacos , Diseño de Fármacos , Farmacorresistencia Bacteriana Múltiple , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Humanos , Membrana Dobles de Lípidos/química , Masculino , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana , Fosfolípidos/química , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacología , Conejos , Pruebas de Irritación de la Piel , Estereoisomerismo , Relación Estructura-Actividad , Uridina Monofosfato/síntesis química , Uridina Monofosfato/química , Uridina Monofosfato/farmacologíaRESUMEN
BACKGROUND: Patients chronically infected with genotype 3 hepatitis C virus (HCV) have faster disease progression and are less responsive to current direct-acting antiviral regimens than patients infected with other genotypes. We conducted an open-label trial to evaluate the safety, tolerability, and efficacy of ledipasvir and sofosbuvir plus ribavirin in patients with genotype 3 HCV infection. METHODS: We enrolled treatment-naive patients with and without compensated cirrhosis at 15 sites in Canada. All patients were treated with ledipasvir-sofosbuvir (90 mg and 400 mg) plus weight-based ribavirin for 12 weeks. The primary endpoint was sustained virologic response 12 weeks after treatment (SVR12). Secondary endpoints included evaluation of baseline and treatment-emergent drug resistance. RESULTS: Of the 111 patients enrolled, 105 (95%) had subtype 3a HCV and 39 (35%) had compensated cirrhosis. SVR12 was achieved by 99 of 111 patients (89%; 95% confidence interval, 82%-94%). Of the 39 patients with cirrhosis, 31 (79%) achieved SVR12, compared with 68 of 72 (94%) patients without cirrhosis. No treatment-emergent resistance mutations occurred in those who failed treatment. One patient discontinued treatment due to liver cancer and died 22 days after treatment discontinuation. The most common adverse events were fatigue (51%), headache (36%), and nausea (23%). CONCLUSIONS: In this multicenter trial involving treatment-naive patients with genotype 3 HCV, 12 weeks of ledipasvir-sofosbuvir provided a high level of SVR in those without cirrhosis. CLINICAL TRIALS REGISTRATION: NCT02413593.
Asunto(s)
Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Fluorenos/uso terapéutico , Hepacivirus , Hepatitis C Crónica/tratamiento farmacológico , Ribavirina/uso terapéutico , Uridina Monofosfato/análogos & derivados , Adulto , Anciano , Antivirales/efectos adversos , Antivirales/farmacología , Bencimidazoles/efectos adversos , Bencimidazoles/farmacología , Farmacorresistencia Viral/genética , Femenino , Fluorenos/efectos adversos , Fluorenos/farmacología , Genotipo , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepatitis C Crónica/virología , Humanos , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/virología , Masculino , Persona de Mediana Edad , Ribavirina/efectos adversos , Ribavirina/farmacología , Sofosbuvir , Respuesta Virológica Sostenida , Uridina Monofosfato/efectos adversos , Uridina Monofosfato/farmacología , Uridina Monofosfato/uso terapéuticoRESUMEN
INTRODUCTION: The sofosbuvir (SOF) plus ledipasvir (LDV) fixed dose combination is the first direct action antiviral (DAA) single-treatment regimen (STR) to be commercialized. It is approved for the treatment of Hepatitis C virus (HCV) genotypes 1,3,4,5 and 6. Following approval in 2014, new pharmacokinetics and pharmacodynamics data were reported, which led to important clinical applications. Areas covered: This article reviews the pharmacokinetic and pharmacodynamic properties of the SOF/LDV fixed dose combination for the treatment of HCV. The topics covered include data regarding the drug´s absorption, distribution, metabolism and excretion and antiviral activity strategies such as the clinical dose selection and treatment duration. Expert opinion: The SOF/LDV fixed dose combination has good pharmacological properties that lead to a high sustained virological response after 12 or 24 weeks of treatment; there is minimal interference with other drugs or associated renal or hepatic impairment, such that dose adjustment is not necessary.
Asunto(s)
Antivirales/administración & dosificación , Bencimidazoles/administración & dosificación , Fluorenos/administración & dosificación , Hepatitis C/tratamiento farmacológico , Uridina Monofosfato/análogos & derivados , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Relación Dosis-Respuesta a Droga , Fluorenos/farmacocinética , Fluorenos/farmacología , Genotipo , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Hepatitis C/virología , Humanos , Sofosbuvir , Factores de Tiempo , Resultado del Tratamiento , Uridina Monofosfato/administración & dosificación , Uridina Monofosfato/farmacocinética , Uridina Monofosfato/farmacologíaRESUMEN
After decades of intensive research on adenosine-3',5'-cyclic monophosphate (cAMP)- and guanosine-3',5'-cyclic monophosphate (cGMP)-related second messenger systems, also the noncanonical congeners cyclic cytidine-3',5'-monophosphate (cCMP) and cyclic uridine-3',5'-monophosphate (cUMP) gained more and more interest. Until the late 1980s, only a small number of cCMP and cUMP analogs with sometimes undefined purities had been described. Moreover, most of these compounds had been rather synthesized as precursors of antitumor and antiviral nucleoside-5'-monophosphates and hence had not been tested for any second messenger activity. Along with the recurring interest in cCMP- and cUMP-related signaling in the early 2000s, it became evident that well-characterized small molecule analogs with reliable purities would serve as highly valuable tools for the evaluation of a putative second messenger role of cyclic pyrimidine nucleotides. Meanwhile, for this purpose new cCMP and cUMP derivatives have been developed, and already known analogs have been resynthesized and highly purified. This chapter summarizes early medicinal chemistry work on cCMP and cUMP and analogs thereof, followed by a description of recent synthetic developments and an outlook on potential future directions.
Asunto(s)
CMP Cíclico/síntesis química , Nucleótidos Cíclicos/síntesis química , Profármacos/síntesis química , Uridina Monofosfato/síntesis química , Animales , Cristalización , CMP Cíclico/análogos & derivados , CMP Cíclico/metabolismo , CMP Cíclico/farmacología , Humanos , Estructura Molecular , Nucleótidos Cíclicos/metabolismo , Nucleótidos Cíclicos/farmacología , Permeabilidad , Profármacos/metabolismo , Profármacos/farmacología , Uridina Monofosfato/metabolismo , Uridina Monofosfato/farmacologíaRESUMEN
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.
Asunto(s)
Antivirales/farmacocinética , Antivirales/uso terapéutico , Bencimidazoles/farmacocinética , Bencimidazoles/uso terapéutico , Fluorenos/farmacocinética , Fluorenos/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Uridina Monofosfato/análogos & derivados , Animales , Antivirales/farmacología , Área Bajo la Curva , Bencimidazoles/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Fluorenos/farmacología , Semivida , Humanos , Concentración de Iones de Hidrógeno , Fallo Hepático/metabolismo , Tasa de Depuración Metabólica , Insuficiencia Renal/metabolismo , Sofosbuvir , Respuesta Virológica Sostenida , Uridina Monofosfato/farmacocinética , Uridina Monofosfato/farmacología , Uridina Monofosfato/uso terapéuticoRESUMEN
High rates of sustained virologic response (SVR) has been achieved in Japanese patients with chronic hepatitis C virus (HCV) genotype (GT)1 and GT2 infection treated with ledipasvir/sofosbuvir (LDV/SOF) ±ribavirin (RBV) and SOF+RBV, respectively. We evaluated the effect of baseline HCV NS5A and NS5B resistance-associated variants (RAVs) on treatment outcome and characterized variants at virologic failure. Baseline deep sequencing for NS5A and NS5B genes was performed for all GT1 patients. Deep sequencing of NS5A (GT1 only) and NS5B (GT1 and GT2) was performed for patients who failed treatment or discontinued early with detectable HCV RNA (i.e., >25 IU/mL). In patients with HCV GT1 infection, 22.3% (GT1a: 2/11; GT1b: 74/330) had ≥1 baseline NS5A RAV. The most frequent NS5A RAVs in GT1b were Y93H (17.9%, 59/330) and L31M (2.4%, 8/330). Despite the presence of NS5A RAVs at baseline, 100% and 97% of patients achieved SVR12, compared with 100% and 99% for those with no NS5A RAVs with LDV/SOF and LDV/SOF+RBV, respectively. All patients with NS5B RAVs at baseline achieved SVR12. Of the 153 patients with GT2 infection (GT2a 60.1%, GT2b 39.9%), 3.3% (5/153) experienced viral relapse. No S282T or other NS5B RAVs were detected at baseline or relapse; no change in susceptibility to SOF or RBV was observed at relapse. In conclusion, LDV/SOF and SOF+RBV demonstrate a high barrier to resistance in Japanese patients with HCV GT1 and GT2 infection. The presence of baseline NS5A RAVs did not impact treatment outcome in GT1 Japanese patients treated with LDV/SOF for 12 weeks.
Asunto(s)
Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Farmacorresistencia Viral , Fluorenos/uso terapéutico , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Sofosbuvir/uso terapéutico , Uridina Monofosfato/análogos & derivados , Sustitución de Aminoácidos , Antivirales/farmacología , Bencimidazoles/farmacología , Ensayos Clínicos Fase III como Asunto , Fluorenos/farmacología , Genotipo , Hepacivirus/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Japón , Análisis de Secuencia de ADN , Sofosbuvir/farmacología , Resultado del Tratamiento , Uridina Monofosfato/farmacología , Uridina Monofosfato/uso terapéutico , Proteínas no Estructurales Virales/genéticaRESUMEN
PURPOSE OF REVIEW: Novel direct-acting antiviral (DAA) agents are highly effective in the treatment of hepatitis C, achieving unprecedented rates of sustained virological response, a functional cure. However, a significant minority of patients belong to 'difficult-to-treat' groups, in which efficacy of DAAs appears less robust. The review article aims to discuss additional treatment strategies which may be employed in these patient cohorts, as well as evidence for the potential role of experimental DAAs. RECENT FINDINGS: Patients with genotype 3 infection have consistently lower rates of virological clearance following DAA therapy when compared with other genotypes. However, in combination with sofosbuvir, the novel nonstructural protein 5A inhibitor daclatasvir has demonstrated high efficacy in the treatment of noncirrhotic genotype 3 infection. Recent data from phase 2 and 3 clinical studies support the use of currently approved DAA regimens in the treatment of patients with hepatitis C virus and human immunodeficiency virus (HIV) coinfection. Sustained virological response rates in coinfected patients are analogous to those observed in monoinfection, such that HIV infection itself does not pose a barrier to DAA efficacy. In posttransplant populations, DAAs have again shown great potential, with trial data validating use of sofosbuvir/ledipasvir. SUMMARY: Unmet need persists in certain subsets of the hepatitis C patient population. The arrival on scene of novel DAAs is likely to further expand the repertoire of available therapy for these 'difficult-to-treat' groups.