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BACKGROUND: Influenza A results in significant morbidity and mortality. VIR-2482, an engineered human monoclonal antibody with extended half-life, targets a highly conserved epitope on the stem region of influenza A hemagglutinin, and may protect against seasonal and pandemic influenza. METHODS: This double-blind, randomized, placebo-controlled, phase 2 study examined the safety and efficacy of VIR-2482 for seasonal influenza A illness prevention in unvaccinated healthy adults. Participants (N = 2977) were randomized 1:1:1 to receive VIR-2482 450 mg, VIR-2482 1200 mg, or placebo via intramuscular (IM) injection. Primary and secondary efficacy endpoints were the proportions of participants with reverse transcriptase-polymerase chain reaction (RT-PCR)-confirmed influenza A infection and either protocol-defined influenza-like illness (ILI) and Centers for Disease Control and Prevention (CDC)-defined ILI or World Health Organization (WHO)-defined ILI, respectively. RESULTS: VIR-2482 450 mg and 1200 mg prophylaxis did not reduce the risk of protocol-defined ILI with RT-PCR-confirmed influenza A versus placebo (relative risk reduction [RRR], 3.8% [95% CI: -67.3, 44.6] and 15.9% [95% CI: -49.3, 52.3], respectively). At the 1200 mg dose, the RRRs in influenza A illness were 57.2% [95% CI: -2.5, 82.2] using CDC-ILI and 44.1% [95% CI: -50.5, 79.3] using WHO-ILI definitions, respectively. Serum VIR-2482 levels were similar regardless of influenza status; variants with reduced VIR-2482 susceptibility were not detected. Local injection-site reactions were mild and similar across groups. CONCLUSION: VIR-2482 1200 mg IM was well tolerated but did not significantly prevent protocol-defined ILI. Secondary endpoint analyses suggest this dose may have reduced influenza A illness.
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The objective of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), and immunogenicity of VIR-2482 in healthy adult subjects. A phase 1, first-in-human, randomized, double-blind, placebo-controlled dose-escalation study was conducted. One hundred participants were allocated to four cohorts (60 mg, 300 mg, 1,200 mg, and 1,800 mg). In each cohort, participants were randomized in a 4:1 ratio (active:placebo) to receive either VIR-2482 or volume-matched placebo by gluteal intramuscular injection. Participants remained at the investigative site under observation for 48 h, and adverse events (AEs) were collected for 56 days. PK and immunogenicity were measured up to 52 weeks post-dose. VIR-2482 was well tolerated at all doses studied. The overall incidence of AEs was comparable between VIR-2482 (68.8%) and placebo (85.0%). Nineteen VIR-2482 (23.8%) and six placebo (30.0%) recipients had Grade 1 or 2 AEs that were considered to be related to the study intervention. There were no treatment-related serious AEs. Injection-site reactions (ISRs) were reported in six (7.5%) VIR-2482 recipients, while no such reactions were reported among the placebo recipients. All ISRs were Grade 1, and there was no relationship with the dose. Median VIR-2482 serum elimination half-life ranged from 56.7 to 70.6 days across cohorts. The serum area under the curve and Cmax were dose-proportional. Nasopharyngeal VIR-2482 concentrations were approximately 2%-5% of serum levels and were less than dose-proportional. The incidence of immunogenicity across all cohorts was 1.3%. Overall, the safety, tolerability, and pharmacokinetic profile of VIR-2482 at doses up to 1,800 mg supported its further investigation as a long-acting antibody for the prevention of influenza A illness. This study has been registered at ClinicalTrials.gov under identifier NCT04033406.
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Anticuerpos Monoclonales , Gripe Humana , Adulto , Humanos , Anticuerpos Monoclonales/efectos adversos , Gripe Humana/tratamiento farmacológico , Gripe Humana/prevención & control , Voluntarios Sanos , Método Doble CiegoRESUMEN
INTRODUCTION: Treatment with monoclonal antibodies provides rapid, passive immunity and may stop COVID-19 disease progression. The study evaluated the effect of bamlanivimab (BAM) or BAM + etesevimab (ETE)/sotrovimab compared to placebo on SARS-CoV-2 viral load in patients with COVID-19. METHODS: The phase 2, randomized, single-dose study included patients aged between ≥ 18 and < 65 years, not hospitalized at the time of randomization, and had ≥ 1 mild or moderate COVID-19 symptoms. Study included arms 1-6 (placebo, BAM 175 mg + ETE 350 mg, BAM 700 mg + ETE 1400 mg, BAM 2800 mg + ETE 2800 mg, BAM 700 mg alone, and BAM 350 mg + ETE 700 mg, respectively), BAM 700 mg + ETE 700 mg unintentional dosing; and arms 7 and 8 (BAM 700 mg + sotrovimab 500 mg and placebo, respectively). The primary endpoint was proportion of patients with SARS-CoV-2 log viral load > 5.27 on day 7 (persistently high viral load [PHVL]) who received BAM or BAM + (ETE or sotrovimab). RESULTS: A total of 725 patients, mean age 39.6 years (range 18-75 years), 50.2% male were randomized and infused with study drug in arms 1-6; and a total 202 patients, mean age 38 years (range 18-63 years), 53.5% female were randomized and infused with study drug in arms 7 and 8. A significantly lower proportion of patients in arms 2-6 and arm 7 experienced PHVL on day 7 compared to placebo. On day 7, patients in arms 2, 3, and 6 consistently experienced significantly greater reduction in viral load than placebo. Significant improvement was observed in time to viral load clearance and time to symptom improvement by day 29 in some arms compared to placebo. No new safety concerns were observed with drug combinations. CONCLUSION: The study demonstrated that a significantly lower proportion of patients with mild-to-moderate COVID-19 treated with BAM or BAM + (ETE or sotrovimab) experienced a PHVL at day 7. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04634409.
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Background: Convenient administration of coronavirus disease 2019 (COVID-19) treatment in community settings is desirable. Sotrovimab is a pan-sarbecovirus dual-action monoclonal antibody formulated for intravenous (IV) or intramuscular (IM) administration for early treatment of mild/moderate COVID-19. Method: This multicenter phase 3 study based on a randomized open-label design tested the noninferiority of IM to IV administration according to an absolute noninferiority margin of 3.5%. From June to August 2021, patients aged ≥12 years with COVID-19, who were neither hospitalized nor receiving supplemental oxygen but were at high risk for progression, were randomized 1:1:1 to receive sotrovimab as a single 500-mg IV infusion or a 500- or 250-mg IM injection. The primary composite endpoint was progression to (1) all-cause hospitalization for >24 hours for acute management of illness or (2) all-cause death through day 29. Results: Sotrovimab 500â mg IM was noninferior to 500â mg IV: 10 (2.7%) of 376 participants vs 5 (1.3%) of 378 met the primary endpoint, respectively (absolute adjusted risk difference, 1.06%; 95% CI, -1.15% to 3.26%). The 95% CI upper limit was lower than the prespecified noninferiority margin of 3.5%. The 250-mg IM group was discontinued early because of the greater proportion of hospitalizations vs the 500-mg groups. Serious adverse events occurred in <1% to 2% of participants across groups. Four participants experienced serious disease-related events and died (500â mg IM, 2/393, <1%; 250â mg IM, 2/195, 1%). Conclusions: Sotrovimab 500-mg IM injection was well tolerated and noninferior to IV administration. IM administration could expand outpatient treatment access for COVID-19. Clinical Trials Registration: ClinicalTrials.gov: NCT04913675.
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Sotrovimab is a recombinant human monoclonal antibody that has been shown to prevent progression to hospitalization or death in non-hospitalized high-risk patients with mild to moderate coronavirus disease 2019 following either intravenous (i.v.) or intramuscular (i.m.) administration. Population pharmacokinetic (PopPK) and exposure-response (ER) analyses were performed to characterize single dose sotrovimab pharmacokinetics (PK) and the relationship between exposure and response (probability of progression), as well as covariates that may contribute to between-participant variability in sotrovimab PK and efficacy following i.v. or i.m. administration. Sotrovimab PK was described by a two-compartment model with linear elimination; i.m. absorption was characterized by a sigmoid absorption model. PopPK covariate analysis led to the addition of the effect of body weight on systemic clearance and peripheral volume of distribution, sex on i.m. bioavailability and first-order absorption rate (KA), and body mass index on KA. However, the magnitude of covariate effect was not pronounced and was therefore not expected to be clinically relevant based on available data to date. For ER analysis, sotrovimab exposure measures were predicted using the final PopPK model. An ER model was developed using the exposure measure of sotrovimab concentration at 168 h that described the relationship between exposure and probability of progression within the ER dataset for COMET-TAIL. The number of risk factors (≤1 vs. >1) was incorporated as an additive shift on the model-estimated placebo response but had no impact on overall drug response. Limitations in the ER model may prevent generalization of these results to describe the sotrovimab exposure-progression relationship across severe acute respiratory syndrome-coronavirus 2 variants.
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COVID-19 , Humanos , SARS-CoV-2 , Anticuerpos Monoclonales HumanizadosRESUMEN
Understanding who is at risk of progression to severe coronavirus disease 2019 (COVID-19) is key to clinical decision making and effective treatment. We study correlates of disease severity in the COMET-ICE clinical trial that randomized 1:1 to placebo or to sotrovimab, a monoclonal antibody for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (ClinicalTrials.gov04545060). Laboratory parameters identify study participants at greater risk of severe disease, including a high neutrophil-to-lymphocyte ratio (NLR), a negative SARS-CoV-2 serologic test, and whole-blood transcriptome profiles. Sotrovimab treatment is associated with normalization of NLR and the transcriptomic profile and with a decrease of viral RNA in nasopharyngeal samples. Transcriptomics provides the most sensitive detection of participants who would go on to be hospitalized or die. To facilitate timely measurement, we identify a 10-gene signature with similar predictive accuracy. We identify markers of risk for disease progression and demonstrate that normalization of these parameters occurs with antibody treatment of established infection.
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Tratamiento Farmacológico de COVID-19 , Anticuerpos Monoclonales Humanizados , Anticuerpos Neutralizantes , Humanos , ARN Viral , SARS-CoV-2RESUMEN
Importance: Older patients and those with comorbidities who are infected with SARS-CoV-2 may be at increased risk of hospitalization and death. Sotrovimab is a neutralizing antibody for the treatment of high-risk patients to prevent COVID-19 progression. Objective: To evaluate the efficacy and adverse events of sotrovimab in preventing progression of mild to moderate COVID-19 to severe disease. Design, Setting, and Participants: Randomized clinical trial including 1057 nonhospitalized patients with symptomatic, mild to moderate COVID-19 and at least 1 risk factor for progression conducted at 57 sites in Brazil, Canada, Peru, Spain, and the US from August 27, 2020, through March 11, 2021; follow-up data were collected through April 8, 2021. Interventions: Patients were randomized (1:1) to an intravenous infusion with 500 mg of sotrovimab (n = 528) or placebo (n = 529). Main Outcomes and Measures: The primary outcome was the proportion of patients with COVID-19 progression through day 29 (all-cause hospitalization lasting >24 hours for acute illness management or death); 5 secondary outcomes were tested in hierarchal order, including a composite of all-cause emergency department (ED) visit, hospitalization of any duration for acute illness management, or death through day 29 and progression to severe or critical respiratory COVID-19 requiring supplemental oxygen or mechanical ventilation. Results: Enrollment was stopped early for efficacy at the prespecified interim analysis. Among 1057 patients randomized (median age, 53 years [IQR, 42-62], 20% were ≥65 years of age, and 65% Latinx), the median duration of follow-up was 103 days for sotrovimab and 102 days for placebo. All-cause hospitalization lasting longer than 24 hours or death was significantly reduced with sotrovimab (6/528 [1%]) vs placebo (30/529 [6%]) (adjusted relative risk [RR], 0.21 [95% CI, 0.09 to 0.50]; absolute difference, -4.53% [95% CI, -6.70% to -2.37%]; P < .001). Four of the 5 secondary outcomes were statistically significant in favor of sotrovimab, including reduced ED visit, hospitalization, or death (13/528 [2%] for sotrovimab vs 39/529 [7%] for placebo; adjusted RR, 0.34 [95% CI, 0.19 to 0.63]; absolute difference, -4.91% [95% CI, -7.50% to -2.32%]; P < .001) and progression to severe or critical respiratory COVID-19 (7/528 [1%] for sotrovimab vs 28/529 [5%] for placebo; adjusted RR, 0.26 [95% CI, 0.12 to 0.59]; absolute difference, -3.97% [95% CI, -6.11% to -1.82%]; P = .002). Adverse events were infrequent and similar between treatment groups (22% for sotrovimab vs 23% for placebo); the most common events were diarrhea with sotrovimab (n = 8; 2%) and COVID-19 pneumonia with placebo (n = 22; 4%). Conclusions and Relevance: Among nonhospitalized patients with mild to moderate COVID-19 and at risk of disease progression, a single intravenous dose of sotrovimab, compared with placebo, significantly reduced the risk of a composite end point of all-cause hospitalization or death through day 29. The findings support sotrovimab as a treatment option for nonhospitalized, high-risk patients with mild to moderate COVID-19, although efficacy against SARS-CoV-2 variants that have emerged since the study was completed is unknown. Trial Registration: ClinicalTrials.gov Identifier: NCT04545060.
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Antivirales , Tratamiento Farmacológico de COVID-19 , COVID-19 , SARS-CoV-2 , Enfermedad Aguda , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Neutralizantes/uso terapéutico , Antivirales/administración & dosificación , Antivirales/uso terapéutico , COVID-19/mortalidad , Progresión de la Enfermedad , Hospitalización , Humanos , Infusiones Intravenosas , Persona de Mediana Edad , Respiración Artificial , Resultado del TratamientoRESUMEN
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.
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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
Letermovir, a cytomegalovirus (CMV) terminase-complex inhibitor, is indicated for prophylaxis of CMV infection and disease in adult CMV-seropositive recipients of allogeneic hematopoietic cell transplantation (HCT). In a phase III, double-blind, randomized trial, letermovir significantly reduced the risk of clinically significant CMV infection (CS-CMVi) vs placebo through Week 24 post-HCT. This analysis investigated outcomes in participants with detectable CMV DNA at randomization, who were excluded from the primary efficacy analysis. In total, 70 of 565 randomized participants had detectable CMV DNA at randomization (letermovir 48; placebo 22). Study treatment completion rates were greater in letermovir-treated participants compared with placebo (52.1% vs 9.1%). The incidence of CS-CMVi or imputed primary endpoint events through Week 24 were 64.6% and 90.9% in the letermovir and placebo groups, respectively (treatment difference -26.1%; P = .010). Kaplan-Meier event rates for CS-CMVi onset through Week 14 (end-of-treatment period) were 33.1% for letermovir and 86.6% for placebo (P < .001). Median viral loads at the CS-CMVi events was similar in both treatment arms. All-cause mortality through Week 24 posttransplant was 15.0% for letermovir and 18.2% for placebo; through Week 48, mortality rates were 26.5% and 40.9%, respectively (P = .268). Overall, clinical outcomes were similar to those reported for participants with undetectable CMV DNA at randomization.
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Infecciones por Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Acetatos , Adulto , Antivirales/uso terapéutico , Citomegalovirus/genética , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/prevención & control , ADN , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Quinazolinas , Distribución AleatoriaRESUMEN
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.
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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
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.
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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
Ruzasvir (MK-8408, an NS5A inhibitor) and uprifosbuvir (MK-3682, a nonstructural protein 5B nucleotide inhibitor) are highly potent direct-acting antiviral agents for the treatment of hepatitis C virus (HCV) infection. A phase III clinical trial evaluating the two-drug combination of ruzasvir 60 mg plus uprifosbuvir 450 mg suggested suboptimal efficacy in certain HCV genotypes (C-BREEZE 1; NCT02759315). The aim of the present study was to evaluate the efficacy and safety of ruzasvir in combination with uprifosbuvir administered at a higher dose than that assessed in the earlier study (C-BREEZE 2: NCT02956629/Merck protocol PN041). Treatment-naïve or interferon (with or without ribavirin)-experienced participants with or without compensated cirrhosis were enrolled. All participants received ruzasvir 180 mg plus uprifosbuvir 450 mg once daily for 12 weeks. The primary objectives were the proportion of participants with HCV RNA <15 lU/mL at 12 weeks after the end of study therapy (SVR12), and safety and tolerability of the study drug. Overall, 282 participants were enrolled. SVR12 (n/N) was 91.3% (42/46) in participants infected with HCV genotype (GT) 1a; GT1b, 96.7% (29/30); GT2, 91.5% (43/47); GT3, 73.8% (45/61); GT4, 98.2% (55/56); GT5, 100.0% (18/18); and GT6, 90.9% (20/22). Adverse events (AEs) were reported by 61.3% of participants; drug-related AEs were reported by 33.3%. The most frequent (≥5% of participants) drug-related AEs in all participants were fatigue (7.8%) and headache (7.4%). In conclusion, the two-drug combination of ruzasvir 180 mg plus uprifosbuvir 450 mg for 12 weeks was highly effective and well tolerated in participants infected with HCV GT1, GT2, GT4, GT5 and GT6, with a lower efficacy in GT3-infected persons.
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Antivirales/administración & dosificación , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Pirrolidinas/administración & dosificación , Respuesta Virológica Sostenida , Tiazoles/administración & dosificación , Uridina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Antivirales/uso terapéutico , Esquema de Medicación , Quimioterapia Combinada , Femenino , Genotipo , Hepacivirus/genética , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Humanos , Interferones/uso terapéutico , Masculino , Persona de Mediana Edad , Pirrolidinas/uso terapéutico , ARN Viral/sangre , Ribavirina/uso terapéutico , Tiazoles/uso terapéutico , Uridina/administración & dosificación , Uridina/uso terapéutico , Adulto JovenRESUMEN
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.
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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
In clinical trials, the three-drug regimen of ruzasvir (RZR) 60 mg, uprifosbuvir (UPR) 450 mg and grazoprevir 100 mg, with or without ribavirin, has demonstrated promising efficacy and excellent tolerability across a wide range of hepatitis C virus (HCV)-infected individuals. The present study assessed the efficacy and safety of the two-drug combination of RZR 60 mg plus UPR 450 mg administered for 12 weeks in participants with HCV genotype (GT) 1-6 infection. In this open-label clinical trial, treatment-naive or -experienced and cirrhotic or noncirrhotic participants with chronic HCV GT1-6 infection received RZR 60 mg plus UPR 450 mg orally once daily for 12 weeks (NCT02759315/protocol PN035). The primary efficacy endpoint was sustained virologic response at 12 weeks after the end of therapy (SVR12). One hundred and sixty participants were enrolled. SVR12 rates were 96% (52 of 54) in participants with GT1a infection; 100% (15 of 15) in those with GT1b infection; 97% (28 of 29) in those with GT2 infection; 77% (30 of 39) in those with GT3 infection; 90% (18 of 20) in those with GT4 infection; and 67% (2 of 3) in those with GT6 infection. Drug-related adverse events (AEs) reported by >5% of participants were fatigue (n = 10, 6.3%) and diarrhoea (n = 9, 5.6%). Five participants reported a total of 11 serious AEs, none considered drug-related. One participant experienced on-treatment alanine aminotransferase/aspartate aminotransferase elevations that resolved without intervention. Data from the present study indicate that the combination of RZR 60 mg plus UPR 450 mg once daily for 12 weeks was well tolerated overall but was effective only for certain genotypes.
Asunto(s)
Antivirales/administración & dosificación , Hepatitis C Crónica/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Pirrolidinas/administración & dosificación , Tiazoles/administración & dosificación , Uridina/análogos & derivados , Adulto , Antivirales/uso terapéutico , Esquema de Medicación , Quimioterapia Combinada , Femenino , Genotipo , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Pirrolidinas/uso terapéutico , Respuesta Virológica Sostenida , Tiazoles/uso terapéutico , Uridina/administración & dosificación , Uridina/uso terapéuticoRESUMEN
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
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
The aims of these phase I trials were to evaluate the pharmacokinetic interaction between elbasvir (EBR) or grazoprevir (GZR) and buprenorphine/naloxone (BUP/NAL). Trial 1 was a single-dose trial in healthy participants. Trial 2 was a multiple-dose trial in participants on BUP/NAL maintenance therapy. Coadministration of EBR or GZR with BUP/NAL had minimal effect on the pharmacokinetics of BUP/NAL, EBR, and GZR. The geometric mean ratios (GMRs (90% CI)) for BUP, norbuprenorphine, and NAL AUC0-∞ were 0.98 (0.89-1.08), 0.97 (0.86-1.09), and 0.88 (0.78-1.00) in the presence/absence of EBR; 0.98 (0.81-1.19), 1.13 (0.97-1.32), and 1.10 (0.82-1.47) in the presence/absence of GZR. The GMRs (90% CI) for EBR and GZR AUC0-∞ in the absence/presence of BUP/NAL were 1.22 (0.98-1.52) and 0.86 (0.63-1.18). In conclusion, no dose adjustment for BUP/NAL, EBR, or GZR is required for patients with HCV infection receiving EBR/GZR and BUP/NAL maintenance therapy.
Asunto(s)
Analgésicos Opioides/agonistas , Antivirales/farmacocinética , Benzofuranos/farmacocinética , Combinación Buprenorfina y Naloxona/farmacocinética , Imidazoles/farmacocinética , Quinoxalinas/farmacocinética , Adulto , Amidas , Antivirales/administración & dosificación , Área Bajo la Curva , Benzofuranos/administración & dosificación , Combinación Buprenorfina y Naloxona/administración & dosificación , Carbamatos , Ciclopropanos , Interacciones Farmacológicas , Quimioterapia Combinada/métodos , Femenino , Voluntarios Sanos , Hepatitis C/complicaciones , Hepatitis C/tratamiento farmacológico , Humanos , Imidazoles/administración & dosificación , Masculino , Persona de Mediana Edad , Tratamiento de Sustitución de Opiáceos/métodos , Trastornos Relacionados con Opioides/complicaciones , Trastornos Relacionados con Opioides/rehabilitación , Quinoxalinas/administración & dosificación , Sulfonamidas , Adulto JovenRESUMEN
We conducted two phase I trials to evaluate the pharmacokinetic interactions between elbasvir (EBR), grazoprevir (GZR), and methadone (MK-8742-P010 and MK-5172-P030) in non-hepatitis C virus (HCV)-infected participants on methadone maintenance therapy. Coadministration of EBR or GZR with methadone had no clinically meaningful effect on EBR, GZR, or methadone pharmacokinetics. The geometric mean ratios (GMRs) for R- and S-methadone AUC0-24 were 1.03 (90% confidence interval (CI), 0.92-1.15) and 1.09 (90% CI, 0.94-1.26) in the presence/absence of EBR; and 1.09 (90% CI, 1.02-1.17) and 1.23 (90% CI, 1.12-1.35) in the presence/absence of GZR. The GMRs for EBR and GZR AUC0-24 in participants receiving methadone relative to a healthy historical cohort not receiving methadone were 1.20 (90% CI, 0.94-1.53) and 1.03 (90% CI, 0.76-1.41), respectively. These results indicate that no dose adjustment is required for individuals with HCV infection receiving stable methadone therapy and the EBR/GZR fixed-dose regimen.
Asunto(s)
Analgésicos Opioides/agonistas , Antivirales/farmacocinética , Benzofuranos/farmacocinética , Imidazoles/farmacocinética , Metadona/farmacocinética , Quinoxalinas/farmacocinética , Adulto , Amidas , Antivirales/administración & dosificación , Área Bajo la Curva , Benzofuranos/administración & dosificación , Carbamatos , Ciclopropanos , Interacciones Farmacológicas , Quimioterapia Combinada/métodos , Femenino , Voluntarios Sanos , Hepatitis C/complicaciones , Hepatitis C/tratamiento farmacológico , Humanos , Imidazoles/administración & dosificación , Masculino , Metadona/administración & dosificación , Persona de Mediana Edad , Tratamiento de Sustitución de Opiáceos/métodos , Trastornos Relacionados con Opioides/complicaciones , Trastornos Relacionados con Opioides/rehabilitación , Quinoxalinas/administración & dosificación , Sulfonamidas , Adulto JovenRESUMEN
PURPOSE: This study evaluated the single- and multiple-dose pharmacokinetic (PK) variables of elbasvir and grazoprevir in healthy Chinese individuals. METHODS: This study was a 2-part, parallel-arm, open-label trial. In part 1, single-dose PK variables of elbasvir 10/50/100 mg and grazoprevir 50/100/200 mg were evaluated in 10 participants per drug. In part 2, 10-day multiple-dose PK variables of elbasvir 50 mg and grazoprevir 100 mg administered once daily alone and in combination were evaluated in 12 participants. Summary and inferential statistics of the PK parameters are reported. Elbasvir and grazoprevir PK parameters were also compared between Chinese participants and historical data from white participants. FINDINGS: Single-dose elbasvir and grazoprevir median Tmax were 2.9 to 4.0 and 1.9 to 3.0 hours after administration, respectively. Elbasvir AUC0-∞ and Cmax increased in a dose-proportional manner (slope estimate [90% CI], 0.92 [0.84-1.01] and 0.98 [0.86-1.09], respectively), whereas grazoprevir AUC0-∞ and Cmax increased in a greater-than-dose-proportional manner (slope estimate [90% CI], 1.42 [1.27-1.57] and 1.96 [1.64-2.29]). After repeated administration, the accumulation ratios for AUC0-24, 24-hour concentration, and Cmax were 1.55, 1.57, and 1.38 for elbasvir and 2.03, 1.23, and 2.51 for grazoprevir. Co-administration of elbasvir 50 mg and grazoprevir 100 mg once daily did not have a clinically relevant effect on the PK variables of either drug. Median Tmax after co-administration versus alone was 3.0 hours versus 3.0 hours for elbasvir and 3.1 hours versus 3.0 hours for grazoprevir. Geometric mean ratios (90% CI) for elbasvir and grazoprevir AUC0-24 (Chinese/white participants) were 1.58 (1.03-2.42) and 1.21 (0.76-1.92). Elbasvir and grazoprevir, administered alone or concomitantly, were well tolerated. IMPLICATIONS: In healthy Chinese individuals, administration of elbasvir and grazoprevir, alone or concomitantly, was generally well tolerated, with a thoroughly characterized PK profile. Elbasvir and grazoprevir exposures may trend higher in Chinese healthy participants relative to white healthy participants. Protocol number MK-8742 PN022.