RESUMEN
The combination of the hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor elbasvir and the NS3/4A protease inhibitor grazoprevir is a potent, once-daily therapy indicated for the treatment of chronic HCV infection in individuals coinfected with human immunodeficiency virus (HIV). We explored the pharmacokinetic interactions of elbasvir and grazoprevir with ritonavir and ritonavir-boosted HIV protease inhibitors in three phase 1 trials. Drug-drug interaction trials with healthy participants were conducted to evaluate the effect of ritonavir on the pharmacokinetics of grazoprevir (n = 10) and the potential two-way pharmacokinetic interactions of elbasvir (n = 30) or grazoprevir (n = 39) when coadministered with ritonavir-boosted atazanavir, lopinavir, or darunavir. Coadministration of ritonavir with grazoprevir increased grazoprevir exposure; the geometric mean ratio (GMR) for grazoprevir plus ritonavir versus grazoprevir alone area under the concentration-time curve from 0 to 24 h (AUC0-24) was 1.91 (90% confidence interval [CI]; 1.31 to 2.79). Grazoprevir exposure was markedly increased with coadministration of atazanavir-ritonavir, lopinavir-ritonavir, and darunavir-ritonavir, with GMRs for grazoprevir AUC0-24 of 10.58 (90% CI, 7.78 to 14.39), 12.86 (90% CI, 10.25 to 16.13), and 7.50 (90% CI, 5.92 to 9.51), respectively. Elbasvir exposure was increased with coadministration of atazanavir-ritonavir, lopinavir-ritonavir, and darunavir-ritonavir, with GMRs for elbasvir AUC0-24 of 4.76 (90% CI, 4.07 to 5.56), 3.71 (90% CI, 3.05 to 4.53), and 1.66 (90% CI, 1.35 to 2.05), respectively. Grazoprevir and elbasvir had little effect on atazanavir, lopinavir, and darunavir pharmacokinetics. Coadministration of elbasvir-grazoprevir with atazanavir-ritonavir, lopinavir-ritonavir, or darunavir-ritonavir is contraindicated, owing to an increase in grazoprevir exposure. Therefore, HIV treatment regimens without HIV protease inhibitors should be considered for HCV/HIV-coinfected individuals who are being treated with elbasvir-grazoprevir.
Asunto(s)
Antivirales/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/farmacocinética , Hepatitis C/tratamiento farmacológico , Adulto , Amidas , Antivirales/farmacología , Sulfato de Atazanavir/farmacocinética , Sulfato de Atazanavir/farmacología , Benzofuranos/farmacocinética , Benzofuranos/farmacología , Carbamatos , Ciclopropanos , Darunavir/farmacocinética , Darunavir/farmacología , Interacciones Farmacológicas , Femenino , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , Voluntarios Sanos , Hepacivirus/efectos de los fármacos , Humanos , Imidazoles/farmacocinética , Imidazoles/farmacología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Lopinavir/farmacocinética , Lopinavir/farmacología , Masculino , Persona de Mediana Edad , Quinoxalinas/farmacocinética , Quinoxalinas/farmacología , Ritonavir/farmacocinética , Ritonavir/farmacología , Sulfonamidas , Proteínas no Estructurales Virales/antagonistas & inhibidores , Adulto JovenRESUMEN
BACKGROUND: Elbasvir/grazoprevir is a once-daily fixed-dose combination therapy for the treatment of chronic HCV infection, including HCV/HIV coinfection. OBJECTIVES: To evaluate the pharmacokinetic interaction of elbasvir and grazoprevir with raltegravir or dolutegravir. METHODS: Three open-label trials in healthy adult participants were conducted. In the raltegravir trials, participants received a single dose of raltegravir 400 mg, a single dose of elbasvir 50 mg or grazoprevir 200 mg, and raltegravir with either elbasvir or grazoprevir. In the dolutegravir trial, participants received a single dose of dolutegravir 50 mg alone or co-administered with once-daily elbasvir 50 mg and grazoprevir 200 mg. RESULTS: The raltegravir AUC0-∞ geometric mean ratio (GMR) (90% CI) was 1.02 (0.81-1.27) with elbasvir and 1.43 (0.89-2.30) with grazoprevir. Dolutegravir AUC0-∞ GMR (90% CI) was 1.16 (1.00-1.34) with elbasvir and grazoprevir. The elbasvir AUC0-∞ GMR (90% CI) was 0.81 (0.57-1.17) with raltegravir and 0.98 (0.93-1.04) with dolutegravir. The grazoprevir AUC0-24 GMR (90% CI) was 0.89 (0.72-1.09) with raltegravir and 0.81 (0.67-0.97) with dolutegravir. CONCLUSIONS: Elbasvir or grazoprevir co-administered with raltegravir or dolutegravir resulted in no clinically meaningful drug-drug interactions and was generally well tolerated. These results support the assertion that no dose adjustments for elbasvir, grazoprevir, raltegravir or dolutegravir are needed for co-administration in HCV/HIV-coinfected people.
Asunto(s)
Antivirales/uso terapéutico , Coinfección/tratamiento farmacológico , Interacciones Farmacológicas , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/uso terapéutico , Hepatitis C/tratamiento farmacológico , Adulto , Amidas , Terapia Antirretroviral Altamente Activa , Antivirales/administración & dosificación , Antivirales/efectos adversos , Antivirales/farmacocinética , Benzofuranos/administración & dosificación , Benzofuranos/efectos adversos , Benzofuranos/farmacocinética , Benzofuranos/uso terapéutico , Carbamatos , Cromatografía Liquida , Ciclopropanos , Monitoreo de Drogas , Quimioterapia Combinada , Femenino , Infecciones por VIH/virología , Inhibidores de Integrasa VIH/administración & dosificación , Inhibidores de Integrasa VIH/efectos adversos , Inhibidores de Integrasa VIH/farmacocinética , Hepatitis C/virología , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Imidazoles/farmacocinética , Imidazoles/uso terapéutico , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Oxazinas , Piperazinas , Piridonas , Quinoxalinas/administración & dosificación , Quinoxalinas/efectos adversos , Quinoxalinas/farmacocinética , Quinoxalinas/uso terapéutico , Raltegravir Potásico/administración & dosificación , Raltegravir Potásico/efectos adversos , Raltegravir Potásico/uso terapéutico , Sulfonamidas , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: To describe the phase 1 and population pharmacokinetic investigations that support dosing recommendations for elbasvir/grazoprevir (EBR/GZR) in hepatitis C virus-infected people with advanced chronic kidney disease. METHODS: This was an open-label, two-part, multiple-dose trial (MK-5172 PN050; NCT01937975) in 24 non-HCV-infected participants with end-stage renal disease (ESRD) or severe renal impairment who received once-daily EBR 50 mg and GZR 100 mg for 10 days. Population pharmacokinetic analyses from the phase 3 C-SURFER study (PN052, NCT02092350) were also conducted. RESULTS: When comparing haemodialysis (HD) and non-HD days in participants with ESRD, geometric mean ratios (GMRs) (90% confidence intervals [CIs]) for EBR and GZR AUC0-24 were 1.14 (1.08-1.21) and 0.97 (0.87-1.09). When comparing ESRD and healthy participants, GMRs (90% CIs) for EBR and GZR AUC0-24 were 0.99 (0.75-1.30) and 0.83 (0.56-1.22) on HD days, and 0.86 (0.65-1.14) and 0.85 (0.58-1.25) on non-HD days. GMRs (90% CIs) for AUC0-24 in participants with severe renal impairment relative to healthy controls were 1.65 (1.09-2.49) for GZR and 1.86 (1.38-2.51) for EBR. In population modelling of data from C-SURFER, absolute geometric means of steady-state EBR AUC0-24 were 2.78 and 3.07 µM*h (HD and non-HD recipients) and GZR AUC0-24 were 1.80 and 2.34 µM*h (HD and non-HD recipients). CONCLUSIONS: EBR/GZR represents an important treatment option for HCV infection in people with severe renal impairment and those with ESRD. No dosage adjustment of EBR/GZR is required in people with any degree of renal impairment, including those receiving dialysis.
Asunto(s)
Antivirales/farmacocinética , Benzofuranos/farmacocinética , Imidazoles/farmacocinética , Fallo Renal Crónico/tratamiento farmacológico , Quinoxalinas/farmacocinética , Adulto , Amidas , Benzofuranos/sangre , Benzofuranos/uso terapéutico , Carbamatos , Ciclopropanos , Quimioterapia Combinada , Femenino , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/fisiopatología , Humanos , Imidazoles/sangre , Imidazoles/uso terapéutico , Fallo Renal Crónico/terapia , Fallo Renal Crónico/virología , Masculino , Persona de Mediana Edad , Quinoxalinas/sangre , Quinoxalinas/uso terapéutico , Diálisis Renal , SulfonamidasRESUMEN
Grazoprevir (GZR) plus elbasvir is an approved treatment for chronic infection with hepatitis C virus (HCV) genotype 1 or 4. HCV infection complications include liver cirrhosis, end-stage liver disease, and hepatocellular carcinoma. The objective of this study was to evaluate the pharmacokinetics and safety of multiple-dose GZR (200, 100, or 50 mg) in non-HCV participants with mild, moderate, or severe hepatic impairment (HI), respectively, and in healthy matched controls (protocol MK-5172_p013; Merck & Co., Inc., Kenilworth, NJ). Participants with mild, moderate, or severe HI and controls (aged 18 to 65 years) matched for race, age, sex, and body mass index were enrolled in a 3-part, open-label, sequential-panel pharmacokinetic study. Participants received oral doses of GZR 200 mg (two 100-mg tablets), 100 mg (one 100-mg tablet), or 50 mg (two 25-mg tablets) once daily for 10 days. A total of 50 participants were enrolled: 8 with mild HI, 9 with moderate HI, 8 with severe HI, and a corresponding number of healthy matched controls for each hepatic cohort. Participants with HI demonstrated higher GZR exposure than healthy matched controls and showed an increase in exposure with increasing HI severity. The steady-state GZR AUC0-24 (area under the concentration-time curve from 0 to 24 h) for participants with mild, moderate, or severe HI was ≈2-, ≈5-, or ≈12-fold higher, respectively, than that for healthy matched controls. GZR was generally well tolerated in participants with HI. No dose adjustment is required for GZR in people with HCV with mild HI. GZR is contraindicated for those with moderate or severe HI (Child-Pugh class B or C), since they may have significantly increased GZR exposures that may lead to an increased risk of transaminase elevation.
Asunto(s)
Antivirales/uso terapéutico , Benzofuranos/uso terapéutico , Hepacivirus/efectos de los fármacos , Insuficiencia Hepática/metabolismo , Hepatitis C Crónica/tratamiento farmacológico , Imidazoles/uso terapéutico , Inhibidores de Proteasas/uso terapéutico , Quinoxalinas/farmacocinética , Quinoxalinas/uso terapéutico , Adolescente , Adulto , Anciano , Amidas , Antivirales/efectos adversos , Antivirales/farmacocinética , Carbamatos , Ciclopropanos , Quimioterapia Combinada , Femenino , Hepacivirus/enzimología , Humanos , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Inhibidores de Proteasas/farmacocinética , Quinoxalinas/efectos adversos , Sulfonamidas , Adulto JovenRESUMEN
BACKGROUND & AIMS: MK-5172 is an inhibitor of the hepatitis C virus (HCV) nonstructural protein 3/4A protease; MK-5172 is taken once daily and has a higher potency and barrier to resistance than licensed protease inhibitors. We investigated the efficacy and tolerability of MK-5172 with peginterferon and ribavirin (PR) in treatment-naive patients with chronic HCV genotype 1 infection without cirrhosis. METHODS: We performed a multicenter, double-blind, randomized, active-controlled, dose-ranging, response-guided therapy study. A total of 332 patients received MK-5172 (100, 200, 400, or 800 mg) once daily for 12 weeks in combination with PR. Patients in the MK-5172 groups received PR for an additional 12 or 36 weeks, based on response at week 4. Patients in the control group (n = 66) received a combination of boceprevir and PR, dosed in accordance with boceprevir's US product circular. RESULTS: At 24 weeks after the end of therapy, sustained virologic responses were achieved in 89%, 93%, 91%, and 86% of the patients in the groups given the combination of PR and MK-5172 (100, 200, 400, or 800 mg), respectively, vs 61% of controls. In the MK-5172 group receiving 100 mg, 91% of patients had undetectable levels of HCV RNA at week 4 and qualified for the short duration of therapy. The combination of MK-5172 and PR generally was well tolerated. Transient increases in transaminase levels were noted in the MK-5172 groups given 400 and 800 mg, at higher frequencies than in the MK-5172 groups given 100 or 200 mg, or control groups. CONCLUSIONS: Once-daily MK-5172 (100 mg) with PR for 24 or 48 weeks was highly effective and well tolerated among treatment-naive patients with HCV genotype 1 infection without cirrhosis. Studies are underway to evaluate interferon-free MK-5172-based regimens. ClinicalTrials.gov number: NCT01353911.
Asunto(s)
Antivirales/uso terapéutico , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , Quinoxalinas/uso terapéutico , Ribavirina/uso terapéutico , Adolescente , Adulto , Anciano , Amidas , Antivirales/administración & dosificación , Antivirales/efectos adversos , Biomarcadores/sangre , Carbamatos , Ciclopropanos , Método Doble Ciego , Esquema de Medicación , Quimioterapia Combinada , Femenino , Genotipo , Hepacivirus/genética , Hepacivirus/crecimiento & desarrollo , Hepatitis C/diagnóstico , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Interferón-alfa/efectos adversos , Masculino , Persona de Mediana Edad , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Prolina/análogos & derivados , Prolina/uso terapéutico , Quinoxalinas/administración & dosificación , Quinoxalinas/efectos adversos , ARN Viral/sangre , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéutico , Ribavirina/administración & dosificación , Ribavirina/efectos adversos , Sulfonamidas , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
In our efforts to develop CGRP receptor antagonists as backups to MK-3207, 2, we employed a scaffold hopping approach to identify a series of novel oxazolidinone-based compounds. The development of a structurally diverse, potent (20, cAMP+HS IC50=0.67 nM), and selective compound (hERG IC50=19 µM) with favorable rodent pharmacokinetics (F=100%, t1/2=7h) is described. Key to this development was identification of a 3-substituted spirotetrahydropyran ring that afforded a substantial gain in potency (10 to 35-fold).
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Trastornos Migrañosos/tratamiento farmacológico , Oxazolidinonas/farmacología , Oxazolidinonas/uso terapéutico , Animales , Relación Dosis-Respuesta a Droga , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Oxazolidinonas/síntesis química , Oxazolidinonas/química , Ratas , Relación Estructura-ActividadRESUMEN
HCV NS3/4a protease inhibitors are proven therapeutic agents against chronic hepatitis C virus infection, with boceprevir and telaprevir having recently received regulatory approval as add-on therapy to pegylated interferon/ribavirin for patients harboring genotype 1 infections. Overcoming antiviral resistance, broad genotype coverage, and a convenient dosing regimen are important attributes for future agents to be used in combinations without interferon. In this communication, we report the preclinical profile of MK-5172, a novel P2-P4 quinoxaline macrocyclic NS3/4a protease inhibitor currently in clinical development. The compound demonstrates subnanomolar activity against a broad enzyme panel encompassing major hepatitis C virus (HCV) genotypes as well as variants resistant to earlier protease inhibitors. In replicon selections, MK-5172 exerted high selective pressure, which yielded few resistant colonies. In both rat and dog, MK-5172 demonstrates good plasma and liver exposures, with 24-h liver levels suggestive of once-daily dosing. When administered to HCV-infected chimpanzees harboring chronic gt1a or gt1b infections, MK-5172 suppressed viral load between 4 to 5 logs at a dose of 1 mg/kg of body weight twice daily (b.i.d.) for 7 days. Based on its preclinical profile, MK-5172 is anticipated to be broadly active against multiple HCV genotypes and clinically important resistance variants and highly suited for incorporation into newer all-oral regimens.
Asunto(s)
Hepacivirus/efectos de los fármacos , Inhibidores de Proteasas/farmacología , Quinoxalinas/farmacología , Quinoxalinas/farmacocinética , Proteínas no Estructurales Virales/antagonistas & inhibidores , Amidas , Animales , Antivirales/farmacología , Carbamatos , Ciclopropanos , Perros , Farmacorresistencia Viral , Genotipo , Hepacivirus/enzimología , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Hígado/efectos de los fármacos , Pan troglodytes , Quinoxalinas/metabolismo , Ratas , Sulfonamidas , Carga Viral/efectos de los fármacosRESUMEN
We describe the discovery of potent and orally bioavailable tetrahydropyridopyrimidine inhibitors of phosphodiesterase 10A by systematic optimization of a novel HTS lead. Lead compound THPP-1 exhibits nanomolar potencies, excellent pharmacokinetic properties, and a clean off-target profile. It displays in vivo target engagement as measured by increased rat striatal cGMP levels upon oral dosing. It shows dose-dependent efficacy in a key pharmacodynamic assay predictive of antipsychotic activity, the psychostimulant-induced rat hyperlocomotion assay. Further, THPP-1 displays significantly fewer preclinical adverse events in assays measuring prolactin secretion, catalepsy, and weight gain, in contrast to the typical and atypical antipsychotics haloperidol and olanzapine.
Asunto(s)
Descubrimiento de Drogas , Inhibidores de Fosfodiesterasa/uso terapéutico , Piridinas/farmacología , Pirimidinas/farmacología , Esquizofrenia/tratamiento farmacológico , Administración Oral , Animales , GMP Cíclico/análisis , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Inhibidores de Fosfodiesterasa/administración & dosificación , Inhibidores de Fosfodiesterasa/química , Hidrolasas Diéster Fosfóricas/metabolismo , Piridinas/administración & dosificación , Piridinas/química , Pirimidinas/administración & dosificación , Pirimidinas/química , Ratas , Relación Estructura-ActividadRESUMEN
Rational modification of the clinically tested CGRP receptor antagonist MK-3207 (3) afforded an analogue with increased unbound fraction in rat plasma and enhanced aqueous solubility, 2-[(8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(6S)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridin]-3-yl]acetamide (MK-8825) (6). Compound 6 maintained similar affinity to 3 at the human and rat CGRP receptors but possessed significantly improved in vivo potency in a rat pharmacodynamic model. The overall profile of 6 indicates it should find utility as a rat tool to investigate effects of CGRP receptor blockade in vivo.
Asunto(s)
Analgésicos/síntesis química , Analgésicos/farmacología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Trastornos Migrañosos/tratamiento farmacológico , Piridinas/síntesis química , Piridinas/farmacología , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Administración Oral , Analgésicos/sangre , Animales , Disponibilidad Biológica , Modelos Animales de Enfermedad , Perros , Humanos , Macaca mulatta , Ratones , Piridinas/sangre , Ratas , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Especificidad de la Especie , Compuestos de Espiro/sangreRESUMEN
A series of macrocyclic compounds containing a cyclic constraint in the P2-P4 linker region have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K, A156T, A156V, and D168V mutant activity while maintaining high rat liver exposure. The effect of the constraint is most dramatic against gt 1b A156 mutants where ~20-fold improvements in potency are achieved by introduction of a variety of ring systems into the P2-P4 linker.
Asunto(s)
Proteínas Portadoras/antagonistas & inhibidores , Hepacivirus/enzimología , Compuestos Macrocíclicos/química , Inhibidores de Proteasas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Sitios de Unión , Proteínas Portadoras/metabolismo , Dominio Catalítico , Ciclización , Genotipo , Semivida , Hepacivirus/genética , Péptidos y Proteínas de Señalización Intracelular , Cinética , Hígado/metabolismo , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/farmacocinética , Simulación del Acoplamiento Molecular , Mutación , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Ratas , Relación Estructura-Actividad , Proteínas no Estructurales Virales/metabolismoRESUMEN
A series of macrocyclic compounds containing 2-substituted-quinoline moieties have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K mutant activity while maintaining the high rat liver exposure. Cyclization of the 2-substituted quinoline substituent led to a series of tricyclic P2 compounds which also display superb gt3a potency.
Asunto(s)
Proteínas Portadoras/antagonistas & inhibidores , Hepacivirus/enzimología , Compuestos Macrocíclicos/química , Inhibidores de Proteasas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Proteínas Portadoras/metabolismo , Ciclización , Genotipo , Semivida , Hepacivirus/genética , Péptidos y Proteínas de Señalización Intracelular , Cinética , Hígado/metabolismo , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/farmacocinética , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacocinética , Quinolinas/química , Ratas , Relación Estructura-Actividad , Proteínas no Estructurales Virales/metabolismoRESUMEN
Inhibitory effects of asunaprevir, daclatasvir, grazoprevir, paritaprevir, simeprevir, and voxilaprevir, direct-acting antiviral (DAA) drugs for the treatment of chronic hepatitis C virus (HCV) infection, were evaluated in vitro against a range of clinically important drug transporters. In vitro inhibition studies were conducted using transporter transfected cells and membrane vesicles. The risk of clinical drug-drug interactions (DDIs) was assessed using simplified static models recommended by regulatory agencies. Furthermore, we refined and developed static models to predict complex DDIs with several statins (pitavastatin, rosuvastatin, atorvastatin, and pravastatin) by mechanistically assessing differential inhibitory effects of perpetrator drugs on multiple transporters, such as organic anion transporting polypeptides (OATP1B), breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2), organic anion transporter 3 (OAT3), and cytochrome P450 CYP3A enzyme, as they are known to contribute to absorption, distribution, metabolism and excretion (ADME) of above statins. These models successfully predicted a total of 46 statin DDIs, including above DAA drugs and their fix-dose combination regimens. Predicted plasma area under curve ratio (AUCR) with and without perpetrator drugs was within ~ 2-fold of observed values. In contrast, simplified static R-value model resulted in increased false negative and false positive predictions when different prediction cut-off values were applied. Our studies suggest that mechanistic static model is a promising and useful tool to provide more accurate prediction of the risk and magnitude of DDIs with statins in early drug development and may help to improve the management of clinical DDIs for HCV drugs to ensure effective and safe HCV therapy. GRAPHICAL ABSTRACT.
Asunto(s)
Hepatitis C Crónica , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Antivirales , Interacciones Farmacológicas , Hepacivirus/metabolismo , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Proteínas de Transporte de Membrana/metabolismo , Proteínas de Neoplasias/metabolismoRESUMEN
BACKGROUND: Many people infected with hepatitis C virus have comorbidities, including hypercholesterolemia, that are treated with statins. In this study, we evaluated the drug-drug interaction potential of the hepatitis C virus inhibitors elbasvir (EBR) and grazoprevir (GZR) with statins. Pitavastatin, rosuvastatin, pravastatin, and atorvastatin are substrates of organic anion-transporting polypeptide 1B, whereas rosuvastatin and atorvastatin are also breast cancer resistance protein substrates. METHODS: Three open-label, phase I clinical trials in healthy adults were conducted with multiple daily doses of oral GZR or EBR/GZR and single oral doses of statins. Trial 1: GZR 200 mg plus pitavastatin 10 mg. Trial 2: Part 1, GZR 200 mg plus rosuvastatin 10 mg, then EBR 50 mg/GZR 200 mg plus rosuvastatin 10 mg; Part 2, EBR 50 mg/GZR 200 mg plus pravastatin 40 mg. Trial 3: EBR 50 mg/GZR 200 mg plus atorvastatin 10 mg. RESULTS: Neither GZR nor EBR pharmacokinetics were meaningfully affected by statins. Coadministration of EBR/GZR did not result in clinically relevant changes in the exposure of pitavastatin or pravastatin. However, EBR/GZR increased exposure to rosuvastatin (126%) and atorvastatin (94%). Coadministration of statins plus GZR or EBR/GZR was generally well tolerated. CONCLUSIONS: Although statins do not appreciably affect EBR or GZR pharmacokinetics, EBR/GZR can impact the pharmacokinetics of certain statins, likely via inhibition of breast cancer resistance protein but not organic anion-transporting polypeptide 1B. Coadministration of EBR/GZR with pitavastatin or pravastatin does not require adjustment of either dose of statin, whereas the dose of rosuvastatin and atorvastatin should be decreased when coadministered with EBR/GZR.
Asunto(s)
Amidas/farmacocinética , Antivirales/farmacocinética , Benzofuranos/farmacocinética , Carbamatos/farmacocinética , Ciclopropanos/farmacocinética , Imidazoles/farmacocinética , Quinoxalinas/farmacocinética , Sulfonamidas/farmacocinética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Adolescente , Adulto , Atorvastatina/farmacocinética , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Pravastatina/farmacocinética , Quinolinas/farmacocinética , Rosuvastatina Cálcica/farmacocinética , Adulto JovenRESUMEN
The 14th edition of the Workshop on Recent Issues in Bioanalysis (14th WRIB) was held virtually on June 15-29, 2020 with an attendance of over 1000 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations, and regulatory agencies worldwide. The 14th WRIB included three Main Workshops, seven Specialized Workshops that together spanned 11 days in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy, cell therapy and vaccine. Moreover, a comprehensive vaccine assays track; an enhanced cytometry track and updated Industry/Regulators consensus on BMV of biotherapeutics by Mass Spectrometry (hybrid assays, LCMS and HRMS) were special features in 2020. As in previous years, this year's WRIB continued to gather a wide diversity of international industry opinion leaders and regulatory authority experts working on both small and large molecules to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance and achieving scientific excellence on bioanalytical issues. This 2020 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the Global Bioanalytical Community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2020 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication covers the recommendations on (Part 1) Hybrid Assays, Innovation in Small Molecules, & Regulated Bioanalysis. Part 2A (BAV, PK LBA, Flow Cytometry Validation and Cytometry Innovation), Part 2B (Regulatory Input) and Part 3 (Vaccine, Gene/Cell Therapy, NAb Harmonization and Immunogenicity) are published in volume 13 of Bioanalysis, issues 5, and 6 (2021), respectively.
Asunto(s)
Bioensayo/métodos , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Terapia Genética/métodos , Espectrometría de Masas/métodos , Historia del Siglo XXI , HumanosRESUMEN
The administration of hepatitis C virus (HCV) NS3/4A protease inhibitors to patients with chronic HCV infections has demonstrated that they have dramatic antiviral effects and that compounds acting via this mechanism are likely to form a key component of future anti-HCV therapy. We report here on the preclinical profile of MK-7009, an inhibitor of genotype 1a and 1b proteases at subnanomolar concentrations with modestly shifted potency against genotype 2a and 2b proteases at low nanomolar concentrations. Potent activity was also observed in a cell-based HCV replicon assay in the presence of added human serum (50%). In multiple species evaluated in preclinical studies, the MK-7009 concentrations in the liver were maintained at a significant multiple of the cell-based replicon 50% effective concentration over 12 to 24 h following the administration of moderate oral doses (5 to 10 mg per kg of body weight). MK-7009 also had excellent selectivity against both a range of human proteases and a broad panel of pharmacologically relevant ion channels, receptors, and enzymes. On the basis of this favorable profile, MK-7009 was selected for clinical development and is currently being evaluated in controlled clinical trials with both healthy volunteers and HCV-infected patients.
Asunto(s)
Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Indoles/farmacología , Inhibidores de Proteasas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/farmacocinética , Área Bajo la Curva , Línea Celular , Ciclopropanos , Perros , Genotipo , Semivida , Hepacivirus/enzimología , Hepacivirus/genética , Humanos , Indoles/farmacocinética , Interferón alfa-2 , Interferón-alfa/farmacología , Isoindoles , Lactamas Macrocíclicas , Leucina/análogos & derivados , Macaca mulatta , Pan troglodytes , Prolina/análogos & derivados , Inhibidores de Proteasas/farmacocinética , Ratas , Proteínas Recombinantes , Replicón , Especificidad por Sustrato , Sulfonamidas , Proteínas no Estructurales Virales/genéticaRESUMEN
Administration of Neuropeptide S (NPS) has been shown to produce arousal, that is, independent of novelty and to induce wakefulness by suppressing all stages of sleep, as demonstrated by EEG recordings in rat. Medicinal chemistry efforts have identified a quinolinone class of potent NPSR antagonists that readily cross the blood-brain barrier. We detail here optimization efforts resulting in the identification of a potent NPSR antagonist which dose-dependently and specifically inhibited (125)I-NPS binding in the CNS when administered to rats.
Asunto(s)
Receptores de Neuropéptido/antagonistas & inhibidores , Amidas/síntesis química , Amidas/química , Amidas/farmacología , Animales , Barrera Hematoencefálica/metabolismo , Sistema Nervioso Central/metabolismo , Humanos , Radioisótopos de Yodo/química , Unión Proteica , Quinolonas/síntesis química , Quinolonas/química , Quinolonas/farmacología , Ratas , Receptores de Neuropéptido/metabolismo , Relación Estructura-ActividadRESUMEN
Fine-needle aspiration (FNA) for serial hepatic sampling may be an efficient and less invasive alternative to core needle biopsy (CNB), the current standard for liver tissue sampling. In this randomized, open-label trial in 31 participants with hepatitis C virus genotype 1 infection (NCT01678131/Merck protocol PN048), we evaluated the feasibility of using FNA to obtain human liver tissue samples appropriate for measuring hepatic pharmacokinetics (PK), using vaniprevir as a tool compound. The primary end point was successful retrieval of liver tissue specimens with measurable vaniprevir concentrations at two of three specified FNA time points. Twenty-nine patients met the primary end point and, therefore, were included in the PK analyses. Hepatic vaniprevir concentrations obtained with FNA were consistent with known vaniprevir PK properties. The shape of liver FNA and CNB concentration-time profiles were comparable. In conclusion, FNA may be effective for serial tissue sampling to assess hepatic drug exposure in patients with liver disease.
Asunto(s)
Antivirales/farmacocinética , Biopsia con Aguja Fina/métodos , Ciclopropanos/farmacocinética , Hepatitis C Crónica/tratamiento farmacológico , Isoindoles/farmacocinética , Lactamas Macrocíclicas/farmacocinética , Leucina/análogos & derivados , Hígado/metabolismo , Prolina/análogos & derivados , Sulfonamidas/farmacocinética , Adulto , Antivirales/administración & dosificación , Ciclopropanos/administración & dosificación , Femenino , Genotipo , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/virología , Humanos , Isoindoles/administración & dosificación , Lactamas Macrocíclicas/administración & dosificación , Leucina/administración & dosificación , Leucina/farmacocinética , Hígado/virología , Masculino , Persona de Mediana Edad , Prolina/administración & dosificación , Prolina/farmacocinética , Sulfonamidas/administración & dosificación , Distribución Tisular , Adulto JovenRESUMEN
Treatment of individuals coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) requires careful consideration of potential drug-drug interactions. The pharmacokinetic interaction of the HCV fixed-dose combination treatment of elbasvir/grazoprevir (EBR/GZR) when coadministered with the fixed-dose combination HIV treatment of elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine (EVG/COB/TDF/FTC) was evaluated in 22 healthy adults. In period 1, oral doses of EVG/COB/TDF/FTC (150 mg/150 mg/300 mg/200 mg) were administered once daily for 7 days. In period 2, oral doses of EBR/GZR (50 mg/100 mg) were administered once daily for 10 days. In period 3, oral doses of EVG/COB/TDF/FTC were coadministered with EBR/GZR once daily for 10 days. The pharmacokinetics of EVG/COB/TDF/FTC were not clinically meaningfully altered by concomitant EBR/GZR administration. Geometric mean ratios (90%CIs) for area under the plasma concentration-time curve from time 0 to 24 hours (AUC0-24 ) in the presence/absence of EBR/GZR were 1.1 (1.0, 1.2) for elvitegravir; 1.1 (1.0, 1.1) for emtricitabine; 1.2 (1.1, 1.2) for tenofovir; and 1.5 (1.4, 1.6) for cobicistat. In comparison, the AUC0-24 of elbasvir was â¼2 times higher and the AUC0-24 of grazoprevir was â¼5 times higher following concomitant administration of EVG/COB/TDF/FTC and EBR/GZR. Geometric mean ratios (90%CI) for AUC0-24 in the presence/absence of EVG/COB/TDF/FTC were 2.2 (2.0, 2.4) for elbasvir and 5.4 (4.5, 6.4) for grazoprevir. Coadministration of EVG/COB/TDF/FTC and EBR/GZR was generally well tolerated in healthy adults in this study. Nevertheless, because of the increased GZR exposure that occurs with coadministration of EVG/COB/TDF/FTC and EBR/GZR, coadministration of this combination is not recommended in those coinfected with HIV and HCV.
Asunto(s)
Benzofuranos/farmacocinética , Cobicistat/farmacocinética , Emtricitabina/farmacocinética , Imidazoles/farmacocinética , Quinolonas/farmacocinética , Quinoxalinas/farmacocinética , Tenofovir/farmacocinética , Administración Oral , Adulto , Área Bajo la Curva , Benzofuranos/administración & dosificación , Cobicistat/administración & dosificación , Esquema de Medicación , Combinación de Medicamentos , Interacciones Farmacológicas , Emtricitabina/administración & dosificación , Femenino , Voluntarios Sanos , Humanos , Imidazoles/administración & dosificación , Masculino , Persona de Mediana Edad , Quinolonas/administración & dosificación , Quinoxalinas/administración & dosificación , Tenofovir/administración & dosificaciónRESUMEN
Treatment of individuals coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) requires careful consideration of potential drug-drug interactions. We evaluated the pharmacokinetic interaction of the direct-acting antiviral agents elbasvir and grazoprevir coadministered with the nucleotide reverse transcriptase inhibitor tenofovir disoproxil fumarate (TDF). Three open-label, multidose studies in healthy adults were conducted. In the first study (N = 10), participants received TDF 300 mg once daily, elbasvir 50 mg once daily, and elbasvir coadministered with TDF. In the second study (N = 12), participants received TDF 300 mg once daily, grazoprevir 200 mg once daily, and grazoprevir coadministered with TDF. In the third study (N = 14), participants received TDF 300 mg once daily and TDF 300 mg coadministered with coformulated elbasvir/grazoprevir 50 mg/100 mg once daily. Pharmacokinetics and safety were evaluated. Following coadministration, the tenofovir area under the plasma concentration-time curve to 24 hours and maximum plasma concentration geometric mean ratios (90% confidence intervals) for tenofovir and coadministered drug(s) versus tenofovir were 1.3 (1.2, 1.5) and 1.5 (1.3, 1.6), respectively, when coadministered with elbasvir; 1.2 (1.1, 1.3) and 1.1 (1.0, 1.2), respectively, when coadministered with grazoprevir; and 1.3 (1.2, 1.4) and 1.1 (1.0, 1.4), respectively, when coadministered with the elbasvir/grazoprevir coformulation. TDF had minimal effect on elbasvir and grazoprevir pharmacokinetics. Elbasvir and/or grazoprevir coadministered with TDF resulted in no clinically meaningful tenofovir exposure increases and was generally well tolerated, with no deaths, serious adverse events (AEs), discontinuations due to AEs, or laboratory AEs reported. No dose adjustments for elbasvir/grazoprevir or TDF are needed for coadministration in HCV/HIV-coinfected people.
Asunto(s)
Antivirales/farmacocinética , Benzofuranos/farmacocinética , Imidazoles/farmacocinética , Quinoxalinas/farmacocinética , Inhibidores de la Transcriptasa Inversa/farmacocinética , Tenofovir/farmacocinética , Adulto , Antivirales/administración & dosificación , Antivirales/efectos adversos , Área Bajo la Curva , Benzofuranos/administración & dosificación , Benzofuranos/efectos adversos , Esquema de Medicación , Combinación de Medicamentos , Interacciones Farmacológicas , Femenino , VIH/efectos de los fármacos , Voluntarios Sanos , Hepacivirus/efectos de los fármacos , Humanos , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Masculino , Persona de Mediana Edad , Quinoxalinas/administración & dosificación , Quinoxalinas/efectos adversos , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Inhibidores de la Transcriptasa Inversa/efectos adversos , Tenofovir/administración & dosificación , Tenofovir/efectos adversos , Adulto JovenRESUMEN
The 2019 13th Workshop on Recent Issues in Bioanalysis (WRIB) took place in New Orleans, LA, USA on April 1-5, 2019 with an attendance of over 1000 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, week-long event - a full immersion week of bioanalysis, biomarkers, immunogenicity and gene therapy. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small- and large-molecule bioanalysis involving LCMS, hybrid LBA/LCMS, LBA cell-based/flow cytometry assays and qPCR approaches. This 2019 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2019 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 1) covers the recommendations on Innovation in Small Molecules and Oligonucleotides & Mass Spec Method Development Strategies for Large Molecules Bioanalysis. Part 2 (2018 FDA BMV Guidance, 2019 ICH M10 BMV Draft Guideline and regulatory agencies' input on bioanalysis, biomarkers, immunogenicity and gene therapy) and Part 3 (New Insights in Biomarkers Assays Validation, Current & Effective Strategies for Critical Reagent Management, Flow Cytometry Validation in drug discovery & development & CLSI H62, Interpretation of the 2019 FDA Immunogenicity Guidance and The Gene Therapy Bioanalytical Challenges) are published in volume 11 of Bioanalysis, issues 23 and 24 (2019), respectively.