RESUMO
Rationale: Phosphodiesterase-4 (PDE4) inhibitors have demonstrated increased efficacy in patients with chronic obstructive pulmonary disease who had chronic bronchitis or higher blood eosinophil counts. Further characterization of patients who are most likely to benefit is warranted. Objective: To identify determinants of response to the PDE4 inhibitor tanimilast. Methods: A PDE4 gene expression signature in blood was developed by unsupervised clustering of the ECLIPSE study dataset (ClinicalTrials.gov ID: NCT00292552; Gene Expression Omnibus Series ID: GSE76705). The signature was further evaluated using blood and sputum transcriptome data from the BIOMARKER study (NCT03004417; GSE133513), enabling validation of the association between PDE4 signaling and target biomarkers. Predictivity of the associated biomarkers against clinical response was then tested in the phase-2b PIONEER tanimilast study (NCT02986321). Measurements and Main Results: The PDE4 gene expression signature developed in the ECLIPSE dataset classified subgroups of patients associated with different PDE4 signaling in the BIOMARKER cohort with an area under the receiver operator curve of 98%. In the BIOMARKER study, serum IL-8 was the only variable that was consistently associated with PDE4 signaling, with lower levels associated with higher PDE4 activity. In the PIONEER study, the exacerbation rate reduction mediated by tanimilast treatment increased up to twofold in patients with lower IL-8 levels; 36% versus 18%, reaching statistical significance at ⩽20 pg/ml (P = 0.035). The combination with blood eosinophils ⩾150 µl-1 or chronic bronchitis provided further additive exacerbation rate reduction: 45% (P = 0.013) and 47% (P = 0.027), respectively. Conclusions: Using selected heterogeneous datasets, this analysis identifies IL-8 as an independent predictor of PDE4 inhibition, as tanimilast had a greater effect on exacerbation prevention in patients with chronic obstructive pulmonary disease who had lower baseline serum IL-8 levels. Testing of this biomarker in other datasets is warranted. Clinical trial registered with www.clinicaltrials.gov (NCT00292552 [Gene Expression Omnibus Series ID: GSE76705], NCT03004417 [GSE133513], and NCT02986321).
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Bronquite Crônica , Inibidores da Fosfodiesterase 4 , Doença Pulmonar Obstrutiva Crônica , Humanos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/uso terapêutico , Interleucina-8 , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/genética , Inibidores da Fosfodiesterase 4/efeitos adversos , BiomarcadoresRESUMO
BACKGROUND: Tanimilast is a novel and selective inhaled inhibitor of phosphodiesterase-4 in advanced clinical development for chronic obstructive pulmonary disease (COPD). Tanimilast is known to exert prominent anti-inflammatory activity when tested in preclinical experimental models as well as in human clinical studies. Recently, we have demonstrated that it also finely tunes, rather than suppressing, the cytokine network secreted by activated dendritic cells (DCs). This study was designed to characterize the effects of tanimilast on T-cell polarizing properties of DCs and to investigate additional functional and phenotypical features induced by tanimilast. METHODS: DCs at day 6 of culture were stimulated with LPS in the presence or absence of tanimilast or the control drug budesonide. After 24 h, DCs were analyzed for the expression of surface markers of maturation and activation by flow cytometry and cocultured with T cells to investigate cell proliferation and activation/polarization. The regulation of type 2-skewing mediators was investigated by real-time PCR in DCs and compared to results obtained in vivo in a randomized placebo-controlled trial on COPD patients treated with tanimilast. RESULTS: Our results show that both tanimilast and budesonide reduced the production of the immunostimulatory cytokine IFN-γ by CD4+ T cells. However, the two drugs acted at different levels since budesonide mainly blocked T cell proliferation, while tanimilast skewed T cells towards a Th2 phenotype without affecting cell proliferation. In addition, only DCs matured in the presence of tanimilast displayed increased CD86/CD80 ratio and CD141 expression, which correlated with Th2 T cell induction and dead cell uptake respectively. These cells also upregulated cAMP-dependent immunosuppressive molecules such as IDO1, TSP1, VEGF-A and Amphiregulin. Notably, the translational value of these data was confirmed by the finding that these same genes were upregulated also in sputum cells of COPD patients treated with tanimilast as add-on to inhaled glucocorticoids and bronchodilators. CONCLUSION: Taken together, these findings demonstrate distinct immunomodulatory properties of tanimilast associated with a type 2 endotype and CD141 upregulation in DCs and provide a mechanistic rationale for the administration of tanimilast on top of inhaled corticosteroids.
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Inibidores da Fosfodiesterase 4 , Doença Pulmonar Obstrutiva Crônica , Trombomodulina , Budesonida/farmacologia , Budesonida/uso terapêutico , Células Cultivadas , Citocinas/imunologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Humanos , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Trombomodulina/imunologia , Regulação para Cima/efeitos dos fármacosRESUMO
Chronic obstructive pulmonary disease (COPD) patients with higher eosinophil counts are associated with increased clinical response to phosphodiesterase-4-inhibitors (PDE4i). However, the underlying inflammatory mechanisms associated with this increased response is not yet elucidated. This post hoc analysis focused on sputum gene expression in patients with chronic bronchitis who underwent 32-day treatment with two doses of the inhaled PDE4i CHF6001 (tanimilast) or placebo on top of triple therapy. Biological characterization and treatment effects were assessed between patients with different sputum eosinophil levels (eosinophilhigh ≥ 3%; eosinophillow < 3%) at baseline (primary samples) or at the end of the treatment of the placebo arm (validation samples). Forty-one genes were differentially expressed in primary samples (p-adjusted for false discovery rate < 0.05); all up-regulated in eosinophilhigh patients and functionally enriched for type-2 and PDE4 inflammatory processes. Eleven out of nineteen genes having immune system biological processes annotations including IL5RA, ALOX15, IL1RL1, CLC, GATA1 and PDE4D were replicated using validation samples. The expression of a number of these inflammatory mediators was reduced by tanimilast treatment, with greater effects observed in eosinophilhigh patients. These findings suggest that type-2 and PDE4 overexpression in COPD patients with higher sputum eosinophil counts contribute to the differential clinical response to PDE4i observed in previous clinical trials.
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Bronquite Crônica/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Eosinófilos/patologia , Regulação da Expressão Gênica , Inflamação/genética , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/genética , Escarro/citologia , Idoso , Bronquite Crônica/sangue , Bronquite Crônica/complicações , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Feminino , Perfilação da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Inflamação/patologia , Contagem de Leucócitos , Masculino , Placebos , Doença Pulmonar Obstrutiva Crônica/complicações , Reprodutibilidade dos TestesRESUMO
BACKGROUND: This study evaluated the efficacy, safety and tolerability of the novel inhaled phosphodiesterase-4 inhibitor CHF6001 added-on to formoterol in patients with chronic obstructive pulmonary disease (COPD). METHODS: Randomised, double-blind, placebo- and active-controlled, parallel-group study. Eligible patients had symptomatic COPD, post-bronchodilator forced expiratory volume in 1 s (FEV1) 30-70% predicted, and history of ≥1 moderate/severe exacerbation. Patients were randomised to extrafine CHF6001 400, 800, 1200 or 1600 µg twice daily (BID), budesonide, or placebo for 24 weeks. PRIMARY OBJECTIVES: To investigate CHF6001 dose-response for pre-dose FEV1 after 12 weeks, and to identify the optimal dose. Moderate-to-severe exacerbations were a secondary endpoint. RESULTS: Of 1130 patients randomised, 91.9% completed. Changes from baseline in pre-dose FEV1 at Week 12 were small in all groups (including budesonide), with no CHF6001 dose-response, and no significant treatment-placebo differences. For moderate-to-severe exacerbations, CHF6001 rate reductions versus placebo were 13-28% (non-significant). In post-hoc analyses, CHF6001 effects were larger in patients with a chronic bronchitis phenotype (rate reductions versus placebo 24-37%; non-significant), and were further increased in patients with chronic bronchitis and eosinophil count ≥150 cells/µL (49-73%, statistically significant for CHF6001 800 and 1600 µg BID). CHF6001 was well tolerated with no safety signal (including in terms of gastrointestinal adverse events). CONCLUSIONS: CHF6001 had no effect in the primary lung function analysis, although was well-tolerated with no gastrointestinal adverse event signal. Post-hoc analyses focused on exacerbation risk indicate specific patient subgroups who may receive particular benefit from CHF6001. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT02986321 ). Registered 8 Dec 2016.
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Inibidores da Fosfodiesterase 4/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Sulfonamidas/administração & dosagem , para-Aminobenzoatos/administração & dosagem , Administração por Inalação , Adulto , Método Duplo-Cego , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Volume Expiratório Forçado/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Resultado do TratamentoRESUMO
BACKGROUND: Although phosphodiesterase-4 (PDE4) inhibitors have been shown to reduce COPD exacerbation rate, their biological mechanism of action is not completely elucidated at the molecular level. We aimed to characterise the whole genome gene expression profile of the inhaled PDE4-inhibitor CHF6001 on top of triple therapy in sputum cells and whole blood of patients with COPD and chronic bronchitis. METHODS: Whole genome gene expression analysis was carried out by microarray in 54 patients before and after 32 days treatment with CHF6001 800 and 1600 µg and placebo twice daily (BID) in a randomised crossover study. RESULTS: CHF6001 had a strong effect in sputum, with 1471 and 2598 significantly differentially-expressed probe-sets relative to placebo (p-adjusted for False Discovery Rate < 0.05) with 800 and 1600 µg BID, respectively. Functional enrichment analysis showed significant modulation of key inflammatory pathways involved in cytokine activity, pathogen-associated-pattern-recognition activity, oxidative stress and vitamin D with associated inhibition of downstream inflammatory effectors. A large number of pro-inflammatory genes coding for cytokines and matrix-metalloproteinases were significantly differentially expressed for both doses; the majority (> 87%) were downregulated, including macrophage inflammatory protein-1-alpha and 1-beta, interleukin-27-beta, interleukin-12-beta, interleukin-32, tumour necrosis factor-alpha-induced-protein-8, ligand-superfamily-member-15, and matrix-metalloproteinases-7,12 and 14. The effect in blood was not significant. CONCLUSIONS: Inhaled PDE4 inhibition by CHF6001 on top of triple therapy in patients with COPD and chronic bronchitis significantly modulated key inflammatory targets and pathways in the lung but not in blood. Mechanistically these findings support a targeted effect in the lung while minimising unwanted systemic class-effects. TRIAL REGISTRATION: ClinicalTrial.gov, EudraCT, 2015-005550-35. Registered 15 July 2016.
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Bronquite Crônica/tratamento farmacológico , Inibidores da Fosfodiesterase 4/administração & dosagem , Escarro/citologia , Administração por Inalação , Idoso , Anti-Inflamatórios/administração & dosagem , Biomarcadores/sangue , Biomarcadores/metabolismo , Bronquite Crônica/metabolismo , Estudos Cross-Over , Feminino , Humanos , Mediadores da Inflamação , Masculino , Inibidores da Fosfodiesterase 4/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/metabolismo , Escarro/metabolismo , Sulfonamidas , Transcriptoma , para-AminobenzoatosRESUMO
BACKGROUND: CHF6001 is a novel inhaled phosphodiesterase-4 inhibitor. This Phase IIa study assessed the effects of CHF6001 on markers of inflammation in induced sputum and blood in patients with chronic obstructive pulmonary disease (COPD). METHODS: This was a multicentre, three-period (each 32 days), three-way, placebo-controlled, double-blind, complete-block crossover study. Eligible patients had COPD, chronic bronchitis, and were receiving inhaled triple therapy for ≥2 months. Patients received CHF6001 800 or 1600 µg, or matching placebo twice daily via multi-dose dry-powder inhaler (NEXThaler). Induced sputum was collected pre-dose on Day 1, and post-dose on Days 20, 26 and 32. Blood was sampled pre-dose on Day 1, and pre- and post-dose on Day 32. RESULTS: Of 61 randomised patients, 54 (88.5%) completed the study. There were no significant differences between groups for overall sputum cell count, or absolute numbers of neutrophils, eosinophils or lymphocytes. CHF6001 800 µg significantly decreased the absolute number and percentage of macrophages vs placebo. In sputum, compared with placebo both CHF6001 doses significantly decreased leukotriene B4, C-X-C motif chemokine ligand 8, macrophage inflammatory protein 1ß, matrix metalloproteinase 9, and tumour necrosis factor α (TNFα). In blood, both CHF6001 doses significantly decreased serum surfactant protein D vs placebo. CHF6001 1600 µg significantly decreased TNFα ex-vivo (after incubation with lipopolysaccharide). CONCLUSION: The data from this study show that CHF6001 inhaled twice daily has anti-inflammatory effects in the lungs of patients with COPD already treated with triple inhaled therapy. TRIAL REGISTRATION: The study is registered on ClinicalTrials.gov ( NCT03004417 ).
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Mediadores da Inflamação/sangue , Inibidores da Fosfodiesterase 4/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Sulfonamidas/administração & dosagem , para-Aminobenzoatos/administração & dosagem , Idoso , Biomarcadores/sangue , Biomarcadores/metabolismo , Broncodilatadores/administração & dosagem , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Inflamação/diagnóstico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Escarro/metabolismo , Resultado do TratamentoRESUMO
BACKGROUND: Asthma guidelines recommend prescription of inhaled corticosteroids at a reduced dosage in children compared to older patients in order to minimize the systemic exposure and risk of unwanted side effects. In children, pressurized metered dose inhalers (pMDI) are recommended in combination with a valved holding chamber (VHC) to overcome the problem of coordinating inhalation with actuation. However, the influence of age and body size on the systemic exposure of drugs to be administered via a pMDI with VHC is still not fully elucidated. Therefore, we aimed to compare the systemic exposure to the active ingredients of a fixed combination of beclometasone-dipropionate/formoterol-fumarate administered via pMDI with VHC in children, adolescents and adults. METHODS: The pharmacokinetics of formoterol and beclometasone-17-monopropionate (active metabolite of beclometasone-dipropionate) was evaluated over 8 h from three studies, each performed in a different age and body size group. Children (7-11 years, n = 20), adolescents (12-17 years, n = 29) and adults (≥18 years, n = 24) received a single dose of beclometasone/formoterol (children: 200 µg/24 µg, adolescents and adults: 400 µg/24 µg) via pMDI with AeroChamber Plus™. RESULTS: The systemic exposure in children in comparison to adolescents was equivalent for formoterol while it was halved for beclometasone-17-monopropionate in accordance with the halved dose of beclometasone administered in children (90% CIs within 0.8-1.25 for formoterol and 0.4-0.625 for beclometasone-17-monopropionate). The systemic exposure to beclometasone-17-monopropionate and formoterol was equivalent between adolescents and adults. CONCLUSIONS: The systemic exposure to the active ingredients of a fixed dose combination of beclometasone/formoterol administered via pMDI with AeroChamber Plus™ correlates with the nominal dose independently of patient age and body size. Thus, dose reduction in relation to age when using a pMDI with VHC may be unnecessary for reducing the systemic exposure in children.
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Antiasmáticos/farmacocinética , Asma/tratamento farmacológico , Beclometasona/farmacocinética , Etanolaminas/farmacocinética , Administração por Inalação , Adolescente , Adulto , Fatores Etários , Idoso , Antiasmáticos/administração & dosagem , Beclometasona/administração & dosagem , Criança , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Etanolaminas/administração & dosagem , Feminino , Fumarato de Formoterol , Humanos , Masculino , Inaladores Dosimetrados , Pessoa de Meia-Idade , Adulto JovemRESUMO
AIM: The aim was to investigate the pharmacokinetics and pharmacodynamics of an extrafine pressurized metered-dose inhaler (pMDI) fixed combination of beclometasone dipropionate (BDP)/formoterol fumarate (FF) in adolescent and adult asthma. METHODS: This was a three-way crossover study, on 30 asthmatic adolescents receiving BDP/FF pMDI with or without a valved holding chamber (VHC) or a free licenced combination of BDP pMDI and FF pMDI plus a parallel arm of 30 asthmatic adults receiving BDP/FF pMDI. All patients received a single dose of BDP and FF of 400 µg and 24 µg, for each treatment, respectively. Assessments were performed over 8 hours. RESULTS: In adolescents, the 90% confidence intervals (CIs) for the systemic exposure (AUC(0,t)) geometric mean ratio of the fixed combination with or without VHC vs. the free combination were within the bioequivalence range 0.80-1.25, both for beclometasone-17-monopropionate (B17MP, the active metabolite of BDP) and formoterol. Pharmacodynamic variables for plasma potassium and glucose, pulse rate and pulmonary function in adolescents were equivalent between treatments, 95% CI within 0.9, 1.09. The upper level of 90% CIs for AUC(0,t) geometric mean ratio adolescents : adults of B17MP and formoterol after treatment with BDP/FF pMDI was lower than 1.25, 90% CI 0.78, 1.04 and 0.86, 1.17, respectively. CONCLUSIONS: In adolescents the pharmacodynamics and the overall systemic exposure to the active ingredients of an extrafine fixed combination of BDP/FF pMDI with or without a VHC was equivalent to that of a free licenced combination of pMDIs of established safety and efficacy profiles. The systemic exposure in adolescents was not higher than in adults. These results support the indication for use of inhaled corticosteroid/long acting ß2 -adrenoceptor agonist pMDIs in adolescents at the same dosage as in adults.
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Antiasmáticos/farmacocinética , Asma/tratamento farmacológico , Beclometasona/farmacocinética , Fumarato de Formoterol/farmacocinética , Administração por Inalação , Adolescente , Antiasmáticos/administração & dosagem , Antiasmáticos/uso terapêutico , Área Sob a Curva , Asma/sangue , Beclometasona/administração & dosagem , Beclometasona/uso terapêutico , Estudos Cross-Over , Combinação de Medicamentos , Fumarato de Formoterol/administração & dosagem , Fumarato de Formoterol/uso terapêutico , Humanos , Inaladores Dosimetrados , Resultado do TratamentoRESUMO
Liver first-pass metabolism differs considerably among organic nitrates, but little information exists on the mechanism of denitration of these compounds in hepatic tissue. The metabolism of nitrooxybutyl-esters of flurbiprofen and ferulic-acid, a class of organic nitrates with potential therapeutic implication in variety of different conditions, was investigated in comparison with glyceryl trinitrate (GTN) in human liver by a multiple approach, using a spontaneous metabolism-independent nitric oxide (NO) donor [3-(aminopropyl)-1-hydroxy-3-isopropyl-2-oxo-1-triazene (NOC-5)] as a reference tool. Nitrooxybutyl-esters were rapidly and quantitatively metabolized to their respective parent compounds and the organic nitrate moiety nitrooxybutyl-alcohol (NOBA). Differently from GTN, which was rapidly and completely metabolized to nitrite, NOBA was slowly metabolized to nitrate. In contrast to the spontaneous NO donor NOC-5, NOBA and GTN did not generate detectable NO and failed to suppress the activity of cytochrome P450, an enzyme known to be inhibited by NO. The direct identification of NOBA after liver metabolism targets this compound as the functional organic nitrate metabolite of nitrooxybutyl-esters. Moreover, the investigation of the pathways for denitration of NOBA and GTN suggests that organic nitrates are not primarily metabolized to NO in the liver but to different extents of nitrite or nitrate depending in their different chemical structure. Therefore, cytochrome P450-dependent metabolism of concomitant drugs is not likely to be affected by oral coadministration of organic nitrates. However, the first pass may differently affect the pharmacological profile of organic nitrates in connection with the different extent of denitration and the distinct bioactive species generated and exported from the liver (nitrate or nitrite).
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Anti-Inflamatórios não Esteroides/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Fígado/metabolismo , Microssomos Hepáticos/metabolismo , Mitocôndrias Hepáticas/metabolismo , Óxido Nítrico/metabolismo , Nitrocompostos/metabolismo , Anti-Inflamatórios não Esteroides/farmacologia , Butanos/metabolismo , Butanos/farmacologia , Inibidores de Ciclo-Oxigenase/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Inibidores do Citocromo P-450 CYP1A2 , Citosol/efeitos dos fármacos , Citosol/enzimologia , Citosol/metabolismo , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Feminino , Flurbiprofeno/análogos & derivados , Flurbiprofeno/metabolismo , Flurbiprofeno/farmacologia , Sequestradores de Radicais Livres/metabolismo , Sequestradores de Radicais Livres/farmacologia , Humanos , Cinética , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Desintoxicação Metabólica Fase I , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/enzimologia , Nitrocompostos/farmacologia , Nitroglicerina/metabolismo , Nitroglicerina/farmacologia , Vasodilatadores/metabolismo , Vasodilatadores/farmacologiaRESUMO
BACKGROUND: Tobramycin nebuliser solution (TNS) is indicated for maintenance therapy in cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa (PA) infections. Adherence to recommended therapy in CF has always been a challenge and new generation nebulisers are increasingly used "off label" to reduce the time required for inhalation, potentially improving patient compliance. METHODS: In this open-label, randomised, multi-centre, two-period crossover study, 27 CF patients with PA infection received TNS 300 mg/4 mL (TNS4) via the PARI eFlow(®) rapid or PARI LC Plus(®) nebuliser twice daily for 28 days in two study periods separated by a 4-week washout. The pharmacokinetic profile in plasma and sputum were determined after single and multiple dose administration on Day 1 and Day 28, respectively. Nebulisation times and general safety and tolerability profiles were evaluated throughout the study. RESULTS: Plasma tobramycin pharmacokinetic profiles were similar for the eFlow and LC Plus nebulisers both on Day 1 and Day 28. After multiple dose administration for 28 days, the eFlow/LC Plus ratio of geometric means for plasma C(max) and AUC(0-t), were 85.32 (90% CI, 61.24-118.86) and 87.44 (90% CI, 64.87-117.87), respectively. Despite the high variability, sputum tobramycin C(max) and AUC(0-t) for the eFlow on Day 28 tended to be higher than for the LC Plus (90% CI for the ratio, 86.11-226.45 and 81.81-236.71), respectively. Nebulisation times were significantly shorter for the eFlow with a median time for nebulisation of 5 min in comparison to 13 min for the LC Plus. Safety data confirmed a favourable safety profile for TNS4, with the majority of the findings being related to the underlying CF disease. CONCLUSIONS: Plasma and sputum pharmacokinetic data in CF patients with chronic PA infection support comparable pulmonary delivery and safety of TNS4 administered using different nebulisers, with a significantly shorter nebulisation time for the eFlow.
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Antibacterianos/farmacocinética , Fibrose Cística/complicações , Infecções por Pseudomonas/tratamento farmacológico , Tobramicina/farmacocinética , Adolescente , Adulto , Estudos Cross-Over , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nebulizadores e Vaporizadores , Escarro/metabolismo , Tobramicina/administração & dosagem , Tobramicina/efeitos adversosRESUMO
INTRODUCTION: Tacrolimus, the cornerstone of transplantation immunosuppression, is a narrow therapeutic index drug with a low and highly variable bioavailability. Therapeutic drug monitoring based on trough level assessment is mandatory in order to target a personalised exposure and avoid both rejection and toxicity. Population pharmacokinetic (POPPK) models might be a useful tool for improving early attainment of target range by guiding initial doses until steady state is reached and trough levels can be reliably used as surrogate marker of exposure. Here we present the first POPPK for predicting the initial doses of the once-daily prolonged release tacrolimus Envarsus (LCPT) in adult kidney recipients. METHODS: The model was developed exploiting the data from a recent pharmacokinetic randomised clinical study, in which 69 de novo kidney recipients, 33 of whom treated with LCPT, underwent an intensive blood sampling strategy for tacrolimus including four complete pharmacokinetic profiles. RESULTS: The complex and prolonged absorption of LCPT is well described by the three-phase model that incorporates body weight and CYP3A5 genotype as significant covariates accounting for a great proportion of the inter-patient variability: in particular, CYP3A5*1/*3 expressors had a 66% higher LCPT clearance. We have then generated by simulation a personalised dosing strategy based on the model that could improve the early attainment of therapeutic trough levels by almost doubling the proportion of patients within target range (69.3% compared to 36.1% with the standard body weight-based approach) on post-transplantation day 4 and significantly reduce the proportion of overexposed patients at risk of toxicity. CONCLUSIONS: A POPPK model was successfully developed for LCPT in de novo kidney recipients. The model could guide a personalised dosing strategy early after transplantation. For the model to be translated into clinical practice, its beneficial impact of earlier attainment of therapeutic trough levels should be demonstrated on hard clinical outcomes in further studies.
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Transplante de Rim , Tacrolimo , Adulto , Esquema de Medicação , Monitoramento de Medicamentos , Rejeição de Enxerto , Humanos , ImunossupressoresRESUMO
Chronic respiratory diseases are the third leading cause of death, behind cardiovascular diseases and cancer, affecting approximately 550 million of people all over the world. Most of the chronic respiratory diseases are attributable to asthma and chronic obstructive pulmonary disease (COPD) with this latter being the major cause of deaths. Despite differences in etiology and symptoms, a common feature of asthma and COPD is an underlying degree of airways inflammation. The nature and severity of this inflammation might differ between and within different respiratory conditions and pharmacological anti-inflammatory treatments are unlikely to be effective in all patients. A precision medicine approach is needed to selectively target patients to increase the chance of therapeutic success. Inhibitors of the phosphodiesterase 4 (PDE4) enzyme like the oral PDE4 inhibitor roflumilast have shown a potential to reduce inflammatory-mediated processes and the frequency of exacerbations in certain groups of COPD patients with a chronic bronchitis phenotype. However, roflumilast use is dampened by class related side effects as nausea, diarrhea, weight loss and abdominal pain, resulting in both substantial treatment discontinuation in clinical practice and withdrawal from clinical trials. This has prompted the search for PDE4 inhibitors to be given by inhalation to reduce the systemic exposure (and thus optimize the systemic safety) and maximize the therapeutic effect in the lung. Tanimilast (international non-proprietary name of CHF6001) is a novel highly potent and selective inhaled PDE4 inhibitor with proven anti-inflammatory properties in various inflammatory cells, including leukocytes derived from asthma and COPD patients, as well as in experimental rodent models of pulmonary inflammation. Inhaled tanimilast has reached phase III clinical development by showing promising pharmacodynamic results associated with a good tolerability and safety profile, with no evidence of PDE4 inhibitors class-related side effects. In this review we will discuss the main outcomes of preclinical and clinical studies conducted during tanimilast development, with particular emphasis on the characterization of the pharmacodynamic profile that led to the identification of target populations with increased therapeutic potential in inflammatory respiratory diseases.
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Background: Assessments of airways inflammation in patients with chronic obstructive pulmonary disease (COPD) require semi-invasive procedures and specialized sample processing know-how. In this study we aimed to set up and validate a novel non-invasive processing-free method for RNA sequencing (RNAseq) of spontaneous sputum samples collected from COPD patients. Methods: Spontaneous sputum samples were collected and stabilized, with or without selection of plugs and with or without the use of a stabilizer specifically formulated for downstream diagnostic testing (PrimeStore® Molecular Transport Medium). After 8 days storage at ambient temperature RNA was isolated according to an optimized RNAzol® method. An average percentage of fragments longer than 200 nucleotides (DV200) >30% and an individual yield >50 ng were required for progression of samples to sequencing. Finally, to assess if the transcriptome generated would reflect a true endotype of COPD inflammation, the outcome of single-sample gene-set enrichment analysis (ssGSEA) was validated using an independent set of processed induced sputum samples. Results: RNA extracted from spontaneous sputum using a stabilizer showed an average DV200 higher than 30%. 70% of the samples had a yield >50 ng and were submitted to downstream analysis. There was a straightforward correlation in terms of gene expression between samples handled with or without separation of plugs. This was also confirmed by principal component analysis and ssGSEA. The top ten enriched pathways resulting from spontaneous sputum ssGSEA were associated to features of COPD, namely, inflammation, immune responses and oxidative stress; up to 70% of these were in common within the top ten enriched pathways resulting from induced sputum ssGSEA. Conclusion: This analysis confirmed that the typical COPD endotype was represented within spontaneous sputum and supported the current method as a non-invasive processing-free procedure to assess the level of sputum cell inflammation in COPD patients by RNAseq analysis.
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Inorganic nitrite (NO(2)(-)) is emerging as a regulator of physiological functions and tissue responses to ischemia, whereas the more stable nitrate anion (NO(3)(-)) is generally considered to be biologically inert. Bacteria express nitrate reductases that produce nitrite, but mammals lack these specific enzymes. Here we report on nitrate reductase activity in rodent and human tissues that results in formation of nitrite and nitric oxide (NO) and is attenuated by the xanthine oxidoreductase inhibitor allopurinol. Nitrate administration to normoxic rats resulted in elevated levels of circulating nitrite that were again attenuated by allopurinol. Similar effects of nitrate were seen in endothelial NO synthase-deficient and germ-free mice, thereby excluding vascular NO synthase activation and bacteria as the source of nitrite. Nitrate pretreatment attenuated the increase in systemic blood pressure caused by NO synthase inhibition and enhanced blood flow during post-ischemic reperfusion. Our findings suggest a role for mammalian nitrate reduction in regulation of nitrite and NO homeostasis.
Assuntos
Homeostase , Nitrato Redutase/fisiologia , Nitratos , Óxido Nítrico/metabolismo , Nitritos/metabolismo , Adulto , Alopurinol/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Humanos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Nitrato Redutase/metabolismo , Nitratos/sangue , Nitratos/farmacologia , Nitratos/uso terapêutico , Óxido Nítrico Sintase/metabolismo , Nitritos/sangue , Especificidade de Órgãos , Oxirredução , Ratos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/metabolismo , Xantina Desidrogenase/metabolismoRESUMO
BACKGROUND: Japanese longevity is the highest in the world. This is partly explained by low occurrence of cardiovascular diseases, which in turn is attributed to the Japanese traditional diet (JTD). Recent research demonstrates that nitric oxide (NO), a key regulator of vascular integrity, can be generated from nitrate (NO(3)(-)), abundantly found in vegetables. It can reduce blood pressure (BP) via its serial reduction to nitrite (NO(2)(-)) and to bioactive NO. Interestingly, JTD is extremely rich in nitrate and the daily consumption is higher than in any other known diet. OBJECTIVE AND DESIGN: In a randomized, cross-over trial we examined the effect of a 10-day period of JTD on blood pressure in 25 healthy volunteers. Traditional Japanese vegetables were encouraged to be consumed and avoided during the control period. Daily nitrate intake was calculated. RESULTS: Nitrate naturally provided by the JTD was 18.8 mg/kg/bw/day, exceeding the Acceptable Daily Intake by five times (ADI, 3.7 mg/kg/bw). Plasma and salivary levels of nitrate and nitrite were higher at the end of the JTD period. Diastolic BP decreased on average 4.5 mmHg during JTD compared to the control diet (P=0.0066) while systolic BP was not affected. This effect was evident in normotensive subjects and similar to that seen in the recent studies. CONCLUSIONS: An ordinary nitrate rich diet may positively affect blood pressure. Our findings further support the importance of the role of dietary nitrate on BP regulation suggesting one possible explanation of healthy aspects of traditional Japanese food.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Dieta , Nitratos/administração & dosagem , Nitratos/farmacologia , Verduras/química , Adulto , Estudos Cross-Over , Feminino , Humanos , Japão , Masculino , Valores de ReferênciaAssuntos
Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Beclometasona/administração & dosagem , Etanolaminas/administração & dosagem , Administração por Inalação , Adolescente , Antiasmáticos/efeitos adversos , Antiasmáticos/farmacocinética , Antiasmáticos/uso terapêutico , Asma/sangue , Beclometasona/efeitos adversos , Beclometasona/farmacocinética , Beclometasona/uso terapêutico , Disponibilidade Biológica , Estudos Cross-Over , Combinação de Medicamentos , Quimioterapia Combinada , Inaladores de Pó Seco , Etanolaminas/efeitos adversos , Etanolaminas/farmacocinética , Etanolaminas/uso terapêutico , Feminino , Fumarato de Formoterol , Humanos , Masculino , Cooperação do PacienteRESUMO
Concentration-QTcF data obtained from two phase I studies in healthy volunteers treated with a novel phosphodiesterase-4 inhibitor currently under development for the treatment of chronic obstructive pulmonary disease were analyzed by means of mixed-effects modeling. A simple linear mixed-effects model and a more complex model that included oscillatory functions were employed and compared. The slope of the concentration-QTcF relationship was not significantly greater than 0 in both approaches, and the simulations showed that the upper limit of the 90% confidence interval around the mean ΔΔQTcF is not expected to exceed 10 ms within the range of clinically relevant concentrations. An additional simulation study confirmed the robustness of the simple linear mixed-effects model for the analysis of concentration-QT data and supported the modeling of data obtained from studies with different designs (parallel and crossover).
Assuntos
Frequência Cardíaca/efeitos dos fármacos , Inibidores da Fosfodiesterase 4/administração & dosagem , Sulfonamidas/administração & dosagem , para-Aminobenzoatos/administração & dosagem , Ensaios Clínicos Fase I como Assunto , Feminino , Voluntários Saudáveis , Humanos , Masculino , Modelos Teóricos , Inibidores da Fosfodiesterase 4/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Sulfonamidas/farmacologia , para-Aminobenzoatos/farmacologiaRESUMO
INTRODUCTION: Different prolonged-release formulations of tacrolimus are available. To date, the pharmacokinetic (PK) profile of LCP-tacrolimus (LCPT; Envarsus®) has not been compared with PR-Tac (Advagraf®) in de novo kidney transplant recipients. These profiles will guide clinical recommendations for the initiation and dose titration strategies of once-daily tacrolimus formulations. METHODS: This randomized, parallel-group, open-label, multicenter PK study randomized 75 de novo, adult, white kidney transplant recipients to LCPT 0.17 mg/kg/day (n = 37) or PR-Tac 0.20 mg/kg/day (n = 38) for 4 weeks. Dose adjustments were permitted to target a pre-defined therapeutic range based on measured trough blood concentrations. RESULTS: PK analysis (days 1, 3, 7 and 14) included 68 patients (LCPT, n = 33; PR-Tac, n = 35). Similar proportions of patients were within the pre-defined therapeutic tacrolimus trough blood concentration range, with < 12% in each group having below-target trough levels over the study period. LCPT demonstrated ~ 30% greater relative bioavailability [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 1.32 (p = 0.007); day 7, 1.25 (p = 0.051); day 14, 1.43 (p = 0.002)] and ~ 30% lower peak-to-trough percentage fluctuation of blood concentration [LCPT/PR-Tac adjusted geometric mean ratio: day 3, 0.70 (p < 0.001); day 7, 0.68 (p < 0.001); day 14, 0.73 (p = 0.004)] in addition to longer time to maximum blood concentration (tmax), lower maximum concentration (Cmax) and a consistently lower daily dose (~ 40% dose reduction with LCPT vs. PR-Tac by day 28). Safety profiles were similar. CONCLUSION: In de novo kidney transplant recipients, prolonged-release formulations of tacrolimus can reach therapeutic concentrations in the immediate post-transplant period. LCPT has greater relative bioavailability and lower peak-to-trough fluctuation compared with PR-Tac. TRIAL REGISTRATION: Registered at ClinicalTrials.gov; study number NCT02500212. FUNDING: Chiesi Farmaceutici S.p.A.
Assuntos
Imunossupressores/administração & dosagem , Transplante de Rim , Tacrolimo/administração & dosagem , Adulto , Disponibilidade Biológica , Esquema de Medicação , Feminino , Humanos , Imunossupressores/farmacocinética , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Estudos Prospectivos , Projetos de Pesquisa , Tacrolimo/farmacocinética , Resultado do TratamentoRESUMO
Recent studies surprisingly show that dietary inorganic nitrate, abundant in vegetables, can be metabolized in vivo to form nitrite and then bioactive nitric oxide. A reduction in blood pressure was recently noted in healthy volunteers after dietary supplementation with nitrate; an effect consistent with formation of vasodilatory nitric oxide. Oral bacteria have been suggested to play a role in bioactivation of nitrate by first reducing it to the more reactive anion nitrite. In a cross-over designed study in seven healthy volunteers we examined the effects of a commercially available chlorhexidine-containing antibacterial mouthwash on salivary and plasma levels of nitrite measured after an oral intake of sodium nitrate (10mg/kg dissolved in water). In the control situation the salivary and plasma levels of nitrate and nitrite increased greatly after the nitrate load. Rinsing the mouth with the antibacterial mouthwash prior to the nitrate load had no effect on nitrate accumulation in saliva or plasma but abolished its conversion to nitrite in saliva and markedly attenuated the rise in plasma nitrite. We conclude that the acute increase in plasma nitrite seen after a nitrate load is critically dependent on nitrate reduction in the oral cavity by commensal bacteria. The removal of these bacteria with an antibacterial mouthwash will very likely attenuate the NO-dependent biological effects of dietary nitrate.