RESUMEN
BACKGROUND: Dupilumab is a human monoclonal antibody that blocks interleukin-4 and interleukin-13 pathways and has shown efficacy in five different atopic diseases marked by type 2 inflammation, including eosinophilic esophagitis in adults and adolescents. METHODS: In this phase 3 trial, we randomly assigned, in a 2:2:1:1 ratio, patients 1 to 11 years of age with active eosinophilic esophagitis who had had no response to proton-pump inhibitors to 16 weeks of a higher-exposure or lower-exposure subcutaneous dupilumab regimen or to placebo (two groups) (Part A). At the end of Part A, eligible patients in each dupilumab group continued the same regimen and those in the placebo groups were assigned to higher-exposure or lower-exposure dupilumab for 36 weeks (Part B). At each level of exposure, dupilumab was administered in one of four doses tiered according to baseline body weight. The primary end point was histologic remission (peak esophageal intraepithelial eosinophil count, ≤6 per high-power field) at week 16. Key secondary end points were tested hierarchically. RESULTS: In Part A, histologic remission occurred in 25 of the 37 patients (68%) in the higher-exposure group, in 18 of the 31 patients (58%) in the lower-exposure group, and in 1 of the 34 patients (3%) in the placebo group (difference between the higher-exposure regimen and placebo, 65 percentage points [95% confidence interval {CI}, 48 to 81; P<0.001]; difference between the lower-exposure regimen and placebo, 55 percentage points [95% CI, 37 to 73; P<0.001]). The higher-exposure dupilumab regimen led to significant improvements in histologic, endoscopic, and transcriptomic measures as compared with placebo. The improvements in histologic, endoscopic, and transcriptomic measures between baseline and week 52 in all the patients were generally similar to the improvements between baseline and week 16 in the patients who received dupilumab in Part A. In Part A, the incidence of coronavirus disease 2019, nausea, injection-site pain, and headache was at least 10 percentage points higher among the patients who received dupilumab (at either dose) than among those who received placebo. Serious adverse events were reported in 3 patients who received dupilumab during Part A and in 6 patients overall during Part B. CONCLUSIONS: Dupilumab resulted in histologic remission in a significantly higher percentage of children with eosinophilic esophagitis than placebo. The higher-exposure dupilumab regimen also led to improvements in measures of key secondary end points as compared with placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; EoE KIDS ClinicalTrials.gov number, NCT04394351.).
Asunto(s)
Anticuerpos Monoclonales Humanizados , Esofagitis Eosinofílica , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esofagitis Eosinofílica/tratamiento farmacológico , Esofagitis Eosinofílica/inmunología , Esofagitis Eosinofílica/patología , Eosinófilos/inmunología , Eosinófilos/patología , Esófago/efectos de los fármacos , Esófago/inmunología , Esófago/patología , Inyecciones Subcutáneas , Interleucina-13/antagonistas & inhibidores , Interleucina-4/antagonistas & inhibidores , Inducción de Remisión , Inhibidores de la Bomba de Protones/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Dupilumab, a fully human monoclonal antibody, blocks interleukin-4 and interleukin-13 signaling, which have key roles in eosinophilic esophagitis. METHODS: We conducted a three-part, phase 3 trial in which patients 12 years of age or older underwent randomization in a 1:1 ratio to receive subcutaneous dupilumab at a weekly dose of 300 mg or placebo (Part A) or in a 1:1:1 ratio to receive 300 mg of dupilumab either weekly or every 2 weeks or weekly placebo (Part B) up to week 24. Eligible patients who completed Part A or Part B continued the trial in Part C, in which those who completed Part A received dupilumab at a weekly dose of 300 mg up to week 52 (the Part A-C group); Part C that included the eligible patients from Part B is ongoing. The two primary end points at week 24 were histologic remission (≤6 eosinophils per high-power field) and the change from baseline in the Dysphagia Symptom Questionnaire (DSQ) score (range, 0 to 84, with higher values indicating more frequent or more severe dysphagia). RESULTS: In Part A, histologic remission occurred in 25 of 42 patients (60%) who received weekly dupilumab and in 2 of 39 patients (5%) who received placebo (difference, 55 percentage points; 95% confidence interval [CI], 40 to 71; P<0.001). In Part B, histologic remission occurred in 47 of 80 patients (59%) with weekly dupilumab, in 49 of 81 patients (60%) with dupilumab every 2 weeks, and in 5 of 79 patients (6%) with placebo (difference between weekly dupilumab and placebo, 54 percentage points; 95% CI, 41 to 66 [P<0.001]; difference between dupilumab every 2 weeks and placebo, 56 percentage points; 95% CI, 43 to 69 [not significant per hierarchical testing]). The mean (±SD) DSQ scores at baseline were 33.6±12.41 in Part A and 36.7±11.22 in Part B; the scores improved with weekly dupilumab as compared with placebo, with differences of -12.32 (95% CI, -19.11 to -5.54) in Part A and -9.92 (95% CI, -14.81 to -5.02) in Part B (both P<0.001) but not with dupilumab every 2 weeks (difference in Part B, -0.51; 95% CI, -5.42 to 4.41). Serious adverse events occurred in 9 patients during the Part A or B treatment period (in 7 who received weekly dupilumab, 1 who received dupilumab every 2 weeks, and 1 who received placebo) and in 1 patient in the Part A-C group during the Part C treatment period who received placebo in Part A and weekly dupilumab in Part C. CONCLUSIONS: Among patients with eosinophilic esophagitis, subcutaneous dupilumab administered weekly improved histologic outcomes and alleviated symptoms of the disease. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03633617.).
Asunto(s)
Anticuerpos Monoclonales Humanizados , Trastornos de Deglución , Esofagitis Eosinofílica , Adolescente , Adulto , Humanos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Trastornos de Deglución/tratamiento farmacológico , Trastornos de Deglución/etiología , Trastornos de Deglución/patología , Método Doble Ciego , Esofagitis Eosinofílica/complicaciones , Esofagitis Eosinofílica/tratamiento farmacológico , Esofagitis Eosinofílica/patología , Inyecciones Subcutáneas , Resultado del Tratamiento , Niño , Adulto JovenRESUMEN
BACKGROUND: Current systemic treatments for children younger than 6 years with moderate-to-severe atopic dermatitis that is uncontrolled with topical therapies might have suboptimal efficacy and safety. Dupilumab is approved for older children and adults with atopic dermatitis and for other type 2 inflammatory conditions. We aimed to evaluate efficacy and safety of dupilumab with concomitant low-potency topical corticosteroids in children aged 6 months to younger than 6 years with moderate-to-severe atopic dermatitis. METHODS: This randomised, double-blind, placebo-controlled, parallel-group, phase 3 trial was conducted in 31 hospitals, clinics, and academic institutions in Europe and North America. Eligible patients were aged 6 months to younger than 6 years, with moderate-to-severe atopic dermatitis (Investigator's Global Assessment [IGA] score 3-4) diagnosed according to consensus criteria of the American Academy of Dermatology, and an inadequate response to topical corticosteroids. Patients were randomly assigned (1:1) to subcutaneous placebo or dupilumab (bodyweight ≥5 kg to <15 kg: 200 mg; bodyweight ≥15 kg to <30 kg: 300 mg) every 4 weeks plus low-potency topical corticosteroids (hydrocortisone acetate 1% cream) for 16 weeks. Randomisation was stratified by age, baseline bodyweight, and region. Patient allocation was done via a central interactive web response system, and treatment allocation was masked. The primary endpoint at week 16 was the proportion of patients with IGA score 0-1 (clear or almost clear skin). The key secondary endpoint (coprimary endpoint for the EU and EU reference market) at week 16 was the proportion of patients with at least a 75% improvement from baseline in Eczema Area and Severity Index (EASI-75). Primary analyses were done in the full analysis set (ie, all randomly assigned patients, as randomly assigned) and safety analyses were done in all patients who received any study drug. This study was registered with ClinicalTrials.gov, NCT03346434. FINDINGS: Between June 30, 2020, and Feb 12, 2021, 197 patients were screened for eligibility, 162 of whom were randomly assigned to receive dupilumab (n=83) or placebo (n=79) plus topical corticosteroids. At week 16, significantly more patients in the dupilumab group than in the placebo group had IGA 0-1 (23 [28%] vs three [4%], difference 24% [95% CI 13-34]; p<0·0001) and EASI-75 (44 [53%] vs eight [11%], difference 42% [95% CI 29-55]; p<0·0001). Overall prevalence of adverse events was similar in the dupilumab group (53 [64%] of 83 patients) and placebo group (58 [74%] of 78 patients). Conjunctivitis incidence was higher in the dupilumab group (four [5%]) than the placebo group (none). No dupilumab-related adverse events were serious or led to treatment discontinuation. INTERPRETATION: Dupilumab significantly improved atopic dermatitis signs and symptoms versus placebo in children younger than 6 years. Dupilumab was well tolerated and showed an acceptable safety profile, similar to results in older children and adults. FUNDING: Sanofi and Regeneron Pharmaceuticals.
Asunto(s)
Dermatitis Atópica , Fármacos Dermatológicos , Adolescente , Adulto , Niño , Dermatitis Atópica/tratamiento farmacológico , Fármacos Dermatológicos/efectos adversos , Glucocorticoides/uso terapéutico , Humanos , Inmunoglobulina A/uso terapéutico , Preparaciones Farmacéuticas , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Estados UnidosRESUMEN
BACKGROUND: While the majority of patients with atopic dermatitis (AD) achieve disease control with dupilumab treatment, there is variability in which patients achieve clear disease. The predictors of these responses are currently unclear. Integrated models were developed to evaluate the exposure-response (E-R) relationship of dupilumab in children, adolescents, and adults with AD. METHODS: Data from six Phase II and III clinical studies were pooled (2,366 adults [> 18 years], 243 adolescents [≥ 12 to < 18 years] and 359 children [≥ 6 to < 12 years]) for model development. Efficacy was assessed using the Eczema Area and Severity Index (EASI) and Investigator's Global Assessment (IGA). Indirect response models were applied to link measures of efficacy and functional serum dupilumab concentrations. The covariates on individual placebo-corrected response were assessed. Clinical trial scenarios were simulated to compare E-R relationships across age groups. Safety was not explored. RESULTS: After correcting for differences in placebo response and dupilumab exposure: 1) older age, higher body weight, lower baseline thymus and activation-regulated chemokine, and Asian race were associated with slightly lower EASI response, and no clear covariates were identified on IGA response; 2) clinical trial simulations generally showed slightly higher response at a given dupilumab concentration in children compared to adults and adolescents with severe and moderate AD. CONCLUSIONS: The collectively tested covariates explain some of the variability in dupilumab response in patients with AD. Patients in all age groups showed adequate response to dupilumab; however, children showed slightly higher drug effects compared to adults and adolescents at equivalent concentrations.
Asunto(s)
Dermatitis Atópica , Adolescente , Adulto , Niño , Humanos , Dermatitis Atópica/tratamiento farmacológico , Método Doble Ciego , Inyecciones Subcutáneas , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como AsuntoRESUMEN
BACKGROUND: Treatment of patients coinfected with hepatitis C and human immunodeficiency viruses (HCV; HIV) requires careful consideration of potential drug-drug interactions between HCV direct-acting antiviral agents (DAA) and HIV antiretrovirals. Glecaprevir/pibrentasvir is a fixed-dose combination of an NS3/4A protease inhibitor and an NS5A inhibitor approved for the treatment of chronic HCV genotype 1-6 infection, including patients with HIV coinfection. METHODS: A series of phase 1 studies was conducted to evaluate potential interactions of glecaprevir and pibrentasvir with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, abacavir/dolutegravir/lamivudine, raltegravir, rilpivirine, atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, or efavirenz/emtricitabine/tenofovir disoproxil fumarate. Pharmacokinetics of the antiretrovirals and DAAs were characterized when administered alone and in combination to quantify changes in systemic drug exposure. RESULTS: Glecaprevir area under the curve increased >4-fold in the presence of ritonavir-boosted HIV protease inhibitors, while pibrentasvir concentrations were not significantly affected; elevations in alanine transaminase occurred in combination with atazanavir/ritonavir only. Exposures of glecaprevir and pibrentasvir may be significantly decreased by efavirenz. Coadministration with glecaprevir and pibrentasvir did not result in clinically significant changes in the exposure of any antiretroviral agents. CONCLUSIONS: Atazanavir is contraindicated with glecaprevir/pibrentasvir and use of boosted protease inhibitors or efavirenz is not recommended. No clinically significant interactions were observed with other studied antiretrovirals.
Asunto(s)
Antirretrovirales/farmacología , Bencimidazoles/farmacología , Coinfección/tratamiento farmacológico , Interacciones Farmacológicas , Infecciones por VIH/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Pirrolidinas/farmacología , Quinoxalinas/farmacología , Sulfonamidas/farmacología , Adulto , Antirretrovirales/farmacocinética , Antirretrovirales/uso terapéutico , Bencimidazoles/farmacocinética , Bencimidazoles/uso terapéutico , Contraindicaciones de los Medicamentos , Combinación de Medicamentos , Femenino , Hepatitis C Crónica/complicaciones , Humanos , Masculino , Pirrolidinas/farmacocinética , Pirrolidinas/uso terapéutico , Quinoxalinas/farmacocinética , Quinoxalinas/uso terapéutico , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapéuticoRESUMEN
BACKGROUND & AIMS: Proton pump inhibitors (PPIs) are commonly prescribed to treat acid-related disorders. Some direct-acting antiviral regimens for chronic hepatitis C virus (HCV) infection have reduced efficacy in patients taking concomitant acid-reducing agents, including PPIs, due to interactions between drugs. We analyzed data from 9 multicenter, phase 2 and 3 trials to determine the efficacy and pharmacokinetics of an HCV therapeutic regimen comprising glecaprevir and pibrentasvir (glecaprevir/pibrentasvir) in patients taking concomitant acid-reducing agents. METHODS: We analyzed data from 2369 patients infected with HCV genotypes 1-6 and compensated liver disease treated with an all-oral regimen of glecaprevir/pibrentasvir for 8-16 weeks. We compared efficacy and pharmacokinetics among patients receiving at least 1 dose of an acid-reducing agent (a PPI, an H2 blocker, or antacid). High-dose PPI was defined as daily dose greater than 20 mg omeprazole dose equivalent. The objectives were to evaluate rate of sustained virologic response 12 weeks post-treatment (SVR12) and to assess steady-state glecaprevir and pibrentasvir exposures in patients on acid-reducing agents. RESULTS: Of the 401 patients (17%) who reported use of acid-reducing agents, 263 took PPIs (11%; 109 patients took a high-dose PPI and 154 patients took a low-dose PPI). Rates of SVR12 were 97.0% among patients who used acid-reducing agents and 97.5% among those not using acid-reducing agents (P = .6). An SVR12 was achieved in 96.3% taking a high-dose PPI and 97.4% taking a low-dose PPI, with no virologic failures in those receiving a high-dose PPI (P = .7). Glecaprevir, but not pibrentasvir, bioavailability was affected; its exposure decreased by 41% in patients taking a high-dose PPI. CONCLUSIONS: In an analysis of data from 9 clinical trials, we observed a high rate of SVR12 (approximately 97%) among patients treated with glecaprevir/pibrentasvir for HCV infection-even among patients taking concomitant ARA or high-dose PPI. This was despite decreased glecaprevir exposures in patients when on high-dose PPIs. ClinicalTrials.gov numbers, NCT02243280 (SURVEYOR-I), NCT02243293 (SURVEYOR-II), NCT02604017 (ENDURANCE-1), NCT02640482 (ENDURANCE-2), NCT02640157 (ENDURANCE-3), NCT02636595 (ENDURANCE-4), NCT02642432 (EXPEDITION-1), NCT02651194 (EXPEDITION-4), NCT02446717 (MAGELLAN-I).
Asunto(s)
Antivirales/administración & dosificación , Antivirales/farmacocinética , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacocinética , Hepatitis C Crónica/tratamiento farmacológico , Inhibidores de la Bomba de Protones/administración & dosificación , Pirrolidinas/administración & dosificación , Pirrolidinas/farmacocinética , Quinoxalinas/administración & dosificación , Quinoxalinas/farmacocinética , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacocinética , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Animales , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Combinación de Medicamentos , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Respuesta Virológica Sostenida , Resultado del Tratamiento , Adulto JovenRESUMEN
Glecaprevir and pibrentasvir are oral direct-acting antiviral agents approved in combination for treatment of chronic hepatitis C viral infection. In vitro studies identified the combination as potentially clinically relevant inhibitors of the efflux transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and the hepatic uptake transporters organic anion transporting polypeptide (OATP) 1B1 and OATP1B3. Glecaprevir inhibited P-gp, BCRP, OATP1B1, and OATP1B3 with IC50 values of 0.33, 2.3, 0.017, and 0.064 µM, respectively. Pibrentasvir inhibited P-gp, BCRP, and OATP1B1 with IC50 values of 0.036, 14, and 1.3 µM, respectively. Neither agent inhibited organic cation transporter (OCT) 1, OCT2, organic anion transporter (OAT) 1, OAT3, multidrug and toxin extrusion (MATE) 1, or MATE2K. Open-label phase 1 clinical drug-drug interaction studies were conducted in healthy subjects to evaluate interaction potential of glecaprevir/pibrentasvir and coadministered selective substrates for P-gp (digoxin, dabigatran etexilate, and sofosbuvir), BCRP (rosuvastatin and sofosbuvir), and OATP1B1/3 (pravastatin and rosuvastatin). The pharmacokinetic maximum plasma concentration (C max) and area under the concentration-time curve (AUC) parameters were evaluated for probe substrates alone and in combination with glecaprevir/pibrentasvir. The C max central values increased by 72%, 105%, 123%, 462%, and 66% for digoxin, dabigatran, pravastatin, rosuvastatin, and sofosbuvir, respectively, and the AUC central values increased by 48%, 138%, 130%, 115%, and 125% for digoxin, dabigatran, pravastatin, rosuvastatin, and sofosbuvir, respectively. Exposure of sofosbuvir metabolite GS-331007 (nucleoside analog) was similar with or without glecaprevir/pibrentasvir. The outcomes of the clinical drug-drug interaction studies confirmed clinically relevant inhibition of P-gp, BCRP, and OATP1B1/3, and were used to provide dosing guidance for the concomitant use of glecaprevir/pibrentasvir with relevant transporter substrates.
Asunto(s)
Bencimidazoles/farmacología , Pirrolidinas/farmacología , Quinoxalinas/farmacología , Sulfonamidas/farmacología , Investigación Biomédica Traslacional , Adulto , Anciano , Bencimidazoles/farmacocinética , Transporte Biológico/efectos de los fármacos , Combinación de Medicamentos , Interacciones Farmacológicas , Femenino , Voluntarios Sanos , Humanos , Masculino , Proteínas de Transporte de Membrana/metabolismo , Persona de Mediana Edad , Pirrolidinas/farmacocinética , Quinoxalinas/farmacocinética , Sulfonamidas/farmacocinética , Distribución Tisular , Adulto JovenRESUMEN
PURPOSE: This study characterized the effects of hepatic impairment on the pharmacokinetics and safety of glecaprevir and pibrentasvir, two direct-acting antivirals used for treatment of chronic HCV infection. METHODS: HCV-negative subjects with normal hepatic function, or with mild (Child-Pugh [CP]-A), moderate (CP-B), or severe (CP-C) hepatic impairment received single doses of pibrentasvir 120 mg alone or with glecaprevir 200 mg or 300 mg (n = 6/functional group/dose). Plasma pharmacokinetics and protein binding were evaluated. Doses were separated by ≥ 14 days of washout. RESULTS: For the approved combination of glecaprevir 300 mg with pibrentasvir 120 mg, glecaprevir AUC was increased by 33% (CP-A), to 2.0-fold (CP-B), and to 11-fold (CP-C) relative to normal subjects; pibrentasvir AUC was ≤ 26% different (CP-A or CP-B) and increased to 2.1-fold (CP-C). For glecaprevir 200 mg with pibrentasvir 120 mg, glecaprevir AUC was increased by 80% (CP-A) or to 2.8-fold (CP-B), while pibrentasvir AUC was unaffected in the same subjects (≤ 12% difference). Pibrentasvir 120 mg alone AUC increased 51% (CP-A), 31% (CP-B), and to 5.2-fold (CP-C). The unbound fraction of glecaprevir was higher in CP-C subjects than normal subjects and pibrentasvir protein binding was similar across groups. The most common adverse event was headache; no events were serious. CONCLUSION: This study supported evaluation of the glecaprevir 300 mg with pibrentasvir 120-mg combination in HCV-infected subjects with CP-A hepatic impairment without dose adjustment. Elevated glecaprevir and/or pibrentasvir exposures are expected in HCV-infected patients with CP-B or CP-C hepatic impairment.
Asunto(s)
Antivirales/efectos adversos , Antivirales/farmacocinética , Bencimidazoles/efectos adversos , Bencimidazoles/farmacocinética , Hepatopatías/dietoterapia , Quinoxalinas/efectos adversos , Quinoxalinas/farmacocinética , Sulfonamidas/efectos adversos , Sulfonamidas/farmacocinética , Adolescente , Ácidos Aminoisobutíricos , Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Ciclopropanos , Quimioterapia Combinada , Femenino , Genotipo , Hepacivirus/efectos de los fármacos , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Hígado/efectos de los fármacos , Hepatopatías/metabolismo , Masculino , Persona de Mediana Edad , Prolina/análogos & derivados , Pirrolidinas , Quinoxalinas/uso terapéutico , Sulfonamidas/uso terapéuticoRESUMEN
Background: Once-daily glecaprevir coformulated with pibrentasvir (glecaprevir/pibrentasvir) demonstrated high rates of sustained virologic response 12 weeks after treatment (SVR12) in patients with hepatitis C virus (HCV) genotype 1-6 infection. This phase 3 study evaluated the efficacy and safety of glecaprevir/pibrentasvir in patients with chronic HCV genotype 1-6 and human immunodeficiency virus type 1 (HIV-1) coinfection, including patients with compensated cirrhosis. Methods: EXPEDITION-2 was a phase 3, multicenter, open-label study evaluating glecaprevir/pibrentasvir (300 mg/120 mg) in HCV genotype 1-6/HIV-1-coinfected adults without and with compensated cirrhosis for 8 and 12 weeks, respectively. Patients were either HCV treatment-naive or experienced with sofosbuvir, ribavirin, or interferon, and antiretroviral therapy (ART) naive or on a stable ART regimen. Treatment-experienced genotype 3-infected patients were excluded. The primary endpoint was the SVR12 rate. Results: In total, 153 patients were enrolled, including 16 (10%) with cirrhosis. The SVR12 rate was 98% (n = 150/153; 95% confidence interval, 95.8-100), with no virologic failures in 137 patients treated for 8 weeks. One genotype 3-infected patient with cirrhosis had on-treatment virologic failure. Most adverse events were mild in severity; 4 patients (2.6%) had serious adverse events, all deemed unrelated to glecaprevir/pibrentasvir. Treatment discontinuation was rare (<1%). All patients treated with ART maintained HIV-1 suppression (<200 copies/mL) during treatment. Conclusions: Glecaprevir/pibrentasvir for 8 weeks in noncirrhotic and 12 weeks in cirrhotic patients is a highly efficacious and well-tolerated treatment for HCV/HIV-1 coinfection, regardless of baseline HCV load or prior treatment with interferon or sofosbuvir. Clinical trial registration: NCT02738138.
Asunto(s)
Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Hepatitis C/tratamiento farmacológico , Pirrolidinas/uso terapéutico , Quinoxalinas/uso terapéutico , Sulfonamidas/uso terapéutico , Adulto , Animales , Coinfección , Combinación de Medicamentos , Femenino , VIH-1 , Humanos , Cirrosis Hepática , Masculino , Adulto JovenRESUMEN
Hepatitis C virus (HCV) infection is an independent risk factor for developing chronic renal impairment and end-stage renal disease. Limited treatment options are available for HCV genotype 2, 3, 5, and 6 infections in patients with an estimated glomerular filtration rate (eGFR) of <30 ml/min. Glecaprevir and pibrentasvir are active against all six major HCV genotypes, are primarily excreted in the bile, and have minimal renal elimination. Therefore, combined treatment with these direct-acting antivirals may be useful for patients with HCV infection and chronic kidney disease. A phase 1, multicenter, open-label study evaluated the effects of renal impairment on the pharmacokinetics and safety of glecaprevir-pibrentasvir. In substudy 1, 38 subjects with stage 2 to 5 chronic kidney disease who were not on dialysis or who had normal renal function received single doses of the combination of 300 mg glecaprevir and 120 mg pibrentasvir. In substudy 2, 8 subjects requiring hemodialysis received single doses of the combination of 300 mg glecaprevir and 120 mg pibrentasvir under dialysis and nondialysis conditions. Regression analyses demonstrated increased glecaprevir and pibrentasvir plasma exposures, as determined by the area under the curve, with decreasing renal function, up to 56% and 46%, respectively, in subjects with an eGFR of <15 ml/min/1.73 m2 In dialysis-dependent subjects, glecaprevir and pibrentasvir exposures were similar (≤18% difference) when study drugs were administered before hemodialysis or on a nondialysis day. Adverse events were mostly mild, with the most common being self-limited fatigue (3 subjects). The study findings support the clinical evaluation of glecaprevir-pibrentasvir without dose adjustment in HCV-infected subjects with renal impairment. (This study has been registered at ClinicalTrials.gov under registration number NCT02442258.).
Asunto(s)
Antivirales/farmacocinética , Bencimidazoles/farmacocinética , Fallo Renal Crónico/sangre , Quinoxalinas/farmacocinética , Diálisis Renal , Insuficiencia Renal Crónica/sangre , Sulfonamidas/farmacocinética , Adulto , Anciano , Ácidos Aminoisobutíricos , Antivirales/sangre , Área Bajo la Curva , Bencimidazoles/sangre , Ciclopropanos , Esquema de Medicación , Quimioterapia Combinada/métodos , Femenino , Tasa de Filtración Glomerular/fisiología , Hepacivirus , Hepatitis C , Humanos , Fallo Renal Crónico/fisiopatología , Lactamas Macrocíclicas , Leucina/análogos & derivados , Masculino , Persona de Mediana Edad , Prolina/análogos & derivados , Pirrolidinas , Quinoxalinas/sangre , Insuficiencia Renal Crónica/fisiopatología , Sulfonamidas/sangreRESUMEN
The combination of glecaprevir (formerly ABT-493), a nonstructural protein 3/4A (NS3/4A) protease inhibitor, and pibrentasvir (formerly ABT-530), an NS5A protein inhibitor, is being developed as treatment for HCV genotype 1 to 6 infection. The pharmacokinetics, pharmacodynamics, safety, and tolerability of methadone or buprenorphine-naloxone when coadministered with the glecaprevir-pibrentasvir combination in HCV-negative subjects on stable opioid maintenance therapy were investigated in a phase 1, single-center, two-arm, multiple-dose, open-label sequential study. Subjects received methadone (arm 1) or buprenorphine-naloxone (arm 2) once daily (QD) per their existing individual prescriptions alone (days 1 to 9) and then in combination with glecaprevir at 300 mg QD and pibrentasvir at 120 mg QD (days 10 to 16) each morning. Dose-normalized exposures were similar with and without glecaprevir and pibrentasvir for (R)- and (S)-methadone (≤5% difference) and for buprenorphine and naloxone (≤24% difference); the norbuprenorphine area under the curve was 30% higher with glecaprevir and pibrentasvir, consistent with maximum and trough plasma concentrations that increased by 21% to 25%. No changes in pupil response, short opiate withdrawal scale score, or desire for drugs questionnaire were observed when glecaprevir and pibrentasvir were added to methadone or buprenorphine-naloxone therapy. No dose adjustment is required when glecaprevir and pibrentasvir are coadministered with methadone or buprenorphine-naloxone.
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Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Combinación Buprenorfina y Naloxona/farmacocinética , Combinación Buprenorfina y Naloxona/uso terapéutico , Metadona/farmacocinética , Metadona/uso terapéutico , Tratamiento de Sustitución de Opiáceos/métodos , Trastornos Relacionados con Opioides/tratamiento farmacológico , Inhibidores de Proteasas/uso terapéutico , Quinoxalinas/uso terapéutico , Sulfonamidas/uso terapéutico , Adulto , Ácidos Aminoisobutíricos , Buprenorfina/análogos & derivados , Buprenorfina/sangre , Buprenorfina/uso terapéutico , Ciclopropanos , Interacciones Farmacológicas , Femenino , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Masculino , Persona de Mediana Edad , Naloxona/sangre , Naloxona/uso terapéutico , Prolina/análogos & derivados , Pirrolidinas , Encuestas y Cuestionarios , Adulto JovenRESUMEN
The development of inhibitory antibodies against factor VIII (FVIII) is a major challenge in hemophilia A (HA) therapy. Such antibodies develop in nearly 30% of patients receiving replacement FVIII, abrogating therapeutic efficacy. This work evaluated whether B-domain deleted FVIII encapsulated in phosphatidylinositol containing lipid nanoparticles (PI-BDD FVIII) could serve as an efficacious FVIII replacement therapy in the presence of inhibitors. The HA mice were given clinically relevant doses of FVIII to develop inhibitors. The efficacy of free and PI-BDD FVIII was studied in inhibitor-positive HA mice using a tail clip assay. Mathematical modeling of these data was conducted to evaluate the hypothesis that lipid association sterically shields the protein from inhibitor binding. The immunization protocol resulted in a mean inhibitory titer level of 198 ± 52 BU/ml. Free BDD FVIII was ineffective at controlling blood loss in inhibitor-positive HA mice as early as 2 h post dose. In contrast, PI-BDD FVIII treated animals retained partial hemostatic efficacy as long as 18 h post dose. Mathematical modeling supports the hypotheses that a greater fraction of lipid-associated FVIII remains unbound to inhibitors and that PI-BDD FVIII has lower binding affinity to inhibitors than does the free protein. In addition, the modeling approaches extend current efforts to model the impact of immunogenicity on PK and the therapeutically meaningful endpoint of efficacy, thereby addressing an important knowledge gap, particularly in the FVIII scientific literature. Clinical translation of these findings could result in a significant improvement in the quality of care of inhibitor-positive HA patients. Copyright © 2016 John Wiley & Sons, Ltd.
Asunto(s)
Anticuerpos/sangre , Factor VIII/administración & dosificación , Hemofilia A/tratamiento farmacológico , Nanopartículas/administración & dosificación , Animales , Factor VIII/inmunología , Factor VIII/farmacocinética , Factor VIII/uso terapéutico , Hemofilia A/sangre , Hemofilia A/inmunología , Ratones Endogámicos C57BL , Modelos Biológicos , Fosfatidilinositoles/química , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapéutico , Resultado del TratamientoRESUMEN
Factor VIII (FVIII) is an important cofactor in the blood coagulation cascade and its deficiency or dysfunction causes hemophilia A (HA), a bleeding disorder. Replacement with recombinant FVIII is limited by a short half-life and the development of inhibitory antibodies. A phosphatidylinositol (PI) containing lipid nanoparticle was developed that, when associated with FVIII, reduces immunogenicity and prolongs circulation of the therapeutic protein in HA mice. A multiple dose level pharmacokinetic (PK) study of human free FVIII and its FVIII-PI complex over a clinically relevant range of doses (20, 40 and 200 IU/kg) was conducted in HA mice to investigate linearity of the PK and to determine if the reduced catabolism of FVIII following association with PI particles, previously only observed in the terminal phase following 400 IU/kg, could be extendable over a range of doses. The findings suggest that the disposition of FVIII is best characterized by a two-compartment model with saturable Michaelis-Menten elimination. Spontaneous complexation of FVIII with PI particles significantly increases plasma survival of the protein at 20 and 40 IU/kg doses. Human simulations at 40 IU/kg project an increase in the terminal half-life and the time to reach a minimum therapeutic threshold of 0.01 IU/ml of 5.4 h and 40 h, respectively, compared with free FVIII. Formulation with PI containing lipid particles may represent a viable delivery strategy for improving FVIII therapy.
Asunto(s)
Factor VIII/farmacocinética , Hemofilia A/tratamiento farmacológico , Nanopartículas , Fosfatidilinositoles/química , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Factor VIII/administración & dosificación , Factor VIII/química , Semivida , Humanos , Lípidos/química , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Allergic disease prevalence has increased globally with the subset of type 2 inflammatory diseases playing a substantial role. Type 2 inflammatory diseases may differ in clinical presentation, but they exhibit shared pathophysiology that is targeted by the unique pharmacology of dupilumab. Dupilumab binds to the interleukin (IL)-4 receptor alpha subunit (IL-4Rα) that blocks IL-4 and IL-13 signaling, two key drivers of type 2 inflammation. Herein, we review the mechanism of action and pharmacology of dupilumab, and the clinical evidence that led to the regulatory approvals of dupilumab for the treatment of numerous type 2 inflammatory diseases: atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis, eosinophilic esophagitis, and prurigo nodularis.
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Anticuerpos Monoclonales Humanizados , Dermatitis Atópica , Interleucina-13 , Subunidad alfa del Receptor de Interleucina-4 , Investigación Biomédica Traslacional , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Subunidad alfa del Receptor de Interleucina-4/antagonistas & inhibidores , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/inmunología , Interleucina-13/antagonistas & inhibidores , Interleucina-13/metabolismo , Interleucina-13/inmunología , Interleucina-4/antagonistas & inhibidores , Interleucina-4/metabolismo , Asma/tratamiento farmacológico , Asma/inmunología , Esofagitis Eosinofílica/tratamiento farmacológico , Esofagitis Eosinofílica/inmunología , Transducción de Señal/efectos de los fármacos , Pólipos Nasales/tratamiento farmacológico , Pólipos Nasales/inmunología , Prurigo/tratamiento farmacológico , Ciencia Traslacional Biomédica , Sinusitis/tratamiento farmacológico , Sinusitis/inmunologíaRESUMEN
Subcutaneous (s.c.) administration of monoclonal antibodies (mAbs) can reduce treatment burden for patients and healthcare systems compared with intravenous (i.v.) infusion through shorter administration times, made possible by convenient, patient-centric devices. A deeper understanding of clinical pharmacology principles related to efficacy and safety of s.c.-administered mAbs over the past decade has streamlined s.c. product development. This review presents learnings from key constituents of the s.c. mAb development pathway, including pharmacology, administration variables, immunogenicity, and delivery devices. Restricted mAb transportation through the hypodermis explains their incomplete absorption at a relatively slow rate (pharmacokinetic (PK)) and may impact mAb-cellular interactions and/or onset and magnitude of physiological responses (pharmacodynamic). Injection volumes, formulation, rate and site of injection, and needle attributes may affect PKs and the occurrence/severity of adverse events like injection-site reactions or pain, with important consequences for treatment adherence. A review of immunogenicity data for numerous compounds reveals that incidence of anti-drug antibodies (ADAs) is generally comparable across i.v. and s.c. routes, and complementary factors including response magnitude (ADA titer), persistence over time, and neutralizing antibody presence are needed to assess clinical impact. Finally, four case studies showcase how s.c. biologics have been clinically developed: (i) by implementation of i.v./s.c. bridging strategies to streamline PD-1/PD-L1 inhibitor development, (ii) through co-development with i.v. presentations for anti-severe acute respiratory syndrome-coronavirus 2 antibodies to support rapid deployment of both formulations, (iii) as the lead route for bispecific T cell engagers (BTCEs) to mitigate BTCE-mediated cytokine release syndrome, and (iv) for pediatric patients in the case of dupilumab.
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Anticuerpos Monoclonales , Tejido Subcutáneo , Humanos , Niño , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Neutralizantes , Administración IntravenosaRESUMEN
Interleukin-33 (IL-33) is a proinflammatory alarmin cytokine released by damaged epithelial tissue cells that initiates and amplifies both type 1 and type 2 inflammatory cascades. A role for IL-33 in atopic dermatitis (AD; a chronic, relapsing type 2 inflammatory disease of the skin) has been proposed. Itepekimab is a novel human IgG4P monoclonal antibody against IL-33, currently in clinical development for chronic obstructive pulmonary disease (COPD). Two global phase II studies-a dose-ranging itepekimab monotherapy study (NCT03738423) and a proof-of-concept study of itepekimab alone and in combination with dupilumab (NCT03736967)-were conducted in patients with moderate-to-severe AD to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy; both studies were terminated following an interim analysis of the proof-of-concept study, which failed to demonstrate the efficacy of itepekimab. In these two studies, itepekimab exhibited linear and dose-proportional pharmacokinetics. Pharmacodynamics of total IL-33 indicated that itepekimab saturated binding to the target in serum at 300 mg q2w and q4w doses, and decreased blood eosinophil counts. Concentration-time profiles of itepekimab and total IL-33 were similar for itepekimab with or without dupilumab, and between East Asian and non-East Asian subgroups. Itepekimab was generally well tolerated, both alone and in combination with dupilumab. The lack of clinical efficacy for itepekimab observed in these studies suggests that IL-33 may not be a key pathogenic driver in moderate-to-severe AD.
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Anticuerpos Monoclonales Humanizados , Dermatitis Atópica , Interleucina-33 , Humanos , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/inmunología , Masculino , Femenino , Adulto , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Quimioterapia Combinada/métodos , Adulto Joven , Prueba de Estudio Conceptual , Relación Dosis-Respuesta a Droga , Anciano , Método Doble CiegoRESUMEN
The fixed-dose combination of the direct acting antivirals glecaprevir (GLE) and pibrentasvir (PIB) is an oral, once-daily treatment for all six major genotypes of chronic hepatitis C virus infection. A single and multiple-dose rifampin study (N = 12) and a carbamazepine study (N = 12) were conducted in healthy subjects to evaluate the effects of CYP3A/P-gp induction and OATP inhibition on the pharmacokinetics of GLE and PIB. In study 1, GLE 300 mg + PIB 120 mg was administered as a single dose either alone, after single and multiple daily doses of rifampin 600 mg, or 24 h after the last rifampin dose. In study 2, GLE 300 mg + PIB 120 mg was administered as a single dose either alone or after multiple doses of carbamazepine 200 mg. Relative to GLE + PIB alone, exposure of GLE was significantly increased by the first co-administered rifampin dose due to OATP inhibition, significantly decreased 24 h after the last rifampin dose due to CYP3A/P-gp induction, and slightly increased when co-administered with steady-state rifampin due to a combination of inhibition and induction forces. Exposure of PIB was not affected when co-administered with the first rifampin dose but was significantly decreased with steady-state rifampin co-administration, or 24 h after the last rifampin dose due to P-gp induction. Carbamazepine significantly decreased GLE and PIB exposure, mainly attributed to P-gp induction. The regimens tested were generally well-tolerated by the subjects and no new safety issues were identified.
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Hepatitis C Crónica , Transportadores de Anión Orgánico , Humanos , Antivirales , Hepatitis C Crónica/tratamiento farmacológico , Rifampin/efectos adversos , Citocromo P-450 CYP3A/genética , Interacciones Farmacológicas , Transportadores de Anión Orgánico/genética , Hepacivirus , GenotipoRESUMEN
BACKGROUND: For children aged 6-11 years with uncontrolled severe atopic dermatitis (AD), 16 weeks of treatment with dupilumab resulted in substantial clinical benefit compared with placebo with an acceptable safety profile. However, longer-term safety and efficacy data are important to inform longitudinal AD management. OBJECTIVES: This analysis of data from an open-label extension study (LIBERTY AD PED-OLE, NCT02612454) reports the long-term safety, efficacy, and pharmacokinetics of dupilumab in children with severe AD who had participated in the pivotal dupilumab LIBERTY AD PEDS study (NCT03345914). METHODS: Enrolled patients initially received subcutaneous dupilumab 300 mg every 4 weeks (q4w). The q4w regimen could be uptitrated to dupilumab dose regimens of 200 or 300 mg every 2 weeks (q2w; for body weight < 60 or ≥ 60 kg, respectively) for patients who did not achieve an Investigator's Global Assessment (IGA) score of 0/1 (clear/almost clear skin) at week 16, or prior to week 16 as rescue treatment. Additional patients were uptitrated to a weight-tiered q2w regimen following a protocol amendment. Patients who maintained an IGA score of 0/1 continuously for a 12-week period after week 40 discontinued dupilumab. They were monitored for relapse and were reinitiated on dupilumab if required. RESULTS: Data for 321 patients (mean age 8.6 years) were analyzed, 254 (79%) of whom had completed the scheduled 52-week visit at the database lock. Most treatment-emergent adverse events were mild/moderate. By week 52, 41% of patients achieved an IGA score of 0/1, and 97%, 82%, and 50%, respectively, had at least a 50%, 75%, and 90% improvement from the parent study baseline in Eczema Area and Severity Index (EASI). By week 52, 29% of patients in the overall population had clear/almost clear skin sustained for 12 weeks and had stopped medication; of these, 40% relapsed and were subsequently reinitiated on treatment, with a mean time to reinitiation of 13.5 (standard deviation 5.2) weeks. Following reinitiation of dupilumab, 41% of the patients with evaluable data at the time of database lock had regained an IGA 0/1 clinical response. CONCLUSIONS: Consistent with results seen in adults and adolescents, long-term treatment with dupilumab in children aged 6-11 years with severe AD showed an acceptable safety profile and incremental clinical benefit. A substantial proportion of children who stopped dupilumab treatment after achieving clear/almost clear skin subsequently experienced disease recurrence, and required reinitiation of dupilumab, suggesting that continuous treatment may be necessary for maintenance of clinical benefit. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02612454.
Atopic dermatitis (AD) is a chronic disease that causes recurrent inflamed and rough skin rashes with itching and often soreness. In children with AD, treatment with a medication called dupilumab has shown improvements in their disease and quality of life. But most clinical trials of dupilumab in children have only lasted for 16 weeks. We investigated the effect of dupilumab in children treated for a longer time. The 321 children (aged 611 years) who were included in this study had taken part in a clinical trial of dupilumab because they had severe AD. They were treated with either dupilumab or a placebo (a dummy treatment) for 16 weeks. When that trial ended, they were then all treated with dupilumab for up to a year. Their average AD severity continued to get steadily better over a year of extended treatment, with almost all children reaching 50% skin improvement compared with their AD before treatment. Many children reached a point where their skin was clear or almost clear of AD for a period, and following the rules of the study they stopped taking dupilumab. In many of them, their AD slowly returned without treatment. But if they started to take dupilumab again, their AD improved, and some could even achieve skin clearance again. Over the longer term, the safety of dupilumab was similar to what was seen with short-term treatment. This study showed that children with AD aged 611 years benefited from receiving dupilumab for a longer period of time.
RESUMEN
Dupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, has demonstrated efficacy and an acceptable safety profile in adult and pediatric patients with moderate-to-severe atopic dermatitis (AD) and other type 2 inflammatory diseases. Dupilumab is available in 200- and 300-mg strengths as a prefilled syringe with a needle shield (PFS-S), and more recently as an autoinjector (AI) device. This study was designed to assess the pharmacokinetic (PK) comparability of a single subcutaneous (SC) dose of dupilumab 200 mg, delivered by 2 different devices, AI (test) versus PFS-S (reference). A total of 130 healthy male and female participants were enrolled in this phase 1 parallel design study, with 128 evaluable for PK. Following dupilumab 200-mg SC injection, dupilumab exposure in serum was similar for both AI and PFS-S. The geometric mean ratios of PK parameters with 90% confidence intervals were 1.08 (0.97-1.21) for maximum serum concentration (Cmax ) and 1.11 (0.96-1.28) for area under the serum concentration-time curve until the last quantifiable concentration (AUClast ). Dupilumab administration by both devices was well tolerated, and there were no serious adverse events, or severe treatment-emergent adverse events experienced during the study. Overall, exposure to dupilumab 200 mg was comparable when administered via the AI or PFS-S devices in healthy male and female study participants.
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Anticuerpos Monoclonales Humanizados , Jeringas , Adulto , Anticuerpos Monoclonales Humanizados/farmacocinética , Niño , Femenino , Humanos , Inyecciones Subcutáneas , Masculino , Equivalencia TerapéuticaRESUMEN
Itepekimab is a monoclonal antibody that targets interleukin (IL-33) and has been shown to reduce airway inflammation and associated tissue damage in preclinical studies. We assessed the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamic profiles of single-ascending and multiple-ascending doses of itepekimab in two randomized, double-blind, placebo-controlled phase I studies. Healthy adults (N = 40) were randomized to the single-dose study and patients with moderate asthma (N = 23) to the multiple-dose study. Itepekimab was administered intravenously (0.3, 1, 3, or 10 mg/kg infusion) or subcutaneously (150 mg) in the single-dose study and subcutaneously (75 or 150 mg weekly for 4 weeks) in the multiple-dose study. Itepekimab exhibited linear PKs across studies and dose-proportional increases in mean maximum concentration in serum and area under the concentration-time curve following single intravenous or multiple subcutaneous doses. Itepekimab demonstrated mean subcutaneous bioavailability of 59-73% and a long terminal half-life (30.0-31.6 days). IL-33 concentrations in most healthy participants and patients with asthma were undetectable at baseline. Following administration of itepekimab in both studies, total IL-33 concentrations increased and blood eosinophils decreased, both with durable effect. Itepekimab was well-tolerated in both studies with no detection of treatment-emergent anti-drug antibody responses.