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1.
Gut ; 69(2): 224-230, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31409606

RESUMO

OBJECTIVE: To establish the non-inferior efficacy of vonoprazan versus lansoprazole in the treatment of Asian patients with erosive oesophagitis (EO). DESIGN: In this phase III, double-blind, multicentre study, patients with endoscopically confirmed EO were randomised 1:1 to receive vonoprazan 20 mg or lansoprazole 30 mg, once daily for up to 8 weeks. The primary endpoint was EO healing rate at 8 weeks. The secondary endpoints were EO healing rates at 2 and 4 weeks. Safety endpoints included treatment-emergent adverse events (TEAEs). RESULTS: In the vonoprazan (n=238) and lansoprazole (n=230) arms, 8-week EO healing rates were 92.4% and 91.3%, respectively (difference 1.1% (95% CI -3.822% to 6.087%)). The respective 2-week EO healing rates were 75.0% and 67.8% (difference 7.2% (95% CI -1.054% to 15.371%)), and the respective 4-week EO healing rates were 85.3% and 83.5% (difference 1.8% (95% CI -4.763% to 8.395%)). In patients with baseline Los Angeles classification grade C/D, 2-week, 4-week and 8-week EO healing rates were higher with vonoprazan versus lansoprazole (2 weeks: 62.2% vs 51.5%, difference 10.6% (95% CI -5.708% to 27.002%); 4 weeks: 73.3% vs 67.2%, difference 6.2% (95% CI -8.884 to 21.223); and 8 weeks: 84.0% vs 80.6%, difference 3.4% (95% CI -9.187% to 15.993%)). Overall, EO healing rates appeared higher with vonoprazan versus lansoprazole. TEAE rates were 38.1% and 36.6% in the vonoprazan and lansoprazole group, respectively. CONCLUSION: Our findings demonstrate the non-inferior efficacy of vonoprazan versus lansoprazole in terms of EO healing rate at 8 weeks in this population. Safety outcomes were similar in the two treatment arms. TRIAL REGISTRATION NUMBER: NCT02388724.


Assuntos
Esofagite Péptica/tratamento farmacológico , Lansoprazol/uso terapêutico , Inibidores da Bomba de Prótons/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Lansoprazol/administração & dosagem , Lansoprazol/efeitos adversos , Masculino , Pessoa de Meia-Idade , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Índice de Gravidade de Doença , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Resultado do Tratamento , Cicatrização
2.
N Engl J Med ; 381(23): 2230-2241, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31800988

RESUMO

BACKGROUND: Ubrogepant is an oral, small-molecule calcitonin gene-related peptide receptor antagonist for acute migraine treatment. METHODS: We conducted a randomized trial to evaluate the efficacy, safety, and side-effect profile of ubrogepant. We assigned adults with migraine, with or without aura, in a 1:1:1 ratio to receive an initial dose of placebo, ubrogepant at a dose of 50 mg, or ubrogepant at a dose of 100 mg for treatment of a single migraine attack, with the option to take a second dose. The coprimary efficacy end points were freedom from pain at 2 hours after the initial dose and absence of the most bothersome migraine-associated symptom at 2 hours. Secondary end points included pain relief (at 2 hours), sustained pain relief (from 2 to 24 hours), sustained freedom from pain (from 2 to 24 hours), and absence of symptoms associated with migraine (photophobia, phonophobia, and nausea) at 2 hours. RESULTS: A total of 1672 participants were enrolled; 559 were assigned to receive placebo, 556 to receive 50 mg of ubrogepant, and 557 to receive 100 mg of ubrogepant. The percentage of participants who had freedom from pain at 2 hours was 11.8% in the placebo group, 19.2% in the 50-mg ubrogepant group (P = 0.002, adjusted for multiplicity, for the comparison with placebo), and 21.2% in the 100-mg ubrogepant group (P<0.001). The percentage of participants who had freedom from the most bothersome symptom at 2 hours was 27.8% in the placebo group, 38.6% in the 50-mg ubrogepant group (P = 0.002), and 37.7% in the 100-mg ubrogepant group (P = 0.002). Adverse events within 48 hours after the initial or optional second dose were reported in 12.8% of participants in the placebo group, in 9.4% in the 50-mg ubrogepant group, and in 16.3% in the 100-mg ubrogepant group. The most common adverse events were nausea, somnolence, and dry mouth (reported in 0.4 to 4.1%); these events were more frequent in the 100-mg ubrogepant group (reported in 2.1 to 4.1%). Serious adverse events reported within 30 days in the ubrogepant groups included appendicitis, spontaneous abortion, pericardial effusion, and seizure; none of the events occurred within 48 hours after the dose. CONCLUSIONS: A higher percentage of participants who received ubrogepant than of those who received placebo had freedom from pain and absence of the most bothersome symptom at 2 hours after the dose. The most commonly reported adverse events were nausea, somnolence, and dry mouth. Further trials are needed to determine the durability and safety of ubrogepant for acute migraine treatment and to compare it with other drugs for migraine. (Funded by Allergan; ClinicalTrials.gov number, NCT02828020.).


Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Piridinas/uso terapêutico , Pirróis/uso terapêutico , Adulto , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Hiperacusia/tratamento farmacológico , Estimativa de Kaplan-Meier , Masculino , Transtornos de Enxaqueca/complicações , Náusea/tratamento farmacológico , Náusea/etiologia , Manejo da Dor , Fotofobia/tratamento farmacológico , Piridinas/efeitos adversos , Pirróis/efeitos adversos
3.
JAMA ; 322(19): 1887-1898, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31742631

RESUMO

Importance: Ubrogepant is an oral calcitonin gene-related peptide receptor antagonist under investigation for acute treatment of migraine. Objective: To evaluate the efficacy and tolerability of ubrogepant compared with placebo for acute treatment of a single migraine attack. Design, Setting, and Participants: Phase 3, multicenter, randomized, double-blind, placebo-controlled, single-attack, clinical trial (ACHIEVE II) conducted in the United States (99 primary care and research clinics; August 26, 2016-February 26, 2018). Participants were adults with migraine with or without aura experiencing 2 to 8 migraine attacks per month. Interventions: Ubrogepant 50 mg (n = 562), ubrogepant 25 mg (n = 561), or placebo (n = 563) for a migraine attack of moderate or severe pain intensity. Main Outcomes and Measures: Co-primary efficacy outcomes were pain freedom and absence of the participant-designated most bothersome migraine-associated symptom (among photophobia, phonophobia, and nausea) at 2 hours after taking the medication. Results: Among 1686 randomized participants, 1465 received study treatment (safety population; mean age, 41.5 years; 90% female); 1355 of 1465 (92.5%) were evaluable for efficacy. Pain freedom at 2 hours was reported by 101 of 464 participants (21.8%) in the ubrogepant 50-mg group, 90 of 435 (20.7%) in the ubrogepant 25-mg group, and 65 of 456 (14.3%) in the placebo group (absolute difference for 50 mg vs placebo, 7.5%; 95% CI, 2.6%-12.5%; P = .01; 25 mg vs placebo, 6.4%; 95% CI, 1.5%-11.5%; P = .03). Absence of the most bothersome associated symptom at 2 hours was reported by 180 of 463 participants (38.9%) in the ubrogepant 50-mg group, 148 of 434 (34.1%) in the ubrogepant 25-mg group, and 125 of 456 (27.4%) in the placebo group (absolute difference for 50 mg vs placebo, 11.5%; 95% CI, 5.4%-17.5%; P = .01; 25 mg vs placebo, 6.7%; 95% CI, 0.6%-12.7%; P = .07). The most common adverse events within 48 hours of any dose were nausea (50 mg, 10 of 488 [2.0%]; 25 mg, 12 of 478 [2.5%]; and placebo, 10 of 499 [2.0%]) and dizziness (50 mg, 7 of 488 [1.4%]; 25 mg, 10 of 478 [2.1%]; placebo, 8 of 499 [1.6%]). Conclusions and Relevance: Among adults with migraine, acute treatment with ubrogepant compared with placebo led to significantly greater rates of pain freedom at 2 hours with 50-mg and 25-mg doses, and absence of the most bothersome migraine-associated symptom at 2 hours only with the 50-mg dose. Further research is needed to assess the effectiveness of ubrogepant against other acute treatments for migraine and to evaluate the long-term safety of ubrogepant among unselected patient populations. Trial Registration: ClinicalTrials.gov Identifier: NCT02867709.


Assuntos
Analgésicos/administração & dosagem , Transtornos de Enxaqueca/tratamento farmacológico , Dor/tratamento farmacológico , Piridinas/administração & dosagem , Pirróis/administração & dosagem , Adulto , Idoso , Analgésicos/efeitos adversos , Tontura/induzido quimicamente , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Manejo da Dor , Piridinas/efeitos adversos , Pirróis/efeitos adversos , Adulto Jovem
5.
Expert Opin Drug Saf ; 18(12): 1255-1261, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31646920

RESUMO

Background: The safety and effectiveness of vonoprazan-based Helicobacter pylori (H. pylori) eradication therapy in routine clinical practice, and patient characteristics that influence safety and effectiveness, have not been well investigated.Methods: H. pylori-positive patients with gastric ulcer, duodenal ulcer, idiopathic thrombocytopenic purpura, history of endoscopic treatment of early gastric cancer, and gastritis were enrolled. Patients received vonoprazan 20 mg, amoxicillin (AMPC) 750 mg, and clarithromycin (CAM) 200-400 mg twice daily for 7 days for the first-line eradication. For the second-line eradication, vonoprazan, AMPC, and metronidazole (MTZ) 250 mg were administered. The incidence of adverse drug reactions (ADRs) and eradication rates were evaluated.Results: The incidences of ADRs with vonoprazan/AMPC/CAM and vonoprazan/AMPC/MTZ were 3.22% (16/497) and 1.89% (1/53), respectively. Commonly reported ADRs were diarrhea, nausea, dysgeusia, feces soft, and rash. The eradication rates of the first-line therapy and the second-line therapy were 91.24% (427/468) and 95.45% (42/44), respectively. No notable differences in ADRs and eradication rates were observed when stratified by patient demographic characteristics.Conclusion: No new safety concerns were observed, and the effectiveness of vonoprazan-based triple therapy was confirmed in routine clinical practice.Trial registration: This study is registered at the Japan Pharmaceutical Information Center Clinical Trials Information (JapicCTI-153003).


Assuntos
Antibacterianos/administração & dosagem , Infecções por Helicobacter/tratamento farmacológico , Inibidores da Bomba de Prótons/administração & dosagem , Pirróis/administração & dosagem , Sulfonamidas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Amoxicilina/administração & dosagem , Antibacterianos/efeitos adversos , Claritromicina/administração & dosagem , Quimioterapia Combinada , Feminino , Helicobacter pylori/isolamento & purificação , Humanos , Masculino , Metronidazol/administração & dosagem , Pessoa de Meia-Idade , Vigilância de Produtos Comercializados , Estudos Prospectivos , Inibidores da Bomba de Prótons/efeitos adversos , Pirróis/efeitos adversos , Sulfonamidas/efeitos adversos , Adulto Jovem
6.
Expert Opin Pharmacother ; 20(16): 1953-1960, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31456440

RESUMO

Introduction: Psoriatic arthritis (PsA) is a chronic inflammatory condition that is associated with progressive joint destruction and reduced quality of life. Despite the common use of disease-modifying anti-rheumatic drugs (DMARDs) in PsA, their influence has been investigated in a number of studies with conflicting results. There is also concern about their safety and tolerability. Tofacitinib is an orally administered Janus kinase (JAK) inhibitor that has recently been approved for the treatment of PsA by various international regulatory authorities, including the FDA, EMA, and NICE. Areas covered: In this review, the mechanism of action and the pharmacokinetic properties of tofacitinib are discussed. The data from two large phase III clinical studies evaluating the use of tofacitinib in PsA is also discussed in addition to the findings from other relevant studies. Expert opinion: The clinical data demonstrate significant improvement in disease activity in PsA patients using tofacitinib. There is also an acceptable clinical safety profile for the drug. Tofacitinib has various advantages over several existing drug treatments for PsA including an oral route of administration, a short half-life and a fast onset of action. Consequently, we anticipate that tofacitinib will become an increasingly used targeted synthetic DMARD (tsDMARD) for active PsA over the coming years.


Assuntos
Artrite Psoriásica/tratamento farmacológico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Meia-Vida , Humanos , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Piperidinas/efeitos adversos , Piperidinas/farmacocinética , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Pirróis/efeitos adversos , Pirróis/farmacocinética
8.
Int J Rheum Dis ; 22(8): 1563-1571, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31211506

RESUMO

OBJECTIVES: The relative efficacy and safety of tofacitinib and upadacitinib were assessed in patients with rheumatoid arthritis (RA) with an inadequate response to conventional synthetic (cs) or biologic (b) disease-modifying anti-rheumatic drugs (DMARDs). METHOD: We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of tofacitinib and upadacitinib in combination with methotrexate (MTX) in RA patients with an inadequate cs- or b-DMARD response. RESULTS: Nine RCTs including 5794 patients met the inclusion criteria. There were 15 pairwise comparisons including 10 direct comparisons of 6 interventions. Upadacitinib 15 mg + MTX and upadacitinib 30 mg + MTX were among the most effective treatments for active RA with an inadequate cs- or b-DMARD response, followed by tofacitinib 10 mg + MTX, tofacitinib 5 mg + MTX, and adalimumab + MTX. Ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that upadacitinib 15 mg + MTX and upadacitinib 30 mg + MTX had the highest probability of being the best treatment in terms of the American College of Rheumatology 20 response rate (SUCRA = 0.820, 0.762), followed by tofacitinib 10 mg + MTX (SUCRA = 0.623), tofacitinib 5 mg + MTX (SUCRA = 0.424), adalimumab + MTX (SUCRA = 0.371), and placebo + MTX (SUCRA = 0.001). No significant differences were observed in the incidence of serious adverse events after treatment with tofacitinib + MTX, upadacitinib + MTX, adalimumab + MTX, or placebo + MTX. CONCLUSIONS: In RA patients with an inadequate response to cs- or b-DMARDs, upadacitinib 15 mg + MTX and upadacitinib 30 mg + MTX were the most efficacious interventions and were not associated with significant risks of serious adverse events.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Piperidinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Antirreumáticos/efeitos adversos , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/imunologia , Teorema de Bayes , Quimioterapia Combinada , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Inibidores de Janus Quinases/efeitos adversos , Metotrexato/uso terapêutico , Meta-Análise em Rede , Piperidinas/efeitos adversos , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
10.
Aust Vet J ; 97(5): 162-165, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31025329

RESUMO

CASE REPORT: A 7-year-old female-neutered Maltese Terrier × Papillon dog was presented with tachypnoea and weight loss following 12 months of therapy with toceranib phosphate for a metastatic, histologically-low-grade mast cell tumour. The dog was diagnosed with Pneumocystis canis based on PCR with supportive clinical, radiographic and cytological findings. No other clinical evidence of immunocompromise was identified through assessment of haematology and immunoglobulin quantification. Clinical signs completely resolved with a short course of potentiated sulfonamides and discontinuation of the toceranib. CONCLUSION: To the authors' knowledge this represents the first case of Pneumocystis in a dog secondary to immunomodulatory drug therapy. It is also the first case of opportunist infection secondary to a tyrosine kinase inhibitor in dogs.


Assuntos
Doenças do Cão/induzido quimicamente , Indóis/efeitos adversos , Pneumonia por Pneumocystis/veterinária , Pirróis/efeitos adversos , Animais , Cães , Combinação de Medicamentos , Feminino , Sarcoma de Mastócitos/tratamento farmacológico , Sarcoma de Mastócitos/veterinária , Pneumonia por Pneumocystis/induzido quimicamente , Pneumonia por Pneumocystis/diagnóstico por imagem , Pneumonia por Pneumocystis/tratamento farmacológico , Sulfadoxina/uso terapêutico , Resultado do Tratamento , Trimetoprima/uso terapêutico
11.
J Med Econ ; 22(9): 859-868, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31012362

RESUMO

Aims: To evaluate the cost differences between a treatment strategy including tofacitinib (TOFA) vs treatment strategies including adalimumab (ADA), golimumab (GOL), infliximab (IFX), and vedolizumab (VEDO) among all patients with moderate-to-severe ulcerative colitis (UC) (further stratified by patients naïve/exposed to tumor necrosis factor inhibitors [TNFis]). Materials and methods: An Excel-based decision-analytic model was developed to evaluate costs from the perspective of a third-party US payer over 2 years. Efficacy and safety parameters were taken from prescribing information and published trials. All patients started induction therapy on the first treatment in the strategy and continued if efficacy criteria were met and no major adverse event occurred (in which cases they proceeded to the next treatment in the strategy). Results: The cost per member per month (PMPM) of the TOFA->IFX->VEDO->GOL strategy ($1.11) was lower than that of the ADA->IFX->VEDO->GOL strategy ($1.34; Δ = $-0.23) among the TNFi-naïve population (n = 204 patients out of a plan of one million members). Similarly, the use of TOFA before ADA (i.e. TOFA->ADA->IFX-> VEDO) was also associated with lower PMPM costs than the use of ADA before TOFA (i.e. ADA->TOFA->IFX->VEDO): $1.15 vs $1.25 (Δ = $-0.10). Similar, and often larger, differences were observed in both the overall moderate-to-severe population and the TNFi-exposed population. Sensitivity analyses resulted in the same conclusions. Limitations: Our model relied on efficacy data from prescribing information and published trials, which were not head-to-head and slightly differed with respect to methods. Additionally, our model used representative minor and major ADRs (and the associated costs) to represent toxicity management, which was a simplifying assumption. Conclusions: This analysis, the first of its kind to evaluate TOFA vis-à-vis other advanced therapies in the US, suggests the early use of TOFA among both TNFi-naïve and TNFi-failure patients results in lower PMPM costs compared with other treatment alternatives.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Fármacos Gastrointestinais/economia , Fármacos Gastrointestinais/uso terapêutico , Gastos em Saúde/estatística & dados numéricos , Piperidinas/economia , Piperidinas/uso terapêutico , Pirimidinas/economia , Pirimidinas/uso terapêutico , Pirróis/economia , Pirróis/uso terapêutico , Adalimumab/economia , Adalimumab/uso terapêutico , Anticorpos Monoclonais/economia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/economia , Anticorpos Monoclonais Humanizados/uso terapêutico , Análise Custo-Benefício , Fármacos Gastrointestinais/efeitos adversos , Recursos em Saúde/economia , Recursos em Saúde/estatística & dados numéricos , Serviços de Saúde/economia , Serviços de Saúde/estatística & dados numéricos , Humanos , Infliximab/economia , Infliximab/uso terapêutico , Modelos Econométricos , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Piperidinas/efeitos adversos , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/agonistas , Estados Unidos
13.
J Gastroenterol Hepatol ; 34(8): 1316-1328, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30883868

RESUMO

BACKGROUND AND AIM: Gastroesophageal reflux disease (GERD) is a common disease caused by reflux of gastric contents to the esophagus. Proton-pump inhibitors (PPIs) are recommended as a first-line therapy to treat GERD. Recently, a new potassium-competitive acid blocker, vonoprazan, was launched in Japan. We aimed to evaluate the comparative efficacy of vonoprazan and other PPIs in healing GERD. METHODS: We used MEDLINE and the Cochrane Central Register of Controlled Trials to search the literature. Double-blind randomized controlled trials for PPIs and/or vonoprazan that were published in English or Japanese and assessed healing effects in adult GERD patients were included. To estimate the comparative efficacy of treatments, we performed a Bayesian network meta-analysis to assess the consistency assumption. RESULTS: Of 4001 articles identified in the database, 42 studies were eligible. One study was hand-searched and added to the analysis. For the main analysis of healing effects at 8 weeks, odds ratios (ORs) of vonoprazan (20 mg daily) to esomeprazole (20 mg), rabeprazole (20 mg), lansoprazole (30 mg), and omeprazole (20 mg) were 2.29 (95% credible interval, 0.79-7.06), 3.94 (1.15-14.03), 2.40 (0.90-6.77), and 2.71 (0.98-7.90), respectively. Subgroup analysis for patients with severe esophagitis at baseline showed significantly higher ORs for vonoprazan versus most of the comparator PPIs. CONCLUSIONS: This analysis shows that the GERD healing effect of vonoprazan is higher than that of rabeprazole (20 mg) but not higher than other PPIs. Subgroup analysis indicated that vonoprazan is more effective than most PPIs for patients with severe erosive esophagitis.


Assuntos
Esofagite Péptica/tratamento farmacológico , Refluxo Gastroesofágico/tratamento farmacológico , Inibidores da Bomba de Prótons/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico , Cicatrização/efeitos dos fármacos , Teorema de Bayes , Esofagite Péptica/diagnóstico , Esofagite Péptica/fisiopatologia , Refluxo Gastroesofágico/diagnóstico , Refluxo Gastroesofágico/fisiopatologia , Humanos , Meta-Análise em Rede , Seleção de Pacientes , Inibidores da Bomba de Prótons/efeitos adversos , Pirróis/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Indução de Remissão , Índice de Gravidade de Doença , Sulfonamidas/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
15.
Expert Opin Investig Drugs ; 28(5): 489-496, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30908082

RESUMO

BACKGROUND: An efficacious anti-inflammatory corticosteroid with reduced side effects has been long sought. We report the pooled results from three clinical proof-of-mechanism Phase I studies of BI 653048 in healthy subjects, a functionally selective, nonsteroidal glucocorticoid (GC). RESEARCH DESIGN AND METHODS: Three Phase I trials were conducted: a single rising-dose study and a multiple rising-dose study to evaluate the safety, tolerability, and pharmacokinetics of BI 653048, and a multiple parallel-arm-dose study with intravenous lipopolysaccharide challenge to assess in vivo pharmacodynamics. The pharmacodynamics, efficacy, and safety of BI 653048 and prednisolone were compared. RESULTS: Treatment with 200 mg BI 653048 was associated with a reduced expression of IL1R2, ITGB3, and SDPR versus 20 mg prednisolone; comparable levels of FKBP5, ZBTB16, and DDIT4 expression were observed. Changes in C-peptide, glucose, insulin, and cortisol were moderate compared with prednisolone. A greater reduction of osteocalcin was observed with 200 mg BI 653048 versus 20 mg prednisolone. Comparable anti-inflammatory efficacy was demonstrated for 200 mg BI 653048 and 20 mg prednisolone. BI 653048 was well tolerated in healthy subjects. CONCLUSION: BI 653048 demonstrated the desired anti-inflammatory effects of the nonsteroidal GC; however, the undesirable side-effect profile associated with GC steroids could not be disassociated from BI 653048. TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT02217644, NCT02217631, and NCT02224105.


Assuntos
Anti-Inflamatórios/farmacologia , Benzamidas/farmacologia , Glucocorticoides/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Receptores de Glucocorticoides/agonistas , Adulto , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Ensaios Clínicos Fase I como Assunto , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Humanos , Inflamação/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Osteocalcina/metabolismo , Prednisolona/efeitos adversos , Prednisolona/farmacologia , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Adulto Jovem
16.
Int J Rheum Dis ; 22(6): 1094-1106, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30900375

RESUMO

AIM: We report tofacitinib efficacy and safety in Asia-Pacific patients who participated in the rheumatoid arthritis (RA) clinical development program. METHOD: This post-hoc analysis included pooled data from patients with RA in the Asia-Pacific region treated with tofacitinib with/without conventional synthetic disease-modifying antirheumatic drugs in Phase (P)1, 2, 3, and long-term extension (LTE) studies (one LTE ongoing; January 2016 data-cut). Efficacy was assessed over 24 months in patients who received tofacitinib 5 (N = 397) or 10 (N = 382) mg twice daily or placebo (N = 243) in three P2 and five P3 studies. Endpoints included American College of Rheumatology (ACR)20/50/70 responses, Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28-4[ESR]) and Clinical Disease Activity Index (CDAI) remission rates, and change from baseline in Health Assessment Questionnaire-Disability Index (∆HAQ-DI). Safety data pooled over 92 months from one P1, four P2, six P3, and two LTE studies for all tofacitinib doses (N = 1464) included incidence rates (IRs) (patients with events/100 patient-years) for adverse events (AEs) of special interest. RESULTS: At month 3, patients receiving tofacitinib 5/10 mg twice daily improved vs placebo in ACR20 (69.2%/77.9% vs 27.5%), ACR50 (36.9%/44.4% vs 9.5%), and ACR70 (15.1%/22.4% vs 2.7%) responses, remission rates for DAS28-4(ESR) (8.5%/18.5% vs 2.6%) and CDAI (6.1%/12.3% vs 0.5%), and ∆HAQ-DI (-0.5/-0.6 vs -0.1); improvements were sustained through 24 months. IRs (95% CI) were 9.4 (8.5, 10.3) for serious AEs, 9.1 (8.3, 10.1) for discontinuations due to AEs, 3.7 (3.2, 4.3) for serious infections, 5.9 (5.2, 6.7) for herpes zoster, and 0.8 (0.6, 1.1) for malignancies (excluding non-melanoma skin cancer). CONCLUSION: In Asia-Pacific patients, tofacitinib improved signs/symptoms over 24 months. Safety over 92 months was generally consistent with global tofacitinib studies; however, infection IRs were higher in Asia-Pacific patients.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Piperidinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Adulto , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/fisiopatologia , Ásia/epidemiologia , Ensaios Clínicos como Assunto , Medicina Baseada em Evidências , Feminino , Humanos , Inibidores de Janus Quinases/efeitos adversos , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Infecções Oportunistas/epidemiologia , Piperidinas/efeitos adversos , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Recuperação de Função Fisiológica , Indução de Remissão , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
17.
Drugs ; 79(6): 655-663, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30895473

RESUMO

Tofacitinib (Xeljanz®) is the first Janus kinase (JAK) inhibitor approved at a dosage of 5 mg twice daily (BID) in the EU and the USA for the treatment of active psoriatic arthritis (PsA), where it is indicated in combination with methotrexate for patients who have had an inadequate response or who have been intolerant to a prior therapy with a disease-modifying antirheumatic drug (DMARD). Two well-designed phase III trials (OPAL Broaden and OPAL Beyond) in patients with PsA with or without prior tumour necrosis factor inhibitor (TNFi) therapy showed that tofacitinib 5 mg BID (co-administered with methotrexate or another approved conventional synthetic DMARD) significantly improved the key clinical signs/symptoms and disability associated with PsA after 3 months of treatment, while also improving skin psoriasis, enthesitis, dactylitis, physical function and fatigue. According to interim data, the improvements in clinical signs/symptoms were maintained for up to 30 months in the ongoing long-term extension study OPAL Balance, with minimal radiographic progression seen after 12 months' therapy in the OPAL Broaden study. Tofacitinib 5 mg BID had an acceptable tolerability profile, with low incidences of serious infections, malignancies, cardiovascular events and gastrointestinal perforations over 36 months. Changes in laboratory parameters generally remained stable over 36 months of treatment. Although further studies are required to more definitively establish its efficacy and safety, currently available evidence indicates that tofacitinib expands the treatment options available for the treatment of PsA in patients who have had an inadequate response or who have been intolerant to a prior DMARD therapy.


Assuntos
Artrite Psoriásica/tratamento farmacológico , Metotrexato/uso terapêutico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Relação Dose-Resposta a Droga , Quimioterapia Combinada/métodos , Humanos , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Metotrexato/farmacologia , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Pirimidinas/farmacologia , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Pirróis/farmacologia , Resultado do Tratamento , Adulto Jovem
18.
Clin Drug Investig ; 39(5): 421-428, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30806969

RESUMO

BACKGROUND: Tofacitinib and apremilast have shown considerable efficacy in placebo-controlled trials of active psoriatic arthritis, but the relative efficacy and safety remain unclear because of a lack of head-to-head comparisons. OBJECTIVE: The aim of this study was to assess the relative efficacy and safety of tofacitinib and apremilast at different doses in patients with active psoriatic arthritis. METHOD: We performed a Bayesian network meta-analysis to combine evidence from randomized controlled trials for examination of the efficacy and safety of tofacitinib 10 mg, tofacitinib 5 mg, apremilast 30 mg, and apremilast 20 mg in psoriatic arthritis. RESULTS: Eight randomized controlled trials including 3086 patients met the inclusion criteria. There were ten pairwise comparisons including six direct comparisons of five interventions. All the interventions achieved a significant American College of Rheumatology 20 response compared with placebo. Tofacitinib 10 mg and apremilast 30 mg were among the most effective treatments for active psoriatic arthritis, followed by tofacitinib 5 mg, and apremilast 20 mg. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that tofacitinib 10 mg had the highest probability of being the best treatment in terms of the American College of Rheumatology 20 response rate (SUCRA = 0.785). This was followed by apremilast 30 mg (SUCRA = 0.670), tofacitinib 5 mg (SUCRA = 0.596), apremilast 20 mg (SUCRA = 0.448), and placebo (SUCRA = 0.001). We observed no significant differences in the incidence of serious adverse events after treatment with tofacitinib 10 mg, apremilast 30 mg, tofacitinib 5 mg, apremilast 20 mg, or placebo. CONCLUSIONS: In patients with active psoriatic arthritis, tofacitinib 10 mg and apremilast 30 mg were the most efficacious interventions and were not associated with a significant risk of serious adverse events.


Assuntos
Artrite Psoriásica/tratamento farmacológico , Piperidinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Talidomida/análogos & derivados , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Teorema de Bayes , Humanos , Meta-Análise em Rede , Piperidinas/efeitos adversos , Inibidores de Proteínas Quinases , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Talidomida/efeitos adversos , Talidomida/uso terapêutico , Resultado do Tratamento
19.
Drugs ; 79(4): 477-481, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30806972

RESUMO

Esaxerenone (MINNEBRO™)-a novel oral, non-steroidal, selective mineralocorticoid receptor blocker-is being developed by Daiichi Sankyo for the treatment of hypertension and diabetic nephropathies. In January 2019, based on positive results from a phase III trial conducted in Japan in patients with essential hypertension, esaxerenone received marketing approval in Japan for the treatment of hypertension. This article summarizes the milestones in the development of esaxerenone leading to this first global approval for the treatment of hypertension.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Hipertensão/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Pirróis/uso terapêutico , Sulfonas/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Aprovação de Drogas , Humanos , Japão , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Estrutura Molecular , Pirróis/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Mineralocorticoides/metabolismo , Sulfonas/efeitos adversos
20.
Dig Dis Sci ; 64(7): 1945-1951, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30734234

RESUMO

BACKGROUND AND AIMS: Many inflammatory bowel disease (IBD) patients do not respond to medical therapy. Tofacitinib is a first-in-class, partially selective inhibitor of Janus kinase, recently approved for treating patients with ulcerative colitis (UC). We describe our experience with the use of tofacitinib for treatment of patients with moderate-to-severe IBD. METHODS: This is a retrospective, observational study of the use of tofacitinib in IBD. Patients with medically resistant IBD were treated orally with 5 mg or 10 mg twice daily. Clinical response and adverse events were assessed at 8, 26, and 52 weeks. Objective response was assessed endoscopically, radiologically, and biochemically. RESULTS: 58 patients (53 UC, 4 Crohn's, 1 pouchitis) completed at least 8 weeks of treatment with tofacitinib. 93% of the patients previously failed treatment with anti-TNF. At 8 weeks of treatment, 21 patients (36%) achieved a clinical response, and 19 (33%) achieved clinical remission. Steroid-free remission at 8 weeks was achieved in 15 patients (26%). Of the 48 patients followed for 26 weeks, 21% had clinical, steroid-free remission. Of the 26 patients followed for 12 months, 27% were in clinical, steroid-free remission. Twelve episodes of systemic infections were noted, mostly while on concomitant steroids. One episode of herpes zoster infection was noted during follow-up. CONCLUSIONS: In this cohort of patients with moderate-to-severe, anti-TNF resistant IBD, tofacitinib induced clinical response in 69% of the patients. 27% were in clinical, steroid-free remission by 1 year of treatment. Tofacitinib is an effective therapeutic option for this challenging patient population.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Colite/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Piperidinas/administração & dosagem , Pouchite/tratamento farmacológico , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Centros de Atenção Terciária , Administração Oral , Adulto , Colite/diagnóstico , Colite/enzimologia , Colite/imunologia , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/enzimologia , Colite Ulcerativa/imunologia , Esquema de Medicação , Feminino , Humanos , Inibidores de Janus Quinases/efeitos adversos , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Pouchite/diagnóstico , Pouchite/enzimologia , Pouchite/imunologia , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Indução de Remissão , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
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