Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 13 de 13
Filtrar
1.
J Infect Dis ; 2024 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-39172627

RESUMO

BACKGROUND: An unmet need exists for effective antivirals to treat patients hospitalized with influenza. The results of 2 Phase 3 studies evaluating the efficacy and safety of pimodivir in combination with investigator-chosen standard-of-care (SoC) treatment are presented. METHODS: Hospitalized patients (hospital study; NCT03376321) and high-risk outpatients (outpatient study; NCT03381196) with laboratory-confirmed influenza A infection were randomized 1:1 to 600 mg pimodivir twice daily (BID) + SoC, or placebo BID + SoC for 5 days. For most patients SoC included oseltamivir. Primary endpoints were Hospital Recovery Scale (HRS) at Day 6 (hospital study) and median time to resolution (TTR) of influenza-related symptoms (outpatient study). RESULTS: Pimodivir + SoC (oseltamivir) treatment showed no clinical benefit over placebo + SoC on HRS at Day 6 (common odds ratio, 0.943 [95% CI, 0.609-1.462], P = .397; hospital study). A shorter median TTR of 7 symptoms was estimated with pimodivir + SoC versus placebo (92.6 hours [95% CI, 77.6-104.2] versus 105.1 hours [95% CI, 92.7-128.6], P = .0216; outpatient study). CONCLUSION: Pimodivir + SoC showed no additional clinical benefit versus SoC treatment alone in hospitalized patients. Pimodivir + SoC demonstrated shorter TTR of influenza symptoms versus placebo + SoC in high-risk outpatients.

2.
J Infect Dis ; 226(1): 109-118, 2022 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32604406

RESUMO

BACKGROUND: Both the elderly and individuals with comorbidities are at increased risk of developing influenza-related complications. Novel influenza antivirals are required, given limitations of current drugs (eg, resistance emergence and poor efficacy). Pimodivir is a first-in-class antiviral for influenza A under development for these patients. METHODS: Hospitalized patients with influenza A infection were randomized 2:1 to receive pimodivir 600 mg plus oseltamivir 75 mg or placebo plus oseltamivir 75 mg twice daily for 7 days in this phase 2b study. The primary objective was to compare pimodivir pharmacokinetics in elderly (aged 65-85 years) versus nonelderly adults (aged 18-64 years). Secondary end points included time to patient-reported symptom resolution. RESULTS: Pimodivir pharmacokinetic parameters in nonelderly and elderly patients were similar. Time to influenza symptom resolution was numerically shorter with pimodivir (72.45 hours) than placebo (94.15 hours). There was a lower incidence of influenza-related complications in the pimodivir group (7.9%) versus placebo group (15.6%). Treatment was generally well tolerated. CONCLUSIONS: No apparent relationship was observed between pimodivir pharmacokinetics and age. Our data demonstrate the need for a larger study of pimodivir in addition to oseltamivir to test whether it results in a clinically significant decrease in time-to-influenza-symptom alleviation and/or the frequency of influenza complications. CLINICAL TRIALS REGISTRATION: NCT02532283.


Assuntos
Influenza Humana , Oseltamivir , Adulto , Idoso , Humanos , Antivirais , Influenza Humana/tratamento farmacológico , Oseltamivir/uso terapêutico , Piridinas/uso terapêutico , Pirróis/farmacocinética , Resultado do Tratamento , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais
3.
J Infect Dis ; 219(7): 1026-1034, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30428049

RESUMO

BACKGROUND: Pimodivir, a first-in-class inhibitor of influenza virus polymerase basic protein 2, is being developed for hospitalized and high-risk patients with influenza A. METHODS: In this double-blinded phase 2b study, adults with acute uncomplicated influenza A were randomized 1:1:1:1 to receive one of the following treatments twice daily for 5 days: placebo, pimodivir 300 mg or 600 mg, or pimodivir 600 mg plus oseltamivir 75 mg. Antiviral activity, safety, and pharmacokinetics of pimodivir alone or in combination were evaluated. RESULTS: Of 292 patients randomized, 223 were treated and had confirmed influenza A virus infection. The trial was stopped early because the primary end point was met; the area under the curve of the viral load, determined by quantitative reverse transcription-polymerase chain reaction analysis, in nasal secretions from baseline to day 8 significantly decreased in the active treatment groups, compared with the placebo group (300 mg group, -3.6 day*log10 copies/mL [95% confidence interval {CI}, -7.1 to -0.1]; 600 mg group, -4.5 [95%CI -8.0 to -1.0]; and combination group, -8.6 [95% CI, -12.0 to -5.1]). Pimodivir plus oseltamivir yielded a significantly lower viral load titer over time than placebo and a trend for a shorter time to symptom resolution than placebo. Pimodivir plasma concentrations increased in a dose-proportional manner. The most commonly reported adverse event was mild or moderate diarrhea. CONCLUSIONS: Pimodivir (with or without oseltamivir) resulted in significant virologic improvements over placebo, demonstrated trends in clinical improvement, and was well tolerated. Pimodivir 600 mg twice daily is in further development. CLINICAL TRIALS REGISTRATION: NCT02342249, 2014-004068-39, and CR107745.


Assuntos
Antivirais/uso terapêutico , Vírus da Influenza A , Influenza Humana/tratamento farmacológico , Oseltamivir/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Doença Aguda , Adulto , Antivirais/efeitos adversos , Antivirais/sangue , Antivirais/farmacocinética , Diarreia/induzido quimicamente , Método Duplo-Cego , Farmacorresistência Viral/genética , Quimioterapia Combinada , Término Precoce de Ensaios Clínicos , Feminino , Humanos , Vírus da Influenza A/genética , Vírus da Influenza A/fisiologia , Influenza Humana/virologia , Masculino , Pessoa de Meia-Idade , Oseltamivir/sangue , Piridinas/efeitos adversos , Piridinas/sangue , Piridinas/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/sangue , Pirimidinas/farmacocinética , Pirróis/efeitos adversos , Pirróis/sangue , Pirróis/farmacocinética , Fatores de Tempo , Carga Viral , Proteínas Virais/genética , Eliminação de Partículas Virais
4.
Br J Clin Pharmacol ; 84(11): 2663-2672, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30098042

RESUMO

AIMS: The aim of this study was to evaluate the drug-drug interaction between pimodivir, a novel, non-nucleoside polymerase basic protein 2 (PB2) subunit inhibitor of the influenza A virus polymerase complex, and oseltamivir, to assess the feasibility of this combination therapy. Furthermore, single- and multiple-dose pharmacokinetics and safety of pimodivir in healthy volunteers were assessed. METHODS: In Part 1 of this open-label Phase 1 study, healthy volunteers (n = 18) were randomized to one of six cross-over treatment sequences, each comprising administration of oseltamivir 75 mg or pimodivir 600 mg or combination thereof twice daily on Days 1-4, followed by a single morning dose on Day 5. Between each treatment session, there was a minimum 5-day washout period. In Part 2, healthy volunteers (n = 16) randomly received pimodivir 600 mg or placebo (3:1) twice daily on Days 1-9, followed by a single morning dose on Day 10. Pharmacokinetics of pimodivir, oseltamivir and oseltamivir carboxylate, and safety were assessed. RESULTS: In Part 1, co-administration of pimodivir with oseltamivir increased the Cmax of pimodivir by 31% (90% CI: 0.92-1.85) with no change in Cmin or AUC12h . Pimodivir had no effect on oseltamivir or oseltamivir carboxylate pharmacokinetics. In Part 2, after single- and multiple-dose administration of pimodivir, there was a 1.2- and 1.8-fold increase in Cmax and AUC12h , respectively, between Day 1 and Day 10. The most frequently reported treatment-emergent adverse event was diarrhoea (n = 7 each in Part 1 and 2). CONCLUSION: Combination treatment with pimodivir and oseltamivir in healthy volunteers showed no clinically relevant drug-drug interactions. No safety concerns were identified with pimodivir 600 mg twice daily alone or in combination with oseltamivir 75 mg twice daily.


Assuntos
Antivirais/administração & dosagem , Oseltamivir/análogos & derivados , Piridinas/administração & dosagem , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Adolescente , Adulto , Antivirais/efeitos adversos , Antivirais/farmacocinética , Área Sob a Curva , Estudos Cross-Over , Diarreia/induzido quimicamente , Diarreia/epidemiologia , Método Duplo-Cego , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oseltamivir/administração & dosagem , Oseltamivir/farmacocinética , Piridinas/efeitos adversos , Piridinas/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Pirróis/efeitos adversos , Pirróis/farmacocinética , Fatores de Tempo , Adulto Jovem
5.
Int J Clin Pharmacol Ther ; 52(9): 805-16, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25109510

RESUMO

UNLABELLED: Once-daily darunavir/ritonavir (800/100 mg), plus other antiretrovirals, is recommended for HIV-1-infected patients. Low therapy adherence is linked with poor outcomes. Pill burden can impact adherence. An 800-mg darunavir tablet would reduce pill burden. OBJECTIVES: To assess the relative oral bioavailability (NCT01052883) and bioequivalence (NCT01308658) of a darunavir 800-mg tablet vs. 2 × 400-mg tablets. METHODS: In two phase I, open-label, randomized, crossover, single-center studies, healthy volunteers received once-daily ritonavir (100 mg, days 1 - 5) and a single 800-mg darunavir dose: 2 × 400-mg tablets (reference) or 1 × 800- mg tablet (test) on day 3 and vice versa after a ≥ 7-day wash-out. Each study had fasted (n = 16 (bioavailability); n = 83 (bioequivalence)) and fed panels (n = 16; n = 45, respectively). Pharmacokinetic profiles and tolerability were assessed. RESULTS: No volunteers discontinued for treatment-related reasons. Least-square mean ratios (test vs. reference) for darunavir maximum plasma concentrations (C(max)), area under the concentration-time curve from zero to infinity (AUC(0-∞)) were: 1.06 and 1.15 (bioavailability), and 1.02 and 1.00 (bioequivalence), respectively (fasted); 0.89 and 0.88 (bioavailability), and 0.96 and 0.98 (bioequivalence), respectively (fed). 90% confidence intervals (CI) were within 80.00 - 125.00%, except bioavailability AUC(0-∞) (fed and fasted conditions). Median time to C(max) was comparable for both formulations. No clinically relevant differences in adverse events or laboratory abnormalities occurred between formulations. CONCLUSIONS: Bioequivalence was demonstrated for the 800-mg darunavir tablet (fasted and fed conditions). This formulation can reduce pill burden and potentially increase adherence for HIV-1-infected patients in whom once-daily darunavir/ritonavir 800/100 mg is appropriate.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Administração Oral , Adolescente , Adulto , Fármacos Anti-HIV/sangue , Área Sob a Curva , Disponibilidade Biológica , Química Farmacêutica , Estudos Cross-Over , Darunavir , Esquema de Medicação , Quimioterapia Combinada , Jejum/sangue , Feminino , Meia-Vida , Voluntários Saudáveis , Humanos , Análise dos Mínimos Quadrados , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Período Pós-Prandial , Ritonavir/administração & dosagem , Sulfonamidas/sangue , Comprimidos , Equivalência Terapêutica , Adulto Jovem
6.
Int J Clin Pharmacol Ther ; 51(9): 725-37, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23924679

RESUMO

OBJECTIVES: Three studies were conducted to assess the pharmacokinetics, methods of administration and ease of swallowability of etravirine tablets. METHODS: Two randomized studies in healthy adults investigated the single-dose pharmacokinetics of etravirine in various dosage strengths and the effects of dispersion in water and film-coating. A third study explored swallowability of etravirine 200-mg tablets in HIV-infected patients. First study: 37 volunteers received 1 × 100-mg non-coated tablet (reference), 4 × 25-mg noncoated tablets and 1 × 100-mg non-coated tablet dispersed in 100 ml water. Second study: 24 volunteers received 2 × 100-mg non-coated tablets (reference), 2 × 100-mg coated tablets, 1 × 200-mg non-coated and 1 × 200-mg coated tablet. Pharmacokinetic parameters were determined using non-compartmental analysis and least square means (LSM) ratios and 90% confidence intervals (CI) were calculated. Third study: 49 virologically-suppressed patients already on an etravirine-containing regimen rated the swallowability of two etravirine formulations (200-mg non-coated and 200-mg coated tablets). RESULTS: In the first study LSM ratios (90% CI) for the etravirine area under the plasma concentration-time curve (AUC) administered either as 4 × 25-mg tablets or 100-mg tablet dispersed were: 0.91 (0.85 to 0.98) and 0.97 (0.90 to 1.03), respectively. In the second study, when comparing a 200-mg non-coated and coated tablet to 2 × 100-mg non-coated tablets, LSM ratios for etravirine AUC were 98 to 99%. In the third study, more patients rated the 200-mg than the 100-mg tablets as acceptable to swallow (70% vs. 43%). CONCLUSIONS: Comparable etravirine exposures were observed regardless of formulation or method of administration (i.e., dispersion); 200-mg tablets were rated as easier to swallow than 100-mg tablets.


Assuntos
Piridazinas/farmacocinética , Inibidores da Transcriptase Reversa/farmacocinética , Adulto , Idoso , Disponibilidade Biológica , Química Farmacêutica , Criança , Deglutição , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas , Piridazinas/efeitos adversos , Pirimidinas , Comprimidos
7.
Antivir Ther ; 28(3): 13596535231174273, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37226302

RESUMO

BACKGROUND: Pimodivir is a first-in-class polymerase basic protein 2 (PB2) subunit inhibitor of the influenza A polymerase complex. The randomized double-blinded placebo-controlled phase 2b TOPAZ study demonstrated antiviral activity and safety of twice daily pimodivir alone (300 mg, 600 mg) or in combination with oseltamivir (pimodivir 600 mg, oseltamivir 75 mg) in adult study participants with acute uncomplicated influenza A. The detailed genotypic and phenotypic characterization of viral variants observed in this study are reported. METHODS: Population sequencing of PB2 and neuraminidase genes, and phenotypic susceptibility testing, were performed using baseline and last virus-positive post-baseline nasal swab samples. RESULTS: Sequencing of baseline samples in 206 of 223 (92.4%) randomized study participants with confirmed influenza A infection identified no polymorphisms at any predefined PB2 positions of interest for pimodivir and no phenotypic reduced susceptibility to pimodivir was observed. Post-baseline sequencing data for 105/223 (47.1%) participants identified emergence of PB2 mutations at amino acid positions of interest in 10 (9.5%) participants (pimodivir 300 mg: n = 3; 600 mg: n = 6; combination: n = 1; placebo: n = 0) and included positions S324, F325, S337, K376, T378, and N510. These emerging mutations were typically associated with decreased pimodivir susceptibility, but not viral breakthrough. No reduced phenotypic susceptibility was observed in the one (1.8%) participant with emerging PB2 mutations from the pimodivir plus oseltamivir group. CONCLUSIONS: Participants with acute uncomplicated influenza A treated with pimodivir in the TOPAZ study infrequently developed reduced susceptibility to pimodivir and combining pimodivir with oseltamivir further decreased the risk of reduced susceptibility development.


Assuntos
Vírus da Influenza A , Influenza Humana , Adulto , Humanos , Oseltamivir/uso terapêutico , Influenza Humana/tratamento farmacológico , Genótipo , Antivirais/farmacologia , Antivirais/uso terapêutico , Vírus da Influenza A/genética
8.
Contemp Clin Trials ; 123: 106952, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36202198

RESUMO

BACKGROUND: Currently, no single best primary endpoint exists for measuring the efficacy of treatments in seriously ill patients with respiratory infections, such as influenza, who require hospitalization. The Hospital Recovery Scale is an ordinal endpoint used to evaluate treatment outcomes in clinical studies of hospitalized patients infected with influenza. METHODS: To determine whether Hospital Recovery Scale outcomes correspond to those for other clinical endpoints in patients hospitalized due to influenza, data from the phase 3 randomized, double-blind ZORO clinical trial (NCT01231620) were analyzed. Randomized influenza-infected patients were divided into subgroups of interest based on prespecified baseline and infection-related characteristics, as well as randomized treatment arms (intravenous zanamivir 300 mg or 600 mg, or oral oseltamivir 75 mg). Clinical endpoints relevant to this population were included to analyze differences in outcomes between the subgroups, and correspondence of these endpoints and hospital recovery endpoint was evaluated. RESULTS: Data from 488 patients were analyzed. There were strong correlations (ρs > 0.8) between the Hospital Recovery Scale assessed on the day after completion of a 5-day antiviral therapy (Day 6) and both time to hospital discharge and time to intensive care unit discharge, and moderate to strong correlations (0.6 < ρs < 0.8) between the Hospital Recovery Scale on Day 6 and several other relevant clinical endpoints. CONCLUSIONS: The Hospital Recovery Scale is applicable as a primary endpoint in trials to evaluate new therapies for severely ill patients hospitalized due to influenza, and may have utility in other severe respiratory illnesses such as COVID-19.


Assuntos
COVID-19 , Influenza Humana , Humanos , Influenza Humana/tratamento farmacológico , Influenza Humana/induzido quimicamente , Oseltamivir/uso terapêutico , Hospitalização , Resultado do Tratamento , Hospitais , Antivirais
9.
Lancet ; 370(9581): 29-38, 2007 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-17617270

RESUMO

BACKGROUND: Antiretroviral agents active against drug-resistant HIV-1 are needed for treatment-experienced patients. The aim of this trial was to assess the efficacy, safety, and tolerability of TMC125 (etravirine), a non-nucleoside reverse transcriptase inhibitor (NNRTI). METHODS: DUET-1 is a continuing, multinational randomised, double-blind, placebo-controlled, phase III trial. Treatment-experienced adult patients with virological failure on stable antiretroviral therapy, documented genotypic evidence of NNRTI resistance, viral load over 5000 copies per mL, and three or more primary protease inhibitor mutations were randomly assigned to receive 200 mg TMC125 or placebo twice daily. All patients also received darunavir with low-dose ritonavir and investigator-selected nucleoside reverse transcriptase inhibitors. Enfuvirtide use was optional. The primary endpoint was a confirmed viral load below 50 copies per mL at week 24 (FDA time-to-loss of virological response algorithm). Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, with the number NCT00254046. FINDINGS: 612 patients were randomised and treated (304 in the TMC125 group, 308 in the placebo group). By week 24, 42 (14%) patients in the TMC125 group and 56 (18%) in the placebo group had discontinued, mainly due to virological failure. At week 24, 170 (56%) patients in the TMC125 group and 119 (39%) patients in the placebo group achieved a confirmed viral load of less than 50 copies per mL (difference in response rates 17%; 95% CI 9-25; p=0.005). Most adverse events were mild or moderate in severity. The type and incidence of adverse events, including neuropsychiatric events, seen with TMC125 were generally comparable with placebo, with the exception of rash (61 [20%] patients on TMC125 vs 30 [10%] on placebo) and diarrhoea (36 [12%] patients on TMC125 vs 63 [20%] on placebo). INTERPRETATION: In treatment-experienced patients with NNRTI resistance, treatment with TMC125 achieved better virological suppression at week 24 than did placebo. The safety and tolerability profile of TMC125 was generally comparable with placebo.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Piridazinas/uso terapêutico , Adulto , Idoso , Fármacos Anti-HIV/efeitos adversos , Método Duplo-Cego , Feminino , Infecções por HIV/classificação , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas , Piridazinas/efeitos adversos , Pirimidinas , Índice de Gravidade de Doença
10.
Antivir Ther ; 23(4): 335-344, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29244026

RESUMO

BACKGROUND: Pimodivir (formerly JNJ-63623872) is a novel, non-nucleoside polymerase complex inhibitor with in vitro activity against influenza A virus, including pandemic 2009 H1N1, H7N9, H5N1 strains as well as neuraminidase- and amantadine-resistant strains. METHODS: Randomized, double-blind, placebo-controlled, Phase IIa study. Healthy volunteers (n=104) were inoculated with an influenza A/Wisconsin/67/2005 (H3N2) challenge virus. 72 received pimodivir and 32 placebo. Pimodivir was dosed for 5 days once daily from 24 h after viral inoculation at four dose levels: 100 mg, 400 mg, loading dose 900/600 mg and loading dose 1,200/600 mg. RESULTS: Pimodivir significantly reduced viral shedding (area under the concentration versus time curve [AUC] measured by 50% tissue culture infective dose [TCID50] or qRT-PCR) versus placebo as measured by cell culture assay in the pooled analysis (Jonckheere-Terpstra dose-response trend test [P=0.036]). Reductions were observed in viral shedding (AUC, duration and peak measured by grade), influenza-like symptoms (AUC, duration and peak measured by grade) and clinical symptoms (duration and peak measured by grade) for all pimodivir groups versus placebo, significantly so for the 1,200/600 mg group. In the 1,200/600 mg group viral shedding (AUC) by qRT-PCR was 0.45 versus 18.4 log10 copies/ml*day for pooled placebo (P=0.014). Pimodivir was generally safe and well-tolerated with no serious adverse events or adverse events leading to discontinuation. CONCLUSIONS: Pimodivir has potential to not only reduce viral load but to have a clinical impact on patients as a novel treatment for influenza A virus infection. Further trials are therefore warranted to assess pimodivir.


Assuntos
Antivirais/uso terapêutico , Vírus da Influenza A/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Adolescente , Adulto , Antivirais/administração & dosagem , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Resultado do Tratamento , Carga Viral/efeitos dos fármacos , Voluntários , Adulto Jovem
11.
J Clin Pharmacol ; 54(4): 422-31, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24165884

RESUMO

The effect of etravirine on cytochrome P450 (CYP) enzymes and P-glycoprotein were evaluated in two randomized, crossover trials in healthy subjects. A modified Cooperstown 5 + 1 cocktail was utilized to determine the effects of etravirine on single-dose pharmacokinetics of model CYP probes. The cocktail was administered alone, then, after a 14-day washout, etravirine 200 mg twice daily (bid) was given for 14 days with cocktail on days 1 and 14. In a separate study, digoxin (0.5 mg) was administered alone, then, after a 14-day washout, etravirine 200 mg bid was administered for 12 days with digoxin on day 8. In the cocktail study, the AUClast least squares mean (LSM) ratios (90% confidence intervals [CIs]) for cocktail + etravirine versus cocktail were 0.93 (0.88, 0.99; paraxanthine), 0.58 (0.44, 0.75; 7-OH-S-warfarin), 0.43 (0.20, 0.96; 5-OH-omeprazole), 0.85 (0.78, 0.94; dextrorphan), and 0.69 (0.64, 0.74; midazolam). Digoxin AUC0-8h was slightly increased with etravirine coadministration (LSM ratio 1.18 [0.90, 1.56]). These data suggest that etravirine is a weak CYP3A isozyme inducer and minimally inhibits CYP2C9, 2C19, and P-glycoprotein activity.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Fármacos Anti-HIV/administração & dosagem , Sistema Enzimático do Citocromo P-450/metabolismo , Digoxina/administração & dosagem , Piridazinas/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Adolescente , Adulto , Cafeína/administração & dosagem , Cafeína/farmacocinética , Estudos Cross-Over , Dextrometorfano/administração & dosagem , Dextrometorfano/farmacocinética , Digoxina/farmacocinética , Feminino , Voluntários Saudáveis , Humanos , Masculino , Midazolam/administração & dosagem , Midazolam/farmacocinética , Pessoa de Meia-Idade , Nitrilas , Omeprazol/administração & dosagem , Omeprazol/farmacocinética , Pirimidinas , Teofilina/administração & dosagem , Teofilina/farmacocinética , Varfarina/administração & dosagem , Varfarina/farmacocinética , Adulto Jovem
12.
J Clin Pharmacol ; 54(5): 563-73, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-25975423

RESUMO

Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) may require treatment with an HIV non-nucleoside reverse transcriptase inhibitor (NNRTI), for example, rilpivirine or etravirine, and an HCV direct-acting antiviral drug such as telaprevir. In a two-panel, two-way, crossover study, healthy volunteers were randomized to receive etravirine 200 mg twice daily ± telaprevir 750 mg every 8 hours or rilpivirine 25 mg once daily ± telaprevir 750 mg every 8 hours. Pharmacokinetic assessments were conducted for each drug at steady-state when given alone and when coadministered; statistical analyses were least-square means with 90% confidence intervals. Telaprevir minimum plasma concentration (Cmin), maximum plasma concentration (Cmax), and area under the concentration-time curve (AUC) decreased 25%, 10%, and 16%, respectively, when coadministered with etravirine and 11%, 3%, and 5%, respectively, when coadministered with rilpivirine. Telaprevir did not affect etravirine pharmacokinetics, but increased rilpivirine Cmin, Cmax, and AUC by 93%, 49%, and 78%, respectively. Both combinations were generally well tolerated. The small decrease in telaprevir exposure when coadministered with etravirine is unlikely to be clinically relevant. The interaction between telaprevir and rilpivirine is not likely to be clinically relevant under most circumstances. No dose adjustments are deemed necessary when they are coadministered.


Assuntos
Fármacos Anti-HIV , Nitrilas , Oligopeptídeos , Piridazinas , Pirimidinas , Inibidores da Transcriptase Reversa , Adolescente , Adulto , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Estudos Cross-Over , Interações Medicamentosas , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas/efeitos adversos , Nitrilas/sangue , Nitrilas/farmacocinética , Nitrilas/farmacologia , Oligopeptídeos/efeitos adversos , Oligopeptídeos/sangue , Oligopeptídeos/farmacocinética , Oligopeptídeos/farmacologia , Piridazinas/efeitos adversos , Piridazinas/sangue , Piridazinas/farmacocinética , Piridazinas/farmacologia , Pirimidinas/efeitos adversos , Pirimidinas/sangue , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/sangue , Inibidores da Transcriptase Reversa/farmacocinética , Inibidores da Transcriptase Reversa/farmacologia , Rilpivirina , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA