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1.
J Infect Dis ; 218(5): 748-756, 2018 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-29684148

RESUMO

Background: Respiratory syncytial virus (RSV) disease has no effective treatment. JNJ-53718678 is a fusion inhibitor with selective activity against RSV. Methods: After confirmation of RSV infection or 5 days after inoculation with RSV, participants (n = 69) were randomized to JNJ-53718678 75 mg (n = 15), 200 mg (n = 17), 500 mg (n = 18), or placebo (n = 17) orally once daily for 7 days. Antiviral effects were evaluated by assessing RSV RNA viral load (VL) area under the curve (AUC) from baseline (before the first dose) until discharge, time-to-peak VL, duration of viral shedding, clinical symptoms, and quantity of nasal secretions. Results: Mean VL AUC was lower for individuals treated with different doses of JNJ-53718678 versus placebo (203.8-253.8 vs 432.8 log10 PFUe.hour/mL). Also, mean peak VL, time to peak VL, duration of viral shedding, mean overall symptom score, and nasal secretion weight were lower in each JNJ-53718678-treated group versus placebo. No clear exposure-response relationship was observed. Three participants discontinued due to treatment-emergent adverse events of grade 2 and 1 electrocardiogram change (JNJ-53718678 75 mg and 200 mg, respectively) and grade 2 urticaria (placebo). Conclusions: JNJ-53718678 at all 3 doses substantially reduced VL and clinical disease severity, thus establishing clinical proof of concept and the compound's potential as a novel RSV treatment. Clinical trials registration: ClinicalTrials.gov: NCT02387606; EudraCT number: 2014-005041-41.


Assuntos
Antivirais/administração & dosagem , Imidazolidinas/administração & dosagem , Indóis/administração & dosagem , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Administração Oral , Adolescente , Adulto , Antivirais/farmacologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Voluntários Saudáveis , Humanos , Imidazolidinas/farmacologia , Indóis/farmacologia , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Infecções por Vírus Respiratório Sincicial/patologia , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vírus Sincicial Respiratório Humano/isolamento & purificação , Resultado do Tratamento , Carga Viral , Eliminação de Partículas Virais , Adulto Jovem
2.
Virol J ; 14(1): 101, 2017 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-28569206

RESUMO

BACKGROUND: In study TMC647055HPC2001, a 3-direct-acting-antiviral (DAA) regimen combining NS3/4A protease inhibitor simeprevir (SMV), non-nucleoside NS5B inhibitor TMC647055/ritonavir (RTV) and NS5A inhibitor JNJ-56914845 resulted in high sustained virologic response 12 weeks after actual end of treatment (SVR12) in chronic hepatitis C virus (HCV) genotype 1-infected patients. SVR12 rates were generally lower in the 2-DAA regimen SMV + TMC647055/RTV with or without ribavirin. The objective of this study was to identify and characterise pre-existing and emerging resistance-associated variants (RAVs) in patients enrolled in study TMC647055HPC2001. METHODS: HCV population sequencing analyses were performed on baseline isolates from all patients (n = 90) and post-baseline isolates from patients with virologic failure (n = 22). In addition, deep sequencing and phenotypic analyses were performed on selected baseline and post-baseline isolates. RESULTS: The majority of patients with virologic failure had emerging RAVs to all study drugs at the time of failure: in all 22 patients SMV RAVs emerged at NS3 positions 80, 155, 156 and/or 168, consistent with the known SMV resistance profile. Emerging TMC647055 RAVs at NS5B position 495 were detected in the majority of patients (16/22), and all 5 patients who failed the 3-DAA regimen had emerging JNJ-56914845 RAVs at NS5A positions 30 and/or 31. While at the end of study emerging SMV and TMC647055 RAVs were no longer observed by population sequencing in 40% (8/20) and 62.5% (10/16) of patients with follow-up data available, respectively, emerging JNJ-56914845 RAVs were still detected in all (5/5) patients. CONCLUSIONS: Virologic failure in the 2- and 3-DAA combinations was, in the majority of patients, associated with the emergence of RAVs to all study drugs. While emerging SMV and TMC647055 RAVs became undetectable during follow-up, JNJ-56914845 RAVs in NS5A were still observed at end of study. TRIAL REGISTRATION NUMBER: NCT01724086 (date of registration: September 26, 2012).


Assuntos
Antivirais/uso terapêutico , Genótipo , Hepacivirus/isolamento & purificação , Hepatite C Crônica/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Ritonavir/uso terapêutico , Simeprevir/uso terapêutico , Sulfonamidas/uso terapêutico , Carbamatos/uso terapêutico , Farmacorresistência Viral , Técnicas de Genotipagem , Hepacivirus/classificação , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Ribavirina/uso terapêutico , Análise de Sequência de DNA , Falha de Tratamento , Valina/análogos & derivados , Valina/uso terapêutico
3.
BMC Gastroenterol ; 17(1): 26, 2017 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-28187751

RESUMO

BACKGROUND: A Phase 2a, open-label study (NCT01724086) was conducted to assess the efficacy and safety of a once-daily, 2-direct-acting-antiviral-agent (2-DAA) combination of simeprevir + TMC647055/ritonavir ± ribavirin and of the 3-DAA combination of simeprevir + TMC647055/ritonavir + JNJ-56914845 in chronic hepatitis C virus genotype (GT)1-infected treatment-naïve and prior-relapse patients. METHODS: The study comprised four 12-week treatment panels: Panel 1 (n = 10; GT1a) and Panel 2-Arm 1 (n = 12; GT1b): simeprevir 75 mg once daily + TMC647055 450 mg once daily/ritonavir 30 mg once daily + ribavirin 1000-1200 mg/day; Panel 2-Arm 2 (n = 9; GT1b): simeprevir 75 mg + TMC647055 450 mg/ritonavir 30 mg without ribavirin; Panel 3: simeprevir 75 mg + TMC647055 600 mg/ritonavir 50 mg with (Arm 1: GT1a; n = 7) or without (Arm 2: GT1b; n = 8) ribavirin; Panel 4: simeprevir 75 mg + TMC647055 450 mg/ritonavir 30 mg + JNJ-56914845 30 mg once daily (Arm 1: n = 22; GT1a/GT1b) or 60 mg once daily (Arm 2: n = 22; GT1a/GT1b). Primary endpoint was sustained virologic response 12 weeks after end of treatment (12 weeks of combination treatment; SVR12). RESULTS: In Panel 1 and Panel 2-Arm 1, 5/10 and 6/12 (50%) GT1a/GT1b + ribavirin patients achieved SVR12, versus 3/9 (33%) GT1b without ribavirin patients in Panel 2-Arm 2. In Panel 3-Arm 1 and Panel 3-Arm 2, 6/7 (86%) GT1a + ribavirin and 4/8 (50%) GT1b without ribavirin patients, respectively, achieved SVR12. In Panel 4, 10/14 (71%) and 14/15 (93%) GT1a patients in Arms 1 and 2 achieved SVR12 compared with 8/8 and 7/7 (100%) GT1b patients in each arm, respectively. No deaths, serious adverse events (AEs), Grade 4 AEs or AEs leading to treatment discontinuation occurred. CONCLUSIONS: The 2- and 3-DAA combinations were well tolerated. High SVR rates of 93% and 100% in GT1a- and GT1b-infected patients, respectively, were achieved in this study by combining simeprevir with JNJ-56914845 60 mg and TMC647055/ritonavir. TRIAL REGISTRATION: NCT01724086 (date of registration: September 26, 2012).


Assuntos
Antivirais/uso terapêutico , Carbamatos/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Ribavirina/uso terapêutico , Ritonavir/uso terapêutico , Simeprevir/uso terapêutico , Sulfonamidas/uso terapêutico , Valina/análogos & derivados , Adulto , Idoso , Antivirais/efeitos adversos , Antivirais/farmacocinética , Carbamatos/efeitos adversos , Carbamatos/farmacocinética , Quimioterapia Combinada , Feminino , Genótipo , Hepatite C Crônica/genética , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Ribavirina/efeitos adversos , Ribavirina/farmacocinética , Ritonavir/efeitos adversos , Ritonavir/farmacocinética , Simeprevir/efeitos adversos , Simeprevir/farmacocinética , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Valina/efeitos adversos , Valina/farmacocinética , Valina/uso terapêutico
4.
Gastroenterology ; 143(5): 1176-1178.e6, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22885330

RESUMO

In the TMC435-C101 study, 6 patients infected with hepatitis C virus genotype 1 were treated with the protease inhibitor TMC435 (200 mg once daily) as monotherapy for 5 days. Approximately 1.5 years later, 5 of these patients were re-treated with TMC435 (200 mg once daily) plus pegylated interferon alfa-2a and ribavirin (PegIFNα-2a and RBV) for 4 weeks, followed by PegIFNα-2a and RBV until week 48 (in the Optimal Protease inhibitor Enhancement of Response to therApy [OPERA-1] study). TMC435-resistant variants, which emerged in all 5 patients during the TMC435-C101 study, were no longer detected at the beginning of the OPERA-1 study based on virus population sequencing. During the OPERA-1 study, 3 patients had a sustained virologic response; deep sequencing indicated low-level persistence of resistant variants in the remaining 2 patients, which might have affected their response to re-treatment.


Assuntos
Hepacivirus/genética , Hepatite C/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Inibidores de Proteases/uso terapêutico , RNA Viral/sangue , Sulfonamidas/uso terapêutico , Antivirais/uso terapêutico , Farmacorresistência Viral , Quimioterapia Combinada , Genótipo , Hepatite C/sangue , Hepatite C/virologia , Humanos , Interferon-alfa/uso terapêutico , Masculino , Mutação , Polietilenoglicóis/uso terapêutico , RNA Viral/efeitos dos fármacos , Proteínas Recombinantes/uso terapêutico , Ribavirina/uso terapêutico , Simeprevir , Carga Viral
5.
Gastroenterology ; 138(3): 913-21, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19852962

RESUMO

BACKGROUND & AIMS: The search for targeted anti-hepatitis C virus (HCV) drugs is driven by the adverse effect profile and limited efficacy of the current standard of care (pegylated interferon-alpha/ribavirin). In a first-in-human trial, we tested the safety, tolerability, and pharmacokinetics of the macrocyclic HCV NS3/4A protease inhibitor TMC435 in healthy volunteers, followed by HCV genotype 1-infected patients to assess antiviral activity. METHODS: The TMC435350-C101 study was a phase I, randomized, double-blind, placebo-controlled trial in 49 healthy volunteers, followed by an open-label, nonplacebo-controlled panel in 6 genotype 1 hepatitis C patients. Healthy volunteers received oral, single, ascending doses (up to 600 mg) or 5-day multiple ascending doses (200 mg twice daily or 100, 200, or 400 mg once daily). Patients received 200 mg once daily for 5 days. Pharmacokinetics and safety were evaluated for all panels, and plasma HCV-RNA levels were determined in patients. RESULTS: There were no serious adverse events, no grade 3 reactions, and no treatment-related discontinuations; pharmacokinetics supported a once daily dosing regimen. Plasma HCV-RNA levels dropped rapidly in all patients, with a median maximal reduction of 3.9-log(10) IU/mL and a median of 6 days to maximal reduction. The initial steep reduction of HCV-RNA (median 3.5-log(10) IU/mL at day 3) was followed by a more gradual decline that was maintained over the dosing period. No viral breakthroughs (>1-log(10) IU/mL HCV-RNA increase from nadir) were observed during treatment nor in the 3 days posttreatment; HCV-RNA returned to pretreatment levels by week 4. CONCLUSIONS: Once daily TMC435 given orally was generally safe and well tolerated and demonstrated potent antiviral activity.


Assuntos
Antivirais/administração & dosagem , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Inibidores de Proteases/administração & dosagem , RNA Viral/sangue , Sulfonamidas/administração & dosagem , Carga Viral/efeitos dos fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Adulto , Antivirais/efeitos adversos , Antivirais/farmacocinética , DNA Viral/análise , Método Duplo-Cego , Esquema de Medicação , Feminino , Genótipo , Hepacivirus/enzimologia , Hepacivirus/genética , Hepatite C/diagnóstico , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteases/efeitos adversos , Inibidores de Proteases/farmacocinética , Simeprevir , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Fatores de Tempo , Resultado do Tratamento , Proteínas não Estruturais Virais/genética , Adulto Jovem
6.
Antiviral Res ; 153: 70-77, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29567461

RESUMO

BACKGROUND: PrEP-001 Nasal Powder, a proprietary formulation of polyriboinosinic and polyribocytidylic acid effectively elicits a cellular innate immune response in nasal epithelium. The aim of these 2 studies was to investigate the safety and efficacy of PrEP-001 prophylaxis against rhinovirus (HRV-A16) and influenza-A (H3N2-IAV). METHODS: Healthy subjects randomly received 2 doses of PrEP-001 or placebo, 48 and 24 h pre-challenge with 10 TCID50 of HRV-A16 (Study 1) or H3N2-IAV (Study 2). RESULTS: In Study 1, PrEP-001 reduced median total symptom score from 38.5 to 4.5 (p = 0.004), median symptom duration from 6.0 to 1.7 days and median mucus production from 15 g to 3 g. The percentage of subjects classified as ill was reduced 3-fold (placebo 73%, PrEP-001 23%, p = 0.002). In Study 2, PrEP-001 reduced median total symptom score from 8.0 to 4.1 (p = 0.021), median symptom duration from 4.6 to 3.7 days and median mucus production from 3.6 g to 1.5 g. The percentage of subjects classified as ill was reduced 2-fold (placebo 48%, PrEP-001 24%, p = 0.064). PrEP-001 reduced peak viral shedding in both studies, as assessed by qRT-PCR of nasal lavage. Seroconversion rates were comparable between placebo and PrEP-001 (Study 1: 77% [both arms]; Study 2: placebo 73%, PrEP-001 80%). PrEP-001 was well-tolerated, with no clinically significant adverse events. CONCLUSIONS: PrEP-001 reduced the number of individuals with clinical illness and attenuated severity and duration of HRV-A16 and H3N2-IAV infections without compromising seroconversion, and was well-tolerated. This supports further evaluation of PrEP-001 as a potential pan-viral prophylaxis for upper respiratory tract infections. CLINICAL TRIAL REGISTRATION: Study 1, HRV-A16 study: EudraCT Number 2012-005579-14 (study conducted before ClinicalTrials.gov registration required). Study 2, H3N2-IAV study: EudraCT Number 2015-002895-26 and ClinicalTrials.gov: NCT03220048.


Assuntos
Fatores Imunológicos/administração & dosagem , Influenza Humana/prevenção & controle , Infecções por Picornaviridae/prevenção & controle , Poli I-C/administração & dosagem , Administração Intranasal , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Voluntários Saudáveis , Humanos , Fatores Imunológicos/efeitos adversos , Vírus da Influenza A Subtipo H3N2/imunologia , Influenza Humana/patologia , Mucosa Nasal/imunologia , Infecções por Picornaviridae/patologia , Placebos/administração & dosagem , Poli I-C/efeitos adversos , Pós/administração & dosagem , Pós/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Rhinovirus/imunologia , Resultado do Tratamento
7.
Clin Pharmacokinet ; 56(11): 1331-1342, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28238203

RESUMO

BACKGROUND: JNJ-53718678 is a potent small-molecule inhibitor of the F-glycoprotein-mediated complex membrane fusion process of the respiratory syncytial virus. Here, we report the pharmacokinetics, the population pharmacokinetic modeling, and the safety and tolerability of JNJ-53718678 from the first-in-human, double-blind, randomized, placebo-controlled phase I study. METHODS: Healthy subjects were randomized (6:3) into five single-dose groups (25-1000 mg) or three multiple-dose groups [250 mg every 24 h (q24h), 500 mg q24h, 250 mg every 12 h; fed conditions for 8 days] to receive JNJ-53718678 or placebo. Blood and urine samples were collected at several timepoints up to 72 h after intake of JNJ-53718678 and analyzed using validated liquid chromatography-mass spectrometry methods. A population pharmacokinetic model was developed and validated. RESULTS: Peak plasma concentrations of JNJ-53718678 increased with increasing single (159 ± 54.9 to 6702 ± 1733 ng/mL) and multiple (on day 8, 1528 ± 256 to 2655 ± 591 ng/mL) doses. Steady-state conditions were reached on day 2 of the 8-day dosing regimen. Less than 4% of JNJ-53718678 was excreted in urine across all dose groups. Mean exposure of JNJ-53718678 was 7% lower in the fed state compared with the fasted state at the same dose. A two-compartment model with first-order absorption with parallel linear and non-linear elimination best described the pharmacokinetics of JNJ-53718678. No covariate effects were observed. CONCLUSIONS: A population pharmacokinetic model that describes the concentration data well with good precision of all parameter estimates was developed and validated. JNJ-53718678 was well tolerated at all single and multiple doses studied.


Assuntos
Antivirais/farmacocinética , Imidazolidinas/farmacocinética , Indóis/farmacocinética , Modelos Biológicos , Adolescente , Adulto , Antivirais/efeitos adversos , Antivirais/sangue , Antivirais/urina , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Humanos , Imidazolidinas/efeitos adversos , Imidazolidinas/sangue , Imidazolidinas/urina , Indóis/efeitos adversos , Indóis/sangue , Indóis/urina , Masculino , Pessoa de Meia-Idade , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Adulto Jovem
8.
Drugs R D ; 15(3): 261-70, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26248593

RESUMO

BACKGROUND: Simeprevir is a N3/4 protease inhibitor approved for the treatment of hepatitis C virus (HCV) infection. HCV prevalence is higher in patients with chronic kidney disease compared with the general population; safe and efficacious therapies in renal impairment are needed. OBJECTIVES: To evaluate simeprevir renal excretion in healthy subjects and to compare the simeprevir steady-state pharmacokinetics between subjects with severe renal impairment and healthy subjects. METHODS: In the mass balance study, healthy adults received a single 200-mg dose of (14)C-simeprevir; radioactivity in the urine and feces was quantified until concentrations were <2% of the administered dose and seven or more stools were produced. In the pharmacokinetic study, non-HCV-infected adults with severe renal impairment (estimated glomerular filtration rate ≤29 mL/min/1.73 m(2)) and matched healthy subjects (estimated glomerular filtration rate ≥80 mL/min/1.73 m(2)) received 150 mg simeprevir for 7 days. Pharmacokinetic analysis was performed post-dose on Day 7. RESULTS: (14)C-simeprevir recovery from the urine was low (0.009-0.138% of total dose). The minimum plasma concentration, maximum plasma concentration, and area under the plasma concentration-time curve at 24 h were 71, 34, and 62% higher, respectively, in subjects with severe renal impairment compared with healthy subjects. The mean fraction of simeprevir unbound to protein was <0.0001 (all subjects). Most adverse events were grade I or II; one subject with renal impairment who was receiving fenofibrate presented with grade 3 rhabdomyolysis. CONCLUSIONS: Simeprevir plasma concentrations were mildly elevated in subjects with severe renal impairment. The results suggest that simeprevir may be administered without dose adjustment in patients with renal impairment.


Assuntos
Radioisótopos de Carbono/farmacocinética , Radioisótopos de Carbono/urina , Insuficiência Renal/urina , Simeprevir/farmacocinética , Simeprevir/urina , Adolescente , Adulto , Idoso , Radioisótopos de Carbono/sangue , Fezes/química , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteases/análise , Inibidores de Proteases/sangue , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/urina , Insuficiência Renal/metabolismo , Simeprevir/análise , Simeprevir/sangue , Adulto Jovem
9.
PLoS One ; 10(5): e0126959, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26010881

RESUMO

BACKGROUND: The study assessed the antiviral activity of TMC353121, a respiratory syncytial virus (RSV) fusion inhibitor, in a preclinical non-human primate challenge model with a viral shedding pattern similar to that seen in humans, following continuous infusion (CI). METHODS: African green monkeys were administered TMC353121 through CI, in 2 studies. Study 1 evaluated the prophylactic and therapeutic efficacy of TMC353121 at a target plasma level of 50 ng/mL (n=15; Group 1: prophylactic arm [Px50], 0.033 mg/mL TMC353121, flow rate 2.5 mL/kg/h from 24 hours pre-infection to 10 days; Group 2: therapeutic arm [Tx50], 0.033 mg/mL TMC353121 from 24 hours postinfection to 8 days; Group 3: control [Vh1] vehicle, 24 hours post-infection to 8 days). Study 2 evaluated the prophylactic efficacy of TMC353121 at target plasma levels of 5 and 500 ng/mL (n=12; Group 1: prophylactic 5 arm [Px5], 0.0033 mg/mL TMC353121, flow rate 2.5 mL/kg/h from 72 hours pre-infection to 14 days; Group 2: prophylactic 500 arm [Px500], 0.33 mg/mL TMC353121; Group 3: control [Vh2] vehicle, 14 days). Bronchoalveolar lavage fluid and plasma were collected every 2 days from day 1 postinfection for pharmacokinetics and safety analysis. FINDINGS: TMC353121 showed a dose-dependent antiviral activity, varying from 1 log10 reduction of peak viral load to complete inhibition of the RSV replication. Complete inhibition of RSV shedding was observed for a relatively low plasma exposure (0.39 µg/mL) and was associated with a dose-dependent reduction in INFγ, IL6 and MIP1α. TMC353121 administered as CI for 16 days was generally well-tolerated. CONCLUSION: TMC353121 exerted dose-dependent antiviral effect ranging from full inhibition to absence of antiviral activity, in a preclinical model highly permissive for RSV replication. No new safety findings emerged from the study.


Assuntos
Antivirais/farmacologia , Benzimidazóis/farmacologia , Piridinas/farmacologia , Vírus Sinciciais Respiratórios/fisiologia , Internalização do Vírus/efeitos dos fármacos , Animais , Antivirais/farmacocinética , Área Sob a Curva , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacocinética , Líquido da Lavagem Broncoalveolar/virologia , Chlorocebus aethiops , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Piridinas/administração & dosagem , Piridinas/farmacocinética , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Fatores de Tempo , Eliminação de Partículas Virais/efeitos dos fármacos
10.
J Acquir Immune Defic Syndr ; 65(3): 299-305, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24121757

RESUMO

OBJECTIVES: To evaluate safety, tolerability, and pharmacokinetics of TMC310911, a novel human immunodeficiency virus type-1 protease inhibitor. METHODS: Healthy participants aged 18-55 years with body mass index 18-30 kg/m were enrolled in 2 phase 1 studies. In the first-in-human, single-dose study, 18 participants received placebo or TMC310911 (75-2000 mg) in the double-blind phase and 8 participants received 300 or 600 mg of TMC310911 [administered alone or with 100 mg ritonavir twice daily (bid)] in the subsequent open-label phase. The multiple-dose double-blind study included 5 successive treatment sessions wherein healthy participants received placebo or TMC310911 [300 mg bid, 600 mg once daily or 150 mg bid (plus 100 mg ritonavir bid), 900 mg bid (alone) or 300 mg bid (plus ritonavir 50 mg bid)]; in all sessions, TMC310911 and ritonavir were administered for 6 and 9 days, respectively. RESULTS: In the single-dose study, no dose-limiting toxicity was observed up to 2000 mg of TMC310911. Systemic exposure to TMC310911 generally increased in a dose-proportional manner after the single- or multiple-dose administrations. Coadministration of ritonavir increased the systemic exposure to TMC310911. The mean Cmax and area under plasma concentration-time curve values (single-dose: 1200 mg TMC310911) were higher under fasted conditions than in fed condition. In both studies, most treatment-emergent adverse events were related to gastrointestinal system. CONCLUSIONS: TMC310911 exhibited a linear pharmacokinetic profile after the single- (up to 2000 mg) and multiple-dose (up to 900 mg) administrations; ritonavir improved the pharmacokinetic profile of TMC310911. TMC310911 was generally safe and tolerable when administered with or without ritonavir.


Assuntos
Fármacos Anti-HIV/farmacocinética , Inibidores da Protease de HIV/farmacocinética , Ritonavir/farmacocinética , Adulto , Fármacos Anti-HIV/administração & dosagem , Método Duplo-Cego , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Feminino , Inibidores da Protease de HIV/administração & dosagem , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Ritonavir/administração & dosagem , Adulto Jovem
11.
J Acquir Immune Defic Syndr ; 65(3): 283-9, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24121756

RESUMO

OBJECTIVES: TMC310911 is a novel HIV type-1 (HIV-1) protease inhibitor with broad in vitro antiviral activity. In this phase 2a, open-label randomized study, the antiviral activity, pharmacokinetics, and safety and tolerability of ritonavir-boosted TMC310911 was assessed. METHODS: In this study, treatment-naive HIV-1 patients (aged 18-60 years) received 1 of the 4 dosing regimens of TMC310911: 150 mg twice-daily (bid) (n = 8), 300 mg bid (n = 8), 75 mg bid (n = 9), or 300 mg once-daily (qd) (n = 8), for 14 days, all coadministered with 100 mg of ritonavir, as only antiretroviral therapy. RESULTS: The mean change from baseline in HIV-1 RNA (log10 copies per milliliter; primary efficacy endpoint) was -1.30 (75 mg bid), -1.14 (150 mg bid), -1.07 (300 mg bid), and -1.06 (300 mg qd) on day 8 and -1.53 (75 mg bid), -1.79 (150 mg bid), -1.69 (300 mg bid), and -1.55 (300 mg qd) on day 15. At steady state (day 14), the mean maximum plasma concentration and mean area under the plasma concentration-time curve from 0 to 12 hours tended to increase dose proportionally for bid doses; TMC310911 daily exposures for the 300 mg qd treatment and 150 mg bid treatment were comparable. The most common (≥ 10%) treatment-emergent adverse events were fatigue (27.3%) and nausea (12.1%); no deaths or serious treatment-emergent adverse events were reported in this study. CONCLUSIONS: Combination treatment with TMC310911 and ritonavir showed potent antiviral activity (>1.5 log10 copies/mL decrease in plasma HIV-1 RNA) at all evaluated doses, and treatment was generally safe and well tolerated.


Assuntos
Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/farmacocinética , Inibidores da Protease de HIV/uso terapêutico , Adulto , Fármacos Anti-HIV/efeitos adversos , Sangue/virologia , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Inibidores da Protease de HIV/efeitos adversos , HIV-1/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Ritonavir/uso terapêutico , Resultado do Tratamento , Carga Viral , Adulto Jovem
12.
Methods Mol Biol ; 1030: 373-82, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23821283

RESUMO

Several animal models with varying susceptibilities to respiratory syncytial virus (RSV) infection have been developed to study the specific aspects of RSV disease. Many of these models are used for testing antiviral compounds or in vaccine efficacy studies during preclinical evaluation. In this chapter, we describe the study design of an efficacy study of an RSV inhibitor, performed in a juvenile vervet monkey model for RSV.


Assuntos
Antivirais/farmacologia , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Animais , Antivirais/administração & dosagem , Chlorocebus aethiops , Modelos Animais de Doenças , Humanos , RNA Viral/genética , RNA Viral/isolamento & purificação , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Carga Viral , Ensaio de Placa Viral
13.
Antivir Ther ; 16(7): 1021-33, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22024518

RESUMO

BACKGROUND: Antiviral activity of TMC435, an oral, once-daily, HCV NS3/4A protease inhibitor, was evaluated with pegylated interferon-α2a/ribavirin (P/R) in HCV genotype-1 patients. METHODS: Optimal Protease inhibitor Enhancement of Response to TherApy (OPERA-1; TMC435-C201; NCT00561353) is a Phase IIa, randomized, placebo-controlled study. Treatment-naive patients (n=74) received 25, 75 or 200 mg TMC435 once daily, or placebo for 7 days followed by 21 days of triple therapy with P/R, or triple therapy for 28 days. Treatment-experienced patients (n=37; 56.8% with cirrhosis) received 75, 150 or 200 mg TMC435 once daily, or placebo with P/R for 28 days. Patients continued P/R up to week 48. RESULTS: Treatment-naive patients who received initial monotherapy had a rapid decline in HCV RNA by day 3. At day 7, HCV RNA reductions were greatest for the 75 and 200 mg doses (0.02, -2.63, -3.43 and -4.13 log(10) IU/ml for placebo, and TMC435 25, 75 and 200 mg, respectively). At day 28, all patients who received triple therapy with TMC435 75 or 200 mg had HCV RNA<25 IU/ml versus 4/9 for placebo. In total, 18/28 treatment-experienced patients (9/9 prior relapsers, 9/19 non-responders) who received TMC435 had HCV RNA<25 IU/ml at day 28 versus 0/9 for placebo; similar results were observed for the 150 and 200 mg doses. Most adverse events were grade 1/2. No relevant changes in laboratory parameters occurred, except mild and reversible bilirubin elevations, mostly at the 200 mg dose. CONCLUSIONS: Once-daily TMC435 with P/R showed potent, dose-dependent antiviral activity over 28 days, and had a favourable tolerability profile.


Assuntos
Antivirais/administração & dosagem , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Inibidores de Proteases/administração & dosagem , Ribavirina/administração & dosagem , Sulfonamidas/administração & dosagem , Adolescente , Adulto , Idoso , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Bilirrubina/análise , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Genótipo , Hepatite C/virologia , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Interferon-alfa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/uso terapêutico , Inibidores de Proteases/efeitos adversos , Inibidores de Proteases/uso terapêutico , RNA Viral/sangue , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Ribavirina/farmacologia , Ribavirina/uso terapêutico , Simeprevir , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico , Carga Viral
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