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BACKGROUND: Standard care for treating anemia in patients with CKD includes use of erythropoiesis-stimulating agents, which sometimes involves increased risks of cardiovascular morbidity and mortality. Previous studies in patients with anemia and nondialysis-dependent CKD (NDD-CKD) found significantly elevated hemoglobin levels with use of vadadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, compared with placebo. METHODS: In this phase 3, open-label, active-controlled noninferiority trial, we randomized 304 Japanese adults with anemia in NDD-CKD (including erythropoiesis-stimulating agent users and nonusers) to oral vadadustat or subcutaneous darbepoetin alfa for 52 weeks. The primary efficacy end point was average hemoglobin at weeks 20 and 24. Safety data included adverse events (AEs) and serious AEs. RESULTS: A total of 151 participants received vadadustat and 153 received darbepoetin alfa. Least squares mean of the average hemoglobin at weeks 20 and 24 was 11.66 (95% confidence interval [95% CI], 11.49 to 11.84) g/dl for vadadustat and 11.93 (95% CI, 11.76 to 12.10) g/dl for darbepoetin alfa. The 95% CIs for both treatments were within the target hemoglobin range (11.0-13.0 g/dl), and the lower 95% confidence limit for the difference between groups (-0.50 g/dl) was above the predefined noninferiority margin (-0.75 g/dl), demonstrating noninferiority of vadadustat to darbepoetin alfa. Similar proportions of patients in each group reported AEs and serious AEs. The most frequent AEs with vadadustat were nasopharyngitis, diarrhea, and constipation. CONCLUSIONS: In Japanese patients with NDD-CKD, vadadustat was noninferior to darbepoetin alfa, was effective up to week 52 in terms of average hemoglobin, and was generally well tolerated. These results suggest that vadadustat may be a potential treatment for anemia in this patient population.
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AIM: Valbenazine is approved in the US for treatment of tardive dyskinesia (TD); however, efficacy/safety data in Asian populations are lacking. We assessed the efficacy/safety of valbenazine in Japanese patients. METHODS: This phase II/III, multicenter, randomized, double-blind, placebo-controlled study (NCT03176771) included adult psychiatric patients with TD, who were randomly allocated to receive placebo or valbenazine (once-daily 40- or 80-mg) for a 6-week, double-blind period, after which the placebo group was switched to valbenazine for a 42-week extension. The primary endpoint was change from baseline in Abnormal Involuntary Movement Scale (AIMS) total score at Week 6; clinical global impression of improvement of TD (CGI-TD) was also assessed. RESULTS: Of 256 patients, 86, 85, and 85 were allocated to the 40-mg valbenazine, 80-mg valbenazine, and placebo groups, respectively. Least-squares mean (95% confidence interval) change from baseline in AIMS score at Week 6 was -2.3 (-3.0 to -1.7) in the valbenazine 40-mg group, -3.7 (-4.4 to -3.0) in the 80-mg group, and -0.1 (-0.8 to 0.5) in the placebo group; both treatment groups showed statistically significant improvements vs. placebo. Patients switched to valbenazine at Week 6 showed similar improvements in AIMS scores, which were maintained to Week 48. Improvements in CGI-TD scores were observed for both treatment groups vs. placebo. Incidence of adverse events was highest in the 80-mg group; common events included nasopharyngitis, somnolence, schizophrenia worsening, hypersalivation, insomnia, and tremor. CONCLUSION: The efficacy/safety profile of valbenazine was similar to that of previous clinical trials, supporting its use for TD treatment in Japanese patients.
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Antipsicóticos , Discinesia Tardia , Adulto , Humanos , Discinesia Tardia/tratamento farmacológico , Discinesia Tardia/induzido quimicamente , Japão , Antipsicóticos/efeitos adversos , Tetrabenazina/efeitos adversos , Método Duplo-Cego , Resultado do TratamentoRESUMO
BACKGROUND: Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis. METHODS: The efficacy and safety of vadadustat, compared with darbepoetin alfa, was determined in a Phase 3 double-blind study in Japanese anemic patients on hemodialysis. Patients receiving erythropoiesis-stimulating agents (ESAs) were randomized and switched to either vadadustat or darbepoetin alfa for 52 weeks. Doses were adjusted to maintain a hemoglobin (Hb) level of 10.0-12.0 g/dL. The primary endpoint was average Hb level at Weeks 20 and 24. RESULTS: Of the 323 randomized patients, 120 and 135 completed the 52-week treatment period in the vadadustat and darbepoetin alfa groups, respectively. The average Hb levels at Weeks 20 and 24 [least square mean (LSM) and 95% confidence interval (CI)] were 10.61 (10.45-10.76) and 10.65 (10.50-10.80) g/dL in the vadadustat and darbepoetin alfa groups, respectively, demonstrating vadadustat's noninferiority to darbepoetin alfa (difference: -0.05 g/dL; 95% CI -0.26 to 0.17). In both groups, the mean Hb levels were maintained within the target range for 52 weeks. Furthermore, irrespective of patient backgrounds, the LSMs of Hb at Week 52 were within the target range. The most common adverse events were nasopharyngitis, diarrhea and shunt stenosis, which occurred at similar frequencies in both groups. No new safety concerns were identified. CONCLUSIONS: Vadadustat was as well-tolerated and effective as darbepoetin alfa in maintaining Hb levels within the target range. The findings suggest that vadadustat can be an alternative to ESA in the management of anemia in Japanese hemodialysis patients receiving ESA (ClinicalTrials.gov, NCT03439137).
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Anemia , Eritropoetina , Hematínicos , Anemia/tratamento farmacológico , Anemia/etiologia , Darbepoetina alfa/uso terapêutico , Método Duplo-Cego , Glicina/análogos & derivados , Hematínicos/efeitos adversos , Hemoglobinas/análise , Humanos , Japão , Ácidos Picolínicos , Diálise RenalRESUMO
OBJECTIVE: To evaluate the safety, pharmacokinetics, pharmacodynamics, and exploratory efficacy of amiselimod, an oral selective sphingosine 1-phosphate receptor-1 modulator, in patients with systemic lupus erythematosus (SLE). METHODS: A multicenter, open-label phase Ib trial was conducted in Japan. Patients in Part 1 and Part 2-B received 0.2 mg amiselimod while those in Part 2-A received 0.4 mg amiselimod for 24 weeks. RESULTS: Seventeen subjects received 0.2 or 0.4 mg amiselimod. Amiselimod and amiselimod-P plasma concentrations increased dose-dependently. Peripheral blood lymphocyte count decreased in all patients after amiselimod treatment, with no clear dose response. There were no serious/severe adverse events (AEs) or clinically meaningful cardiac effects. Five subjects were withdrawn from amiselimod treatment following a decrease in lymphocyte count to <200/µl. Anti-double stranded-DNA antibody decreased from baseline to Week 24/end of treatment (EOT), with those in 2 subjects (22.2%) decreasing to within the normal range. Total SLE disease activity index 2000 score decreased by ≥4 at EOT in 7 of 17 subjects. CONCLUSIONS: Amiselimod was generally well tolerated. While no serious AEs or infectious AEs led to discontinuation, low lymphocyte counts of <200/µl were observed as a laboratory abnormality. Our findings suggest the potential efficacy of amiselimod for patients with SLE.Trial registration: ClinicalTrials.gov identifier: NCT02307643.
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Lúpus Eritematoso Sistêmico/tratamento farmacológico , Receptores de Esfingosina-1-Fosfato/administração & dosagem , Adulto , Autoanticorpos/efeitos dos fármacos , Método Duplo-Cego , Feminino , Humanos , Linfócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados não Aleatórios como Assunto , Propanolaminas/administração & dosagem , Propanolaminas/efeitos adversos , Propanolaminas/farmacocinética , Propanolaminas/farmacologiaRESUMO
BACKGROUND: Pediatric ulcerative colitis (UC) is typically more extensive and has a more active disease course than adult UC, and requires early treatment augmentation to achieve and maintain disease remission. The present study aimed to investigate the efficacy, safety, and pharmacokinetic profile of infliximab (IFX) in pediatric patients with moderate-to-severe UC and inadequate response to existing treatment. METHODS: This open-label, uncontrolled, multicenter, Phase 3 trial was conducted at 17 centers in Japan between April 2012 and September 2014. Pediatric patients (aged 6-17 years) diagnosed with moderate-to-severe UC received a treatment protocol comprising 5 mg/kg IFX at Weeks 0, 2, and 6, and Clinical Activity Index (CAI)-based responders at Week 8 also received treatment at 8-week intervals at Weeks 14 and 22, with a final evaluation at Week 30. RESULTS: A total of 21 patients were treated in this study. IFX therapy rapidly improved clinical symptoms, and this effect was maintained for up to 30 weeks. Overall CAI-based remission rate was 42.9% and overall Pediatric Ulcerative Colitis Activity Index (PUCAI)-based remission rate was 19.0%. Median partial Mayo score was 6.0 at baseline and 4.0 at Week 30 (overall). Among the eight patients who underwent sigmoidoscopy, Mayo response was achieved at Week 30 (overall) in three patients (37.5%). Trough serum IFX concentrations in Week 8 CAI-based responders were maintained throughout the study period. Adverse events and serious adverse events were observed in 95.2 and 14.3% of patients, respectively. CONCLUSIONS: These results support the use of IFX in the treatment of pediatric patients with UC with inadequate response to existing treatment. TRIAL REGISTRATION: ClinicalTrials.gov, registration number: NCT01585155 .
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Colite Ulcerativa/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Infliximab/uso terapêutico , Adolescente , Criança , Feminino , Fármacos Gastrointestinais/efeitos adversos , Fármacos Gastrointestinais/farmacocinética , Humanos , Infliximab/efeitos adversos , Infliximab/farmacocinética , Japão , Masculino , Resultado do TratamentoRESUMO
Sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are antihyperglycaemic agents with weight-lowering effects. The efficacy and safety of the SGLT2 inhibitor canagliflozin as add-on therapy in Japanese patients with type 2 diabetes mellitus (T2DM) and inadequate glycaemic control with a GLP-1RA (≥12 weeks) were evaluated in this phase IV study. Patients received canagliflozin 100 mg once daily for 52 weeks. Efficacy endpoints included change in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), body weight, systolic blood pressure (SBP) and HDL cholesterol from baseline to week 52. Safety endpoints included adverse events (AEs), hypoglycaemia and laboratory tests. Of the 71 patients treated with canagliflozin, 63 completed the study. At 52 weeks, HbA1c was significantly reduced from baseline (-0.70%; paired t test, P < .001). Significant changes were also observed in FPG (-34.7 mg/dL), body weight (-4.46%), SBP (-7.90 mm Hg), and HDL cholesterol (7.60%; all P < .001). The incidence of AEs, adverse drug reactions and hypoglycaemia was 71.8%, 32.4% and 9.9%, respectively. All hypoglycaemic events were mild. These findings suggest that the long-term combination of canagliflozin with a GLP-1RA is effective and well tolerated in Japanese patients with T2DM.
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Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Incretinas/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Idoso , Glicemia/metabolismo , Pressão Sanguínea , Peso Corporal , HDL-Colesterol/metabolismo , Quimioterapia Combinada , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemia/induzido quimicamente , Japão , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium glucose co-transporter 2 (SGLT2) inhibitors are frequently used in combination for the treatment of type 2 diabetes mellitus (T2DM). We examined the efficacy and safety of teneligliptin (a DPP-4 inhibitor) added to canagliflozin (an SGLT2 inhibitor) monotherapy in Japanese patients with poorly controlled T2DM as part of the development of a fixed-dose combination of teneligliptin and canagliflozin. Japanese patients treated with canagliflozin (100 mg) for ≥12 weeks were randomized to receive add-on teneligliptin (20 mg; C + T group) or placebo (C + P group) for 24 weeks. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline to Week 24. The between-group differences in reductions from baseline to Week 24 were significantly greater in the C + T group for HbA1c (-0.94%; P < .001). The incidence of adverse events was similar in both groups (55.8% and 49.4% in the C + T and C + P groups, respectively). No episodes of hypoglycaemia were reported. Teneligliptin added to ongoing canagliflozin monotherapy improved glycaemic control and was well tolerated in Japanese patients with inadequately controlled T2DM.
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Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hiperglicemia/prevenção & controle , Moduladores de Transporte de Membrana/uso terapêutico , Pirazóis/uso terapêutico , Tiazolidinas/uso terapêutico , Idoso , Canagliflozina/efeitos adversos , Terapia Combinada/efeitos adversos , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Dieta para Diabéticos , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Método Duplo-Cego , Resistência a Medicamentos , Quimioterapia Combinada/efeitos adversos , Exercício Físico , Feminino , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/prevenção & controle , Japão , Masculino , Moduladores de Transporte de Membrana/efeitos adversos , Pessoa de Meia-Idade , Pirazóis/efeitos adversos , Transportador 2 de Glucose-Sódio/metabolismo , Tiazolidinas/efeitos adversosRESUMO
AIM: The aim of this study was to assess the long-term efficacy and safety of canagliflozin as add-on therapy in Japanese patients with type 2 diabetes mellitus who had inadequate glycaemic control with insulin. MATERIALS AND METHODS: The study comprised a 16-week, double-blind period in which patients were randomized to either placebo (P; N = 70) or canagliflozin (100 mg, CAN; N = 76), followed by a 36-week open-label period in which all patients received canagliflozin. The efficacy endpoints included the change in HbA1c from baseline to end of treatment. The safety endpoints were adverse events, hypoglycaemic events, and laboratory test values. RESULTS: The changes from baseline (mean ± standard deviation, last observation carried forward) in the P/CAN and CAN/CAN groups, respectively, were -1.09% ± 0.85% and -0.88% ± 0.86% for HbA1c, -1.40% ± 2.54% and -2.14% ± 2.75% for body weight, and 7.84% ± 14.37% and 8.91% ± 10.80% for HOMA2-%B (all, P < .001). Adverse events occurred in 85.1% of the P/CAN group and 92.0% of the CAN/CAN group. Hypoglycaemic events occurred in 43.3% and 54.7%, respectively. All hypoglycaemic events were mild in severity and insulin dose reduction decreased the incidence rate of hypoglycaemic events. Post-hoc ordinal logistic modelling/logistic modelling showed that lower serum C-peptide at Week 0 was a risk factor for hypoglycaemia in both the P and CAN groups in the double-blind period as well as in the canagliflozin all-treatment period. CONCLUSIONS: This study demonstrates the long-term efficacy and safety of canagliflozin combined with insulin in Japanese patients.
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Canagliflozina/administração & dosagem , Canagliflozina/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insulina/administração & dosagem , Insulina/efeitos adversos , Adulto , Povo Asiático , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Hemoglobinas Glicadas/efeitos dos fármacos , Hemoglobinas Glicadas/metabolismo , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do TratamentoRESUMO
AIM: To evaluate the long-term safety and efficacy of canagliflozin as add-on therapy in patients with type 2 diabetes mellitus (T2DM) who had inadequate glycaemic control with teneligliptin monotherapy. METHODS: This open-label 52-week study was conducted in Japan. Patients received canagliflozin 100 mg added to teneligliptin 20 mg orally once daily for 52 weeks. The safety endpoint was the incidence of adverse events (AEs). The efficacy endpoints included changes in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG) and body weight from baseline to week 52 (with last observation carried forward). RESULTS: Overall, 153 patients entered the treatment period and 142 completed the study. The overall incidence rates of AEs and drug-related AEs were 69.9% and 22.9%, respectively. Most AEs and drug-related AEs were mild or moderate in severity. There were no previously undescribed safety signals. The mean changes in HbA1c, FPG and body weight were -0.99% (95% confidence interval [CI] -1.12 to -0.85), -38.6 mg/dL (95% CI -43.4 to -33.9) and -3.92% (95% CI -4.53 to -3.31), respectively. These effects were maintained for 52 weeks without attenuation. HbA1c and body weight were both decreased in 82.24% of patients at the end of the treatment period. Reductions in postprandial glucose were observed at weeks 24 and 52. CONCLUSIONS: No new safety risks with this combination were identified, and sustained improvements in HbA1c, FPG and body weight were observed. The findings suggest that long-term co-administration of canagliflozin with teneligliptin is well tolerated and effective in Japanese patients with T2DM who have inadequate glycaemic control on teneligliptin alone.
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Canagliflozina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hiperglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Pirazóis/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose , Tiazolidinas/uso terapêutico , Idoso , Fármacos Antiobesidade/efeitos adversos , Fármacos Antiobesidade/uso terapêutico , Índice de Massa Corporal , Canagliflozina/efeitos adversos , Estudos de Coortes , Terapia Combinada/efeitos adversos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Dieta para Diabéticos , Dieta Redutora , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Resistência a Medicamentos , Quimioterapia Combinada/efeitos adversos , Exercício Físico , Feminino , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/prevenção & controle , Hipoglicemiantes/efeitos adversos , Japão , Masculino , Moduladores de Transporte de Membrana/efeitos adversos , Moduladores de Transporte de Membrana/uso terapêutico , Pessoa de Meia-Idade , Sobrepeso/complicações , Sobrepeso/metabolismo , Sobrepeso/prevenção & controle , Sobrepeso/terapia , Pirazóis/efeitos adversos , Transportador 2 de Glucose-Sódio/metabolismo , Tiazolidinas/efeitos adversosRESUMO
AIMS: To investigate efficacy and safety of the sodium-glucose co-transporter 2 (SGLT2) inhibitor canagliflozin administered as add-on therapy to the dipeptidyl peptidase-4 (DPP-4) inhibitor teneligliptin in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: We conducted a multicentre, randomized, double-blind, placebo-controlled, phase 3 clinical trial in Japanese patients with T2DM who had inadequate glycaemic control with teneligliptin. Patients were randomized to receive teneligliptin 20 mg plus either canagliflozin 100 mg (T + C, n = 70) or placebo (T + P, n = 68) once daily. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 24. Other endpoints included changes in fasting plasma glucose, body weight, proinsulin/C-peptide ratio, homeostatic model assessment 2-%B and adverse events. Patients also underwent mixed-meal tolerance tests. RESULTS: The difference between the T + C and T + P groups for HbA1c change from baseline to week 24 was -0.88% (least-squares mean, P < .001). Fasting plasma glucose, body weight and the proinsulin/C-peptide ratio were significantly lower in the T + C group than in the T + P group. Homeostatic model assessment 2-%B improved with T + C compared with T + P. The T + C group exhibited a decrease in the 2-hour postprandial plasma glucose and plasma glucose area under the curve (AUC)0-2h in a mixed-meal tolerance test. No significant between-group differences were observed for C-peptide AUC0-2h or glucagon AUC0-2h after meals. Incidences of adverse events were 60.0% and 47.1% in the T + C and T + P groups, respectively. No hypoglycaemia was observed. CONCLUSIONS: Canagliflozin administered as add-on therapy to teneligliptin was effective and well tolerated in Japanese T2DM patients.
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Canagliflozina/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Pirazóis/administração & dosagem , Tiazolidinas/administração & dosagem , Idoso , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Peptídeo C/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Método Duplo-Cego , Quimioterapia Combinada , Jejum/sangue , Feminino , Hemoglobinas Glicadas/efeitos dos fármacos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in Japan for the treatment of anemia in patients with chronic kidney disease (CKD). This phase 3, open-label, single-arm study evaluated the efficacy and safety of vadadustat in 24 Japanese patients with CKD-associated anemia on hemodialysis who were not receiving erythropoiesis-stimulating agents (ESAs). Patients received vadadustat for 24 weeks; the starting dose was 300 mg/day and doses were adjusted to achieve the target hemoglobin (Hb) range of 10.0-12.0 g/dL. The least squares mean of average Hb at Weeks 20 and 24 (95% confidence interval) was 10.75 g/dL (10.35, 11.14). The most common adverse event was shunt stenosis (25.0%). Adverse drug reactions (diarrhea and vomiting) occurred in two patients (8.3%) and the severity was mild. Vadadustat increased and maintained Hb levels within the target range and was generally well-tolerated in Japanese patients with anemia on hemodialysis not receiving ESAs.
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Anemia/tratamento farmacológico , Anemia/etiologia , Glicina/análogos & derivados , Ácidos Picolínicos/uso terapêutico , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Feminino , Glicina/uso terapêutico , Hematínicos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
[This corrects the article DOI: 10.1371/journal.pone.0201956.].
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PURPOSE: Vadadustat is an oral hypoxia-inducible factor-prolyl hydroxylase inhibitor approved in Japan for the treatment of anemia in chronic kidney disease. This study investigated drug-drug interactions between vadadustat and oral iron supplements or iron-containing phosphate binders commonly used in Japanese clinical practice by conducting in vitro mechanistic and clinical pharmacokinetic studies. METHODS: In the in vitro assessment, chelate formation of vadadustat with iron-containing agents was investigated in water and in a fed-state simulated intestinal fluid. Chelate formation was assessed by observation of a chelate-specific color, and the concentration of vadadustat was determined. In the single-dose, open-label, randomized, crossover clinical study, healthy male participants received 150 mg of vadadustat with or without oral iron-containing agents. Pharmacokinetic data were collected for up to 24 hours after vadadustat administration. Participants were monitored for adverse events during the study. FINDINGS: Vadadustat formed a chelate precipitate with ferrous sulfate and ferric nitrate, as shown by development of a specific bright orange color in water. The proportions of vadadustat dissolved in the supernatant were 2% and 18%, respectively. Vadadustat did not form a chelate precipitate in a fed-state simulated intestinal fluid in the presence of sodium ferrous citrate, ferric citrate hydrate, or sucroferric oxyhydroxide; the proportion of vadadustat in supernatant ranged from 63% to 89%. In the clinical pharmacokinetic study, coadministration of vadadustat with sodium ferrous citrate, ferric citrate hydrate, sucroferric oxyhydroxide, or ferrous sulfate decreased the AUC0-∞ by 54.0% to 89.7% and Cmax by 42.1% to 91.9%. No serious adverse events were reported. IMPLICATIONS: Chelate formation of vadadustat with iron-containing agents was confirmed by in vitro analysis and depended on the type of iron-containing agent. The AUC0-∞ and Cmax of vadadustat decreased when coadministered with oral iron-containing agents. Our data suggest that the decreases in AUC0-∞ and Cmax are a result of chelation in the gastrointestinal tract; therefore, coadministration of iron-containing agents with vadadustat should use a dosing interval. ClinicalTrials.gov Identifier: NCT03645863.
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Inibidores de Prolil-Hidrolase , Glicina/análogos & derivados , Humanos , Hipóxia , Ferro , Masculino , Ácidos PicolínicosRESUMO
The neuroprotective agent edaravone is an intravenous treatment for amyotrophic lateral sclerosis. As intravenous administration burdens patients, orally administered treatments are needed. This phase 1, open-label, single-dose crossover study in 42 healthy adults evaluated bioequivalence of a 105-mg edaravone oral suspension and intravenous edaravone (60 mg/60 min). The evaluation was whether the 90% confidence intervals (CIs) for the ratio of the maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve from time 0 to the last quantifiable time point and to infinity of unchanged edaravone were between the bioequivalence limit of 0.80 and 1.25. Metabolic profiles and elimination pathways were also compared between the 2 routes. Geometric mean ratios and 90%CIs of area under the plasma concentration-time curve from time 0 to the last quantifiable time point and to infinity for unchanged edaravone satisfied bioequivalence limits. The geometric mean ratio and its lower limit of 90%CI of Cmax of the 105-mg oral suspension compared with 60-mg intravenous formulations for unchanged edaravone fell within bioequivalence limits. Both formulations showed triphasic plasma concentration-time profiles of unchanged edaravone after reaching Cmax . Plasma concentrations of edaravone inactive metabolites after oral administration were higher than with intravenous administration. Edaravone in both routes underwent urinary excretion, mainly as the glucuronide conjugate and, to a lesser extent, as the sulfate conjugate. Urinary excretion of unchanged edaravone was low, and urinary relative composition ratios of unchanged edaravone and metabolites were similar for both formulations. These findings showed equivalent exposure of the 105-mg oral suspension of edaravone to the 60-mg intravenous formulation, supporting further investigation of the oral suspension for treating amyotrophic lateral sclerosis.
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Composição de Medicamentos/métodos , Edaravone/administração & dosagem , Edaravone/metabolismo , Sequestradores de Radicais Livres/administração & dosagem , Sequestradores de Radicais Livres/metabolismo , Administração Oral , Adolescente , Adulto , Estudos Cross-Over , Feminino , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Masculino , Suspensões , Equivalência Terapêutica , Adulto JovemRESUMO
Intravenous (IV) edaravone is approved as an amyotrophic lateral sclerosis (ALS) treatment. Because IV administration places a burden on patients, development of orally administered ALS treatments is needed. Therefore, 2 phase 1 studies of oral formulations of edaravone in healthy subjects examined the pharmacokinetics (PK), safety, racial differences, and drug-drug interactions (DDIs) and investigated the dose of the oral formulation considered to be bioequivalent to the approved dose of the IV formulation. Study 1 was a placebo-controlled, randomized, single-blind study of single-ascending-dose oral edaravone with the dose range of 30 to 300 mg (n = 56). Study 2 was conducted in 2 cohorts (n = 84); the first assessed DDIs with multiple-dose edaravone 120 mg/day given over 5 or 8 days (coadministered with single-dose rosuvastatin, sildenafil, or furosemide), and the second evaluated PK and racial (Japanese/White) differences in PK parameters with doses of 100-mg edaravone. The oral formulation of edaravone was well absorbed, and plasma concentrations of unchanged edaravone increased more than dose proportionally within the dose range of 30 to 300 mg. No effect of race on oral edaravone PK and no notable DDI effects possibly caused by orally administered edaravone were observed. The oral edaravone formulations were safe and tolerable under the assessed conditions. Mathematical modeling determined that equivalent exposures in plasma with the approved dose of the IV edaravone formulation, as reported previously, could be achieved when the oral edaravone formulation was administered at a dose of ≈100 mg, with an absolute bioavailability of ≈60%.
Assuntos
Povo Asiático , Edaravone/administração & dosagem , Edaravone/farmacocinética , Sequestradores de Radicais Livres/administração & dosagem , Sequestradores de Radicais Livres/farmacocinética , População Branca , Administração Oral , Adulto , Relação Dose-Resposta a Droga , Interações Medicamentosas/fisiologia , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Método Simples-Cego , Suspensões , Adulto JovemRESUMO
This randomized, single-blind, 3-way crossover study assessed the effect of edaravone on QT interval, including an exposure-response analysis. Twenty-seven healthy Japanese male volunteers, aged 20 to 49 years, were randomly assigned to receive a single intravenous dose of each treatment in 1 of 3 sequences (n = 9 each): ACB, BAC, and CBA, where A was edaravone 60 mg (therapeutic dose), B was edaravone 300 mg (supratherapeutic dose), and C was normal saline (placebo). Electrocardiographs were collected to assess treatment effects. In an exposure-response analysis, a linear model was determined to be valid and indicated no statistically significant positive slope for the relationship between change from baseline in QTcF (ΔQTcF) and edaravone concentration (0.000155 ms/(ng/mL); P = .1478); upper bounds of 2-sided 90% confidence intervals after placebo adjustment (ΔΔQTcF) were <10 milliseconds at the geometric mean maximum concentration for each edaravone dose. Overall estimated values by time point of ΔΔQTcF ≤0.9 milliseconds, no outlier values, and no morphologic changes suggestive of repolarization abnormalities were observed. Analysis of heart rate, PR interval, and QRS duration also revealed no adverse findings. These data indicate that edaravone, even at supratherapeutic doses, does not produce clinically meaningful QT prolongation and has no clinically relevant cardiac effects.
Assuntos
Edaravone/administração & dosagem , Sequestradores de Radicais Livres/administração & dosagem , Frequência Cardíaca/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Adulto , Estudos Cross-Over , Edaravone/efeitos adversos , Edaravone/sangue , Edaravone/farmacocinética , Eletrocardiografia/efeitos dos fármacos , Sequestradores de Radicais Livres/efeitos adversos , Sequestradores de Radicais Livres/sangue , Sequestradores de Radicais Livres/farmacocinética , Voluntários Saudáveis , Humanos , Síndrome do QT Longo , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/sangue , Fármacos Neuroprotetores/farmacocinética , Método Simples-Cego , Adulto JovemRESUMO
Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anemia in patients with chronic kidney disease (CKD). This phase 3, open-label, 24-week single-arm study evaluated the efficacy and safety of vadadustat in 42 Japanese CKD patients with anemia undergoing peritoneal dialysis. Patients received oral vadadustat for 24 weeks, initiated at 300 mg/day and doses were adjusted to achieve the target hemoglobin (Hb) range of 11.0-13.0 g/dL. Least squares mean of average Hb at weeks 20 and 24 was 11.35 g/dL, which was within the target range. The most frequent adverse events were catheter site infections (23.8%), which were not related to vadadustat treatment. Vadadustat was generally well tolerated and effective in controlling Hb levels within the target range, indicating the usefulness of vadadustat for treating anemia in Japanese CKD patients undergoing peritoneal dialysis.
Assuntos
Anemia/tratamento farmacológico , Anemia/etiologia , Glicina/análogos & derivados , Diálise Peritoneal/efeitos adversos , Ácidos Picolínicos/uso terapêutico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Feminino , Glicina/uso terapêutico , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Diálise Peritoneal/métodos , Resultado do TratamentoRESUMO
PURPOSE: The goal of this study was to compare edaravone pharmacokinetic (PK) variables and tolerability after a single intravenous (IV) infusion of 30 mg over 60 min in subjects with mild renal impairment (estimated glomerular filtration rate 60-89 mL/min/1.73 m2), moderate renal impairment (30-59 mL/min/1.73 m2), or normal renal function (≥90 mL/min/1.73 m2). METHODS: This open-label, single-dose study was conducted in Japan. After a screening period of up to 3 weeks, all subjects received a single IV dose of edaravone 30 mg/h on day 1. Blood samples were collected for PK analysis of edaravone and its sulfate conjugate for up to 48 h postdose. FINDINGS: Edaravone was administered to 30 subjects: 11 with mild (Group 1), 8 with moderate (Group 2), and 11 with no (Group 3) renal impairment. Although geometric least-squares mean values for Cmax and AUC0-∞ for unchanged edaravone were 1.15- and 1.20-fold greater in Group 1 than in Group 3, and were 1.25- and 1.30-fold greater in Group 2 than in Group 3, no statistically significant differences in exposure (Cmax and AUC) to edaravone were noted between the 3 groups (P > 0.05). The geometric least-squares mean values for Cmax and AUC0-∞ for the sulfate conjugate were 1.41- and 1.50-fold greater in Group 1 than in Group 3, and 1.41- and 1.97-fold greater in Group 2 than in Group 3. Differences in exposure (Cmax and AUC) to the sulfate conjugate of edaravone were statistically significant between the 3 study groups (P < 0.0001). A total of 5 treatment-emergent adverse events in 3 subjects in Group 1 were considered by the investigator to be reasonably related to edaravone: headache (2 events/2 subjects), vomiting (2 events/1 subjects), and increased blood bilirubin level (n = 1). These treatment-emergent adverse events were mild and recovered without sequelae. IMPLICATIONS: Mild to moderate renal impairment had no clinically significant effects on the PK profile of edaravone in Japanese subjects, relative to individuals with normal renal function, and there were no significant safety concerns. Thus, edaravone dosage adjustments are unlikely to be needed in patients with mild to moderate renal impairment. Clinicaltrials.gov identifier: NCT03289208.
Assuntos
Edaravone/farmacocinética , Insuficiência Renal/fisiopatologia , Adulto , Idoso , Área Sob a Curva , Edaravone/administração & dosagem , Feminino , Taxa de Filtração Glomerular , Humanos , Japão , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: Two studies were conducted to assess the pharmacokinetic (PK) properties and tolerability of edaravone in Japanese subjects with mild to moderate hepatic impairment or normal hepatic functioning (study 1), and in white subjects with severe hepatic impairment compared to subjects with normal hepatic functioning (study 2). METHODS: Studies 1 and 2 were multicenter, open-label, single-dose studies that included subjects aged 18-75 years. In study 1, subjects were stratified into 3 different groups of hepatic functioning according to Child-Pugh score: mild hepatic impairment, score 5 or 6 (n = 8); moderate hepatic impairment, score 7-9 (n = 6); or normal hepatic functioning (n = 8). In study 2, subjects had severe hepatic impairment (Child-Pugh score 10-14; n = 6) or normal hepatic functioning (n = 6). In both studies, all subjects were given edaravone 30 mg IV infused over 60 min on the morning of day 1. Blood samples for use in PK analyses were collected from days 1-3. The PK properties (Cmax, AUC0-last, and AUC0-∞) of edaravone and its sulfate conjugate metabolite were measured. FINDINGS: In study 1, the geometric least-squares mean (GLSM) Cmax and AUC0-∞ of unchanged edaravone were 1.203- and 1.065-fold greater, respectively, in subjects with mild hepatic impairment versus normal hepatic functioning, and were 1.235- and 1.142-fold greater, respectively, in subjects with moderate hepatic impairment versus normal hepatic functioning. In study 2, GLSM Cmax and AUC0-∞ of unchanged edaravone were 1.203- and 1.190-fold greater, respectively, in subjects with severe hepatic impairment versus normal hepatic functioning. In both studies the AUC0-last, AUC0-∞, unbound AUC from time zero to infinity, and Cmax of unchanged edaravone were increased slightly with increases in Child-Pugh classification. No adverse events considered related to edaravone were reported, except for 1 case of sinus bradycardia in a subject with normal hepatic functioning in study 2. The event was moderate in severity, considered as possibly related to edaravone, and resolved during the study. IMPLICATIONS: Mild to moderate and severe hepatic impairment had no apparent clinically significant effects on the PK profile of edaravone in Japanese and white subjects, respectively, relative to individuals with normal hepatic functioning, and there were no notable tolerability concerns. Thus, edaravone dosage adjustments are unlikely to be needed in edaravone-treated patients with mild to moderate and severe hepatic impairment. ClinicalTrials.gov identifiers: NCT03289234 (mild to moderate hepatic impairment) and NCT03664544 (severe hepatic impairment).
Assuntos
Edaravone/farmacocinética , Sequestradores de Radicais Livres/farmacocinética , Hepatopatias/metabolismo , Fármacos Neuroprotetores/farmacocinética , Adolescente , Adulto , Idoso , Área Sob a Curva , Bradicardia/induzido quimicamente , Edaravone/efeitos adversos , Edaravone/sangue , Feminino , Sequestradores de Radicais Livres/efeitos adversos , Sequestradores de Radicais Livres/sangue , Humanos , Hepatopatias/sangue , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/sangue , Adulto JovemRESUMO
BACKGROUND AND PURPOSE: The antiplatelet agent sarpogrelate is a selective inhibitor of 5-hydroxytryptamine receptors. The purpose of this study was to compare the efficacy and safety of sarpogrelate with those of aspirin in Japanese ischemic stroke patients. METHODS: In total, 1510 patients with recent cerebral infarction (1 week to 6 months after onset) were randomly assigned to receive either sarpogrelate (100 mg TID) or aspirin (81 mg/d). Mean follow-up period was 1.59 years. The primary efficacy end point was recurrence of cerebral infarction. Clusters of serious vascular events (stroke, acute coronary syndrome, or vascular event-related death) were selected as secondary end points. The aim of the primary efficacy analysis was to demonstrate the noninferiority of sarpogrelate with respect to aspirin, with the criterion that the upper limit of the 95% CI of the hazard ratio (sarpogrelate vs aspirin) for recurrence of cerebral infarction should not exceed 1.33. RESULTS: Cerebral infarction recurred in 72 patients (6.09%/y) in the sarpogrelate group and in 58 (4.86%/y) in the aspirin group (hazard ratio=1.25; 95% CI, 0.89 to 1.77; P=0.19). A serious vascular event occurred in 90 (7.61%/y) and in 85 (7.12%/y) patients, respectively (hazard ratio=1.07; 95% CI, 0.80 to 1.44; P=0.65). The overall incidences of bleeding events were 89 (11.9%) and 131 (17.3%), respectively (P<0.01). CONCLUSIONS: Sarpogrelate was not noninferior to aspirin for prevention of recurrence of cerebral infarction. Bleeding events were significantly fewer with sarpogrelate than aspirin. The effect of aspirin in Japanese patients was similar to that in Western studies.