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PURPOSE: Esaxerenone is a novel, oral, nonsteroidal treatment for hypertension. Physiologically based pharmacokinetic (PBPK) modelling was performed to predict the drug-drug interaction (DDI) effect of cytochrome P450 (CYP)3A modulators on esaxerenone pharmacokinetics in healthy subjects and subjects with hepatic impairment. METHODS: In our PBPK model, the fraction of esaxerenone metabolised by CYP3A was estimated from mass-balance data and verified and optimised by clinical DDI study results with strong CYP3A modulators. The model was also verified by the observed pharmacokinetics after multiple oral dosing and by the effect of hepatic impairment on esaxerenone pharmacokinetics. The model was applied to predict the DDI effects on esaxerenone pharmacokinetics with untested CYP3A modulators in healthy subjects and with strong CYP3A modulators in subjects with hepatic impairment. RESULTS: The PBPK model well described esaxerenone pharmacokinetics after multiple oral dosing. The predicted fold changes in esaxerenone plasma exposure after coadministration with strong CYP3A modulators were comparable with the observed data (1.53-fold with itraconazole and 0.31-fold with rifampicin). Predicted DDIs with untested moderate CYP3A modulators were less than the observed DDI with strong CYP3A modulators. The PBPK model also described the effect of hepatic impairment on esaxerenone plasma exposure. The predicted DDI results with strong CYP3A modulators in subjects with hepatic impairment indicate that, for concomitant use of CYP3A modulators, caution is advised for subjects with hepatic impairment, as is for healthy subjects. CONCLUSION: The PBPK model developed predicted esaxerenone pharmacokinetics and DDIs and informed concurrent use of esaxerenone with CYP3A modulators.
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Anti-Hipertensivos/farmacocinética , Indutores do Citocromo P-450 CYP3A/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Falência Hepática/metabolismo , Pirróis/farmacocinética , Sulfonas/farmacocinética , Área Sob a Curva , Simulação por Computador , Interações Medicamentosas , Voluntários Saudáveis , Humanos , Itraconazol/farmacologia , Japão , Taxa de Depuração Metabólica , Modelos Biológicos , Rifampina/farmacologiaRESUMO
AIMS: To investigate the effects of the strong cytochrome P450 (CYP) 3A inhibitor itraconazole and the strong CYP3A inducer rifampicin on the pharmacokinetics of single-dose esaxerenone, a nonsteroidal mineralocorticoid receptor blocker, in healthy Japanese subjects. METHODS: Two open-label, single-sequence, crossover studies were conducted in healthy Japanese males aged 20-45 years. In Study 1 (n = 20), subjects received a single oral 2.5 mg dose of esaxerenone (Days 1, 13), with itraconazole 200 mg twice daily (Day 8) and once daily (Days 9-16). In Study 2 (n = 12), subjects received a single oral 5 mg dose of esaxerenone (Days 1, 13), with rifampicin 600 mg once daily (Days 8-16). The plasma concentration of esaxerenone and esaxerenone metabolites were measured using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated using noncompartmental analysis, and safety was assessed. RESULTS: Esaxerenone exposure increased when coadministered with itraconazole. Geometric least-square mean ratios (90% confidence interval) of peak plasma esaxerenone concentration (Cmax ), area under the plasma concentration-time curve (AUC) from zero until the last measurable concentration (AUClast ) and AUC from zero until infinity (AUCinf ) were 1.13 (1.05, 1.20) ng mL-1 , 1.47 (1.40, 1.54) ng h mL-1 and 1.53 (1.45, 1.62) ng h mL-1 , respectively. Esaxerenone exposure decreased when coadministered with rifampicin. Geometric least-squares mean ratios (90% confidence interval) of esaxerenone Cmax , AUClast and AUCinf were 0.659 (0.599, 0.724), 0.315 (0.300, 0.332) and 0.312 (0.297, 0.328), respectively. CONCLUSION: Itraconazole increased esaxerenone AUCinf by 53.1%, and rifampicin decreased esaxerenone AUCinf by 68.8%. These results suggest that caution is recommended when coadministering esaxerenone with strong inhibitors and inducers of CYP3A.
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Itraconazol , Rifampina , Área Sob a Curva , Estudos Cross-Over , Citocromo P-450 CYP3A , Interações Medicamentosas , Voluntários Saudáveis , Humanos , Itraconazol/efeitos adversos , Japão , Masculino , Pirróis , Receptores de Mineralocorticoides , SulfonasRESUMO
Esaxerenone (CS-3150) is a novel, nonsteroidal, selective mineralocorticoid receptor blocker. The absorption, metabolism, distribution, and excretion of esaxerenone were assessed in in vitro studies and in a clinical study, where [14C]esaxerenone (150 µCi/20 mg) was administered orally to six healthy male subjects. The plasma concentrations of esaxerenone and its metabolites (M4, M11, and M1) were measured using liquid chromatography-tandem mass spectrometry. The recovery of radioactivity was 92.5%, with 38.5% and 54.0% excreted in the urine and feces, respectively. The half-life of radioactivity in blood and plasma was approximately 30 hours, similar to that of the unchanged form in plasma. The blood-to-plasma ratio was 0.628, demonstrating low partitioning to blood components. In plasma, esaxerenone was the most abundant moiety (40.8%), followed by O-glucuronide (21.4%; M4), acyl-glucuronide of amide-bond hydrolysate (8.0%; M11), and the deshydroxyethyl form (1.7%; M1). In vitro studies showed that esaxerenone was a substrate of CYP3A and multiple UDP-glucuronosyltransferase isoforms. Oxidation contributed approximately 30% to its clearance, as indicated by the excretion ratio of oxidized metabolites into urine and feces. Caco-2 studies showed that esaxerenone was a substrate of P-glycoprotein and breast cancer resistance protein; however, the excretion ratios of the unchanged form in the feces and urine were 18.7% and 1.6%, respectively, indicating that these transporters were not important for the absorption and elimination of esaxerenone. Low urinary excretion of esaxerenone suggested that the plasma exposure of esaxerenone was not affected by renal dysfunction. Multiple elimination pathways including oxidation, glucuronidation, and hydrolysis, and the low contribution of transporters, indicated limited drug-drug interaction potential.
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Antagonistas de Receptores de Mineralocorticoides/farmacocinética , Pirróis/farmacocinética , Receptores de Mineralocorticoides/metabolismo , Sulfonas/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Administração Oral , Adulto , Células CACO-2 , Citocromo P-450 CYP3A/metabolismo , Glucuronosiltransferase/metabolismo , Voluntários Saudáveis , Humanos , Absorção Intestinal , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Antagonistas de Receptores de Mineralocorticoides/metabolismo , Proteínas de Neoplasias/metabolismo , Pirróis/administração & dosagem , Pirróis/metabolismo , Sulfonas/administração & dosagem , Sulfonas/metabolismo , Distribuição TecidualRESUMO
BACKGROUND AND AIMS: The incidence of metachronous gastric cancer (MGC) in patients whose primary gastric neoplasm is discovered after Helicobacter pylori eradication remains unclear. Here, we evaluated the long-term effect of previous H pylori eradication on development of MGC after endoscopic submucosal dissection (ESD). METHODS: We analyzed prospectively collected data of consecutive patients with successful H pylori eradication more than 1 year before (eradicated group, 180 patients) or after (control group, 602 patients) initial curative ESD. These patients were also followed by endoscopy for over 2 years. Propensity score matching and inverse probability of treatment weighting (IPTW) were used to adjust for confounding variables during data analysis. The main outcome was the incidence of MGC after initial ESD. RESULTS: In a propensity-matched analysis of 174 pairs, the incidence of MGC was similar in the 2 cohorts (33.9 per 1000 person-years vs 40.8 per 1000 person-years in the control group, P = .454) at a median follow-up of 4.1 years (interquartile range, 3.0-5.6). Incidences were also similar in the 2 groups when data were analyzed using IPTW, even after exclusion of 123 patients with successful H pylori eradication <5 years before initial ESD. Multiple Cox regression analysis revealed age, differentiated-type histology, and initial multiplicity were predictors of MGC in patients after initial curative ESD. CONCLUSIONS: The frequency of follow-up surveillance after initial curative ESD should be kept constant, irrespective of whether H pylori eradication is performed before or after initial curative ESD.
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Adenocarcinoma/cirurgia , Adenoma/cirurgia , Antibacterianos/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Segunda Neoplasia Primária/epidemiologia , Neoplasias Gástricas/cirurgia , Adenocarcinoma/epidemiologia , Adenocarcinoma/patologia , Adenoma/epidemiologia , Adenoma/patologia , Idoso , Ressecção Endoscópica de Mucosa , Feminino , Gastroscopia , Helicobacter pylori , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/patologiaRESUMO
AIMS: To characterize the pharmacokinetics, pharmacodynamics and safety of esaxerenone, a mineralocorticoid receptor antagonist, in healthy adult Japanese men. METHODS: Double-blind, placebo-controlled, sequential, dose-escalation studies were conducted in subjects randomized to receive oral once-daily esaxerenone (ranges: 5-200 mg [single-dose]; 10-100 mg over 10 days [multiple-dose]) or placebo under fasting conditions. Plasma concentrations were analysed by liquid chromatograph-tandem mass spectrometry. Pharmacokinetic parameters were determined by noncompartment analysis. Plasma/urine levels of pharmacodynamic biomarkers for mineralocorticoid receptor activity were evaluated. RESULTS: In total, 48/48 and 39/40 subjects completed the single- and multiple-dose studies, respectively. Exposures were generally dose-proportional. The tmax , t1/2 and CL/F remained unchanged, independent of dose; the respective ranges were 1.5-4.0 h, 22.3-25.1 h, and 4.0-5.2 l h-1 (multiple-dose study). Vz /F ranged from 136.5 to 283.7 l in the multiple-dose study, and exposure reached steady state by day 4. The mean observed accumulation ratio, by dose, ranged from 1.36-1.98. The urinary Na+ /K+ ratio increased after single-dose administration; however, its relationship to the doses tested remains unclear. Plasma renin activity, active renin concentration and aldosterone concentration increased dose-dependently. Although blood potassium levels increased dose-dependently in the multiple-dose study (reaching a maximum mean ± standard deviation of 4.63 ± 0.354 mmol l-1 in the 100-mg group), no safety/tolerability-related problems were detected in either study. CONCLUSIONS: Exposure levels in healthy adults receiving esaxerenone were generally dose-proportional. Dose-dependent changes in plasma pharmacodynamic biomarkers for the mineralocorticoid receptor were identified during multiple-dose treatment and support the pharmacological activity of esaxerenone. No important safety concerns were identified.
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Biomarcadores Farmacológicos/sangue , Hipertensão/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Pirróis/administração & dosagem , Sulfonas/administração & dosagem , Administração Oral , Adulto , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Meia-Vida , Voluntários Saudáveis , Humanos , Japão , Masculino , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Antagonistas de Receptores de Mineralocorticoides/farmacocinética , Pirróis/efeitos adversos , Pirróis/farmacocinética , Sulfonas/efeitos adversos , Sulfonas/farmacocinética , Adulto JovemRESUMO
The present study investigated the effects of diesel exhaust (DE) on an experimental model of bleomycin (BLM)-induced lung injury and fibrosis in mice. BLM was intravenously administered to both Nrf2+/+ and Nrf2-/- C57BL/6J mice on day 0. The mice were exposed to DE for 56 days from 28 days before the BLM injection to 28 days after the BLM injection. Inhalation of DE induced significant inhibition of airway clearance function and the proinflammatory cytokine secretion in macrophages, an increase in neutrophils, and severe lung inflammatory injury, which were greater in Nrf2-/- mice than in Nrf2+/+ mice. In contrast, inhalation of DE was observed to induce a greater increase of hydroxyproline content in the lung tissues and significantly higher pulmonary antioxidant enzyme mRNA expression in the Nrf2+/+ mice than in Nrf2-/- mice. DE is an important risk factor, and Nrf2 regulates the risk of a DE inhalation induced immune response during BLM lung injury and fibrosis in mice.
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Citocinas/metabolismo , Lesão Pulmonar/genética , Fator 2 Relacionado a NF-E2/metabolismo , Emissões de Veículos/toxicidade , Animais , Bleomicina/toxicidade , Fibrose , Hidroxiprolina/metabolismo , Lesão Pulmonar/etiologia , Lesão Pulmonar/imunologia , Lesão Pulmonar/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/genética , Estresse OxidativoRESUMO
Valemetostat is an EZH2/1 inhibitor that has been approved in Japan for the treatment of patients with relapsed/refractory adult T-cell leukemia/lymphoma, based mainly on results from a single-arm phase II trial. It is currently under investigation worldwide for the treatment of other non-Hodgkin lymphomas (NHLs), including peripheral T-cell lymphoma, and for solid tumors. Semi-mechanistic population pharmacokinetic modeling of total and unbound valemetostat and an analysis of the platelet time course during treatment with valemetostat were conducted using data from five clinical trials (two in patients with NHL and three in healthy volunteers). Pharmacokinetic data, including 3162 total/1871 unbound valemetostat observations from 102 patients and 72 healthy volunteers, were described by a three-compartment model with sequential zero-/first-order absorption and saturable binding in the central compartment. Alpha-1-acid glycoprotein (AAG) was the most influential covariate for total valemetostat exposure, yet had little impact on unbound exposure, meaning no dose adjustment was warranted based on AAG levels. The longitudinal platelet data from 101 patients (2313 observations) were adequately described by a modified Friberg model with two proliferation compartments, which characterized unique spontaneous recovery of platelet counts without dose modifications. A model-based simulation quantitatively assessed the proposed dose-adjustment guidance in case of platelet count decreased by comparing the probability of treatment discontinuation due to platelet count decreased with or without the dose adjustment. In summary, the models described observed total and unbound valemetostat concentrations and a unique time course of platelets during treatment, which can justify the clinical dose and provide dose-adjustment guidance.
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Valemetostat is an oral inhibitor of enhancer of zeste homolog (EZH) 2 and EZH1 approved in Japan for the treatment of adult T-cell leukemia/lymphoma (ATLL). To support the approved daily dose of 200 mg and inform dose adjustments in patients with ATLL, Bayesian exposure-response analyses were conducted using data from two clinical trials. The analyses included two efficacy endpoints, overall response by central and investigator assessments in patients with ATLL (n = 38, 150-200 mg), and six safety endpoints in patients with non-Hodgkin lymphoma (n = 102, 150-300 mg), which included grade ≥3 laboratory values for anemia, absolute neutrophil count decreased, and platelet count decreased; any grade ≥3 treatment-emergent adverse event (TEAE); and dose reductions and dose interruptions due to TEAEs. A slightly positive relationship was observed between unbound exposure and efficacy endpoints. A steeper relationship was observed in safety endpoints, compared with efficacy. Candidate covariate effects, except intercepts of the baseline laboratory values, were regularized via spike and slab priors in a Bayesian framework; only the laboratory values for corresponding hematologic TEAEs were shown to be of substantial impact. The target exposure range was established by defining a modified region of practical equivalence (184-887 ng·h/mL), which was expected to provide satisfactory efficacy and acceptable safety within the range of available exposure data. The simulated exposure range considering inter-individual variability showed that 200 mg could reach target exposure in the overall population and across subpopulations of interest, supporting the use of valemetostat 200 mg in patients with ATLL.
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BACKGROUND: Esaxerenone is a novel non-steroidal mineralocorticoid receptor blocker. Here, we assessed efficacy and safety exposure-response relationships of esaxerenone and its covariates and thereby justified the recommended dosage regimens, focusing on the safety benefits of up-titration regimen in patients at higher risk for increased serum potassium (sK+). METHODS: The relationships between model-derived individual esaxerenone exposure and efficacy (blood pressure [BP]) and safety (increased sK+) were evaluated using multivariate linear regression and Cox regression analyses, respectively, using data from 1453 hypertensive patients with or without diabetic kidney disease in five clinical studies. RESULTS: Exposure-efficacy analyses demonstrated that higher exposure was linearly associated with greater BP reduction over the investigated dose range. Exposure-safety analyses showed that higher exposure was associated with a higher risk of increased sK+ under a fixed-dosing regimen; higher baseline sK+ and lower baseline estimated glomerular filtration rate (eGFR) were influential covariates. Model-based simulations suggested that fewer occurrences of increased sK+ are expected under the up-titration regimen (from 1.25 to 5 mg) relative to the fixed-dosing regimen (5 mg) in patients with different combinations of these covariates. CONCLUSIONS: The exposure-response analyses supported the esaxerenone recommended doses and the safety benefits of using the up-titration regimen.
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Diabetes Mellitus , Nefropatias Diabéticas , Hipertensão , Sulfonas , Humanos , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/induzido quimicamente , Receptores de Mineralocorticoides , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Hipertensão/tratamento farmacológico , Hipertensão/induzido quimicamente , Pirróis/efeitos adversos , Diabetes Mellitus/induzido quimicamenteRESUMO
Pexidartinib is a systemic treatment for patients with tenosynovial giant cell tumor not amenable to surgery. Oral absorption of pexidartinib is affected by food; administration with a high-fat meal (HFM) or low-fat meal (LFM) increases absorption by approximately 100% and approximately 60%, respectively, compared with the fasted state. Pexidartinib is currently dosed 250 mg orally twice daily with an LFM (approximately 11-14 g of total fat). We developed a physiologically based pharmacokinetic model to determine the impact on drug exposure of dose timing with respect to meals, meal type, and caloric content. A 15%-16% increase in plasma exposure was predicted when consuming an HFM 1 hour after dosing with an LFM, but almost no effect on pharmacokinetics was predicted when an HFM was consumed 3 hours or more before or after pexidartinib dosing with an LFM. Exposure was not significantly affected when pexidartinib was taken with a 500-kcal LFM over the range of fat (approximately 11-14 g of total fat; 20%-25% calories from fat) for an LFM. These findings on timing of pexidartinib dose with respect to meals should be considered by patients and physicians to reduce the potential for side effects.
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Aminopiridinas , Pirróis , Humanos , Ingestão de Energia , RefeiçõesRESUMO
Valemetostat is an oral, selective inhibitor of enhancer of zeste homolog-2 (EZH2) and EZH1. In a first-in-human phase-1 trial, valemetostat capsules were well tolerated and clinically active in patients with relapsed/refractory non-Hodgkin lymphoma. Subsequently, a film-coated tablet formulation was developed for future clinical trials and commercialization. We report outcomes from 2 phase 1 trials in healthy Japanese participants, assessing the safety, tolerability, and pharmacokinetics (PK) of valemetostat tablets at single ascending doses (50, 100, and 200-mg), the relative bioavailability between capsules and tablets, and the effect of food (high-fat or low-fat meals) on the PK of valemetostat tablets. In the ascending-dose study, valemetostat maximum plasma concentration (Cmax ) and area under the concentration-time curve (AUC) increased dose-proportionally. Valemetostat plasma PK parameters were similar between the capsule and tablet formulations following a single 200-mg dose. Administration of valemetostat, 200 mg after a meal, was associated with 50%-60% lower Cmax , 30%-50% lower AUC, and a median Tmax delay of 2.5-3 hours relative to fasted administration. Valemetostat was well tolerated in healthy subjects; treatment-emergent adverse events were mild (grade 1) in severity. Based on these trials, the tablet formulation of valemetostat is suitable for use in subsequent clinical trials and should be administered under fasted conditions to avoid a negative food effect.
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Inibidores Enzimáticos , Jejum , Humanos , Voluntários Saudáveis , Estudos Cross-Over , Disponibilidade Biológica , ComprimidosRESUMO
Diesel exhaust particle (DEP) is the major components of PM2.5, and much attention has focused on PM2.5 in relation to adverse health effects, and many pulmonary diseases. In the present study, we used a human bronchial epithelial cell (HBEC) line to investigate the anti-inflammatory effects of erythromycin (EM) and EM703 - a new derivative of erythromycin without antibacterial effects on the expressions of IL-8 caused by DEP exposure. DEP showed a dose-dependent stimulatory effect on IL-8 product in HBEC. Increases of IL-8 expression by DEP stimulation were significantly blocked by both EM and EM703 pretreatment. Furthermore, NF-κB and Nrf2 activation, the antioxidant enzymes such as HO-1, NQO-1 mRNA expression were increased by DEP exposure and these increases were blocked by both of EM and EM703 pretreatment. Our results suggest that, EM and EM703 may have an inhibitory effect on expression inflammatory cytokines in HBEC induced by DEP not only as an anti-inflammation but also an antioxidant drug. EM and EM703 might contribute to chemical prevention of the risk of pulmonary diseases induced by oxidative stress from environmental pollutant, such as DEP.
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Anti-Inflamatórios/farmacologia , Eritromicina/análogos & derivados , Eritromicina/farmacologia , Material Particulado/farmacologia , Emissões de Veículos/toxicidade , Linhagem Celular , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Células Epiteliais/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-8/biossíntese , Fator 2 Relacionado a NF-E2 , NF-kappa B/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologiaRESUMO
OBJECTIVES: Esaxerenone is a novel, non-steroidal mineralocorticoid receptor (MR) blocker with improved selectivity and affinity for MR. The objectives of this study were to model the population pharmacokinetics of esaxerenone in a diverse population and to evaluate the effect of covariates on pharmacokinetics parameters. METHODS: A total of 8263 plasma esaxerenone concentrations from 166 healthy volunteers, 1097 hypertensive patients and 360 patients with diabetic nephropathy were pooled. A three-compartment model with sequential zero- and first-order absorption was used to describe the time-courses of plasma esaxerenone following single and multiple doses once daily for up to 12 weeks. Covariate effects were estimated using the full covariate modeling approach. Clinical relevance of covariates was ascertained using tornado plots. RESULTS: Esaxerenone was estimated to have high bioavailability (85.3%), low clearance (3.28 L/h) and relatively large distribution volume at steady state (94.8 L). Body weight (-26 to +36%) and coadministration of itraconazole (+64%) or rifampicin (-68%) were associated with a greater influence on esaxerenone exposure. CONCLUSIONS: The most influential covariates on esaxerenone exposure were coadministrations of itraconazole and rifampicin, followed by body weight. The clinical relevance of effects of renal impairment, mild to moderate hepatic impairment, and age is limited.
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Diabetes Mellitus , Nefropatias Diabéticas , Humanos , Nefropatias Diabéticas/tratamento farmacológico , Receptores de Mineralocorticoides , Voluntários Saudáveis , Itraconazol , Rifampina , Hipertensão Essencial , Peso CorporalRESUMO
Valemetostat tosylate (valemetostat) is an oral, potent, dual inhibitor of enhancer of zeste homolog (EZH) 2 and EZH1 under investigation for the treatment of cancer, including non-Hodgkin's lymphomas and solid tumors. Itraconazole and fluconazole are antifungal medications often used as typical inhibitors of cytochrome P450 3A (CYP3A [itraconazole and fluconazole]) and P-glycoprotein (P-gp [itraconazole]) in drug-drug interaction studies. Valemetostat is a substrate of CYP3A and P-gp in vitro. This phase I, open-label, single-sequence crossover study (JapicCTI-183902) assessed the pharmacokinetics (PK) of valemetostat when co-administered with itraconazole (a strong CYP3A inhibitor and P-gp inhibitor) or fluconazole (a moderate CYP3A inhibitor) in healthy Japanese male participants 20-45 years of age. Participants were equally allocated to receive two doses of valemetostat 25 mg, once alone and once with either itraconazole or fluconazole (400-mg induction and 200-mg once daily maintenance). Valemetostat PK parameters with versus without itraconazole or fluconazole were compared using analysis of variance models. Overall, 32 participants were enrolled. Co-administration with itraconazole increased valemetostat peak concentration (Cmax ) by 2.9-fold and area under the plasma concentration-time curve extrapolated to infinity (AUCinf ) by 4.2-fold compared with valemetostat alone. When co-administered with fluconazole, the Cmax and AUCinf of valemetostat were each increased by 1.6-fold. No treatment-related or grade ≥3 adverse events were reported. Appropriate valemetostat dose reductions are warranted when used concomitantly with strong CYP3A and P-gp dual inhibitors.
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Itraconazol , Neoplasias , Humanos , Masculino , Área Sob a Curva , Estudos Cross-Over , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A , Interações Medicamentosas , Inibidores Enzimáticos , Fluconazol/efeitos adversos , Voluntários Saudáveis , Itraconazol/efeitos adversosRESUMO
BACKGROUND: Appropriate sensitivity threshold of accelerometer to measure total sleep time during nap is not established. PURPOSE: Actigraphy-derived total sleep times during naps were calculated using three different sensitivity threshold values and compared with polysomnography. METHOD: The mean age of the 60 subjects (53 men and 7 women) was 22.8, ranging from 22 to 27 years. Determination of the sleep stage by the polygraph and the sleep/wake judgment by the accelerometer obeyed the sleep/wake judgment, and the accelerometer was monitored under different sensitivity threshold settings. The study was carried out during one afternoon with a 3-h nap opportunity. Kappa statistics, correlations, and several indices of accuracy were compared using statistical methods. RESULTS: The mean total sleep times during a nap set for 180 min were 160.4, 151.8, and 140.5 min, respectively, as judged under the low-sensitive, middle-sensitive, high-sensitive settings of an accelerometer worn on the non-dominant wrist. The corresponding mean total sleep time as calculated using a sleep polygraph was 133.0 min. Sleep/wake judgment by three levels of threshold values for the accelerometer showed that high-sensitive threshold showed relatively high specificity (0.452) compared with specificities by the low-sensitive threshold (0.249) or by the middle-sensitive threshold (0.358). The concordance correlation coefficients and 95% confidence intervals (in parenthesis) between the total sleep time judged by polygraph and low-sensitive, middle-sensitive, or high-sensitive accelerometer were 0.40 (0.26-0.51), 0.53 (0.38-0.65), and 0.64 (0.49-0.75), respectively. The Bland-Altman plot of the measurements showed higher agreement between the total sleep time by polygraph and by the accelerometer using the high-sensitive threshold. CONCLUSIONS: From the result obtained in this study, the high-sensitive accelerometer showed the strongest agreement of total sleep time and sleep/wake judgment with the calculated value using the sleep polygraph.
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Acelerometria/instrumentação , Limiar Diferencial/fisiologia , Polissonografia/instrumentação , Fases do Sono/fisiologia , Adulto , Feminino , Humanos , Masculino , Sensibilidade e EspecificidadeRESUMO
We previously found that forest environments reduced stress hormones such as adrenaline and noradrenaline and showed the relaxing effect both in male and female subjects. In the present study, we investigated the effects of walking under forest environments on cardiovascular and metabolic parameters. Sixteen healthy male subjects (mean age 57.4 ± 11.6 years) were selected after obtaining informed consent. The subjects took day trips to a forest park in the suburbs of Tokyo and to an urban area of Tokyo as a control in September 2010. On both trips, they walked for 2 h in the morning and afternoon on a Sunday. Blood and urine were sampled on the morning before each trip and after each trip. Blood pressure was measured on the morning (0800) before each trip, at noon (1300), in the afternoon (1600) during each trip, and on the morning (0800) after each trip. The day trip to the forest park significantly reduced blood pressure and urinary noradrenaline and dopamine levels and significantly increased serum adiponectin and dehydroepiandrosterone sulfate (DHEA-S) levels. Walking exercise also reduced the levels of serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) and urinary dopamine. Taken together, habitual walking in forest environments may lower blood pressure by reducing sympathetic nerve activity and have beneficial effects on blood adiponectin and DHEA-S levels, and habitual walking exercise may have beneficial effects on blood NT-proBNP levels.
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Fenômenos Fisiológicos Cardiovasculares , Metabolismo/fisiologia , Árvores/fisiologia , Caminhada/fisiologia , Adulto , Idoso , Pressão Sanguínea/fisiologia , Cidades , Ingestão de Energia/fisiologia , Meio Ambiente , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Temperatura , Fatores de TempoRESUMO
BACKGROUND AND OBJECTIVE: Esaxerenone showed the potential to inhibit and induce activity against cytochrome P450 (CYP) 3A in in vitro studies. We investigated whether repeated administration of 5 mg/day esaxerenone for 14 days influences the pharmacokinetics of midazolam, a sensitive CYP3A substrate, in healthy Japanese males. METHODS: This single-centre, open-label, single-sequence study had two administration periods: period 1: single oral dose of 2 mg midazolam (day 0); period 2: repeated oral doses of 5 mg/day esaxerenone for 14 days, with a single oral dose of 2 mg midazolam on day 14. Full pharmacokinetic profiles of midazolam and 1-hydroxymidazolam on days 0 and 14 and safety data were obtained. Primary pharmacokinetic endpoints for midazolam were area under the plasma concentration-time curve (AUC) from zero to time of the last measurable concentration (AUClast), AUC from zero to infinity (AUCinf), and peak plasma concentration (Cmax). RESULTS: The study included 28 male subjects. One subject was withdrawn because of a mild adverse event (increased hepatic enzyme levels) that resolved without intervention. Repeated administration of esaxerenone increased midazolam AUClast, AUCinf, and Cmax by about 1.2-fold (1.201, 1.201, and 1.224, respectively) compared with administration of midazolam alone. However, repeated administration of esaxerenone did not affect the elimination half-life of midazolam (2.86 versus 2.63 h with and without esaxerenone). There were no safety concerns associated with concomitant administration of esaxerenone and midazolam. CONCLUSIONS: Esaxerenone 5 mg/day had no clinically significant effect on midazolam pharmacokinetics and was not associated with any safety issues. Esaxerenone can be concomitantly administered with drugs of CYP3A substrates without dose adjustments. CLINICAL TRIAL REGISTRATION: JapiCTI-152832.
Assuntos
Citocromo P-450 CYP3A/efeitos dos fármacos , Midazolam/farmacocinética , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Pirróis/farmacologia , Sulfonas/farmacologia , Administração Oral , Adulto , Área Sob a Curva , Povo Asiático , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas , Meia-Vida , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Hipnóticos e Sedativos/farmacocinética , Masculino , Midazolam/administração & dosagem , Midazolam/efeitos adversos , Midazolam/análogos & derivados , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Sulfonas/administração & dosagem , Sulfonas/efeitos adversos , Adulto JovemRESUMO
The purpose of this study was to evaluate the impact of P-glycoprotein (P-gp) efflux on edoxaban absorption in gastrointestinal tracts quantitatively by a physiologically based pharmacokinetic (PBPK) model constructed with clinical and non-clinical observations (using GastroPlus™ software). An absorption process was described by the advanced compartmental absorption and transit model with the P-gp function. A human PBPK model was constructed by integrating the clinical and non-clinical observations. The constructed model was demonstrated to reproduce the data observed in the mass-balance study. Thus, elimination pathways can be quantitatively incorporated into the model. A constructed model successfully described the difference in slopes of plasma concentration (Cp)-time curve at around 8 - 24 hr post-dose between intravenous infusion and oral administration. Furthermore, the model without P-gp efflux activity can reproduce the Cp-time profile in the absence of P-gp activity observed from the clinical DDI study results. Since the difference of slopes between intravenous infusion and oral administration also disappeared by the absence of P-gp efflux activity, P-gp must be a key molecule to govern edoxaban's PK behavior. The constructed PBPK model will help us to understand the significant contribution of P-gp in edoxaban's disposition in gastrointestinal tracts quantitatively.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Piridinas , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Transporte Biológico , Humanos , Modelos Biológicos , TiazóisRESUMO
This phase 1 single-center, single-dose, double-dummy, placebo-controlled, 4-period and 4-sequence crossover study assessed the potential of esaxerenone, a novel nonsteroidal mineralocorticoid receptor blocker used to treat hypertension, to affect cardiac repolarization. In this double-blind study, 55 subjects were randomized to single doses of 10 mg esaxerenone (therapeutic dose), 40 mg esaxerenone (supratherapeutic dose), 400 mg moxifloxacin, or placebo. Serial electrocardiograms and pharmacokinetics (PK) were obtained over 24 and 168 hours, respectively. The primary end point was Fridericia-corrected QT interval (QTcF). Secondary end points included safety and PK. Assay sensitivity was confirmed as the lower limit of 90% confidence interval (90%CIs) for placebo-corrected change from baseline QTcF (∆∆QTcF) for moxifloxacin was >5 milliseconds at the prespecified times; mean ∆∆QTcF was 12.5 milliseconds at 3 and 4 hours postdose. The upper 90%CI limits of ∆∆QTcF were ≤0 milliseconds at all times for both doses of esaxerenone. No concentration-QTc relationship was identified. Therefore, esaxerenone had no potential to inhibit cardiac repolarization. No deaths or serious adverse events (AEs) occurred; 1 subject discontinued the study because of a treatment-emergent AE unrelated to esaxerenone. This clinical evaluation showed that esaxerenone has no QTc prolongation potential.