RESUMO
The co-administration of dapagliflozin (DPF) and sacubitril/valsartan (LCZ696) has emerged as a promising therapeutic approach for managing heart failure. Given that DPF and LCZ696 are substrates for P-glycoprotein, there is a plausible potential for drug-drug interactions when administered concomitantly. To investigate the pharmacokinetic changes when these drugs are co-administered, we have established and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method capable of simultaneously detecting DPF, LBQ657 (the active metabolite of sacubitril) and valsartan in rat plasma. This method has demonstrated selectivity, sensitivity, and accuracy. Drug-drug interactions were examined by the LC-MS/MS method. The mechanisms were investigated using everted intestinal sac models and Caco-2 cells. The results showed that DPF significantly increased the area under the curve (AUC(0-t)) (3,563.3 ± 651.7 vs. 7,146.5 ± 1,714.9 h µg/L) of LBQ657 (the active metabolite of sacubitril) and the AUC(0-t) (24,022.4 ± 6,774.3 vs. 55,728.3 ± 32,446.3 h µg/L) of valsartan after oral co-administration. Dapagliflozin significantly increased the amount of LBQ657 and valsartan in intestinal sacs by 1- and 1.25-fold at 2.25 h. Caco-2 cell uptake studies confirmed that P-glycoprotein is the transporter involved in this interaction. This finding enhances the understanding of drug-drug interactions in the treatment of heart failure and provides a guidence for clinical therapy.
Assuntos
Aminobutiratos , Compostos Benzidrílicos , Compostos de Bifenilo , Glucosídeos , Tetrazóis , Valsartana , Animais , Humanos , Masculino , Ratos , Aminobutiratos/sangue , Aminobutiratos/farmacocinética , Compostos Benzidrílicos/sangue , Compostos Benzidrílicos/farmacocinética , Compostos de Bifenilo/sangue , Compostos de Bifenilo/farmacocinética , Células CACO-2 , Combinação de Medicamentos , Interações Medicamentosas , Glucosídeos/farmacocinética , Glucosídeos/sangue , Espectrometria de Massa com Cromatografia Líquida , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Tetrazóis/sangue , Tetrazóis/farmacocinética , Valsartana/sangue , Valsartana/farmacocinética , FemininoRESUMO
Importance: The US Food and Drug Administration (FDA) expanded labeling for sacubitril/valsartan for use in individuals with chronic heart failure (HF) with left ventricular ejection fraction (LVEF) lower than normal. The population-level implications of implementation of sacubitril/valsartan at higher LVEF ranges is unknown. While the Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction (PARAGON-HF) trial did not meet its primary end point, the trial may provide useful information in projecting expected clinical events among treated individuals. Objective: To quantify newly eligible treatment candidates for sacubitril/valsartan under the expanded FDA labeling and to apply treatment effects and the number needed to treat (NNT) to prevent 1 worsening HF event derived from subgroups of the PARAGON-HF trial who fall under the revised FDA label. Design, Setting, and Participants: Newly eligible treatment candidates were estimated by mapping the LVEF distribution from 559â¯520 adult patients hospitalized between 2014 and 2019 in the Get With The Guidelines-Heart Failure registry to adults self-identifying with HF in the National Health and Nutrition Examination Survey (2015 to 2018). The NNT with 3 years of treatment for 3 end points of interest (total HF hospitalizations, total HF hospitalizations and cardiovascular death, and total HF hospitalizations and urgent HF visits and cardiovascular death) were estimated from the PARAGON-HF trial. Data were analyzed from February to June 2021. Main Outcomes and Measures: Number of worsening HF events prevented or postponed if eligible patients were treated with sacubitril/valsartan for 3 years. Results: Of an estimated 4â¯682â¯098 adults, the mean (SE) age was 66.3 (0.8) years, 1â¯995â¯037 (42.6%) were women, and 748â¯045 (16.0%) were Black. The potential number of adults projected to be newly eligible varied by the definition of FDA labeling of lower than normal LVEF from 643â¯161 (95% CI, 534â¯433-751â¯888; LVEF of 41% to 50%) to 1â¯838â¯756 (95% CI, 1â¯527â¯911-2â¯149â¯601; LVEF of 41% to 60%). In the PARAGON-HF trial, the NNT to prevent a worsening HF event (range, 7 to 12 patients) was consistent irrespective of specific LVEF range selected. Comprehensive implementation of sacubitril/valsartan among newly eligible patients was empirically estimated to prevent up to 69â¯268 (95% CI, 57â¯558-80â¯978) worsening HF events (LVEF of 41% to 50%) to 182â¯592 (95% CI, 151â¯725-213â¯460) worsening HF events (LVEF of 41% to 60%). Conclusions and Relevance: The expanded FDA labeling is positioned to substantially increase the potential HF population eligible for sacubitril/valsartan by up to 1.8 million individuals and has the potential to prevent or postpone as many as 180â¯000 worsening HF events, depending on the definition of normal LVEF.
Assuntos
Aminobutiratos/farmacocinética , Compostos de Bifenilo/farmacocinética , Rotulagem de Medicamentos/métodos , Insuficiência Cardíaca/tratamento farmacológico , United States Food and Drug Administration/estatística & dados numéricos , Valsartana/farmacocinética , Função Ventricular Esquerda/fisiologia , Idoso , Antagonistas de Receptores de Angiotensina/farmacologia , Progressão da Doença , Combinação de Medicamentos , Feminino , Seguimentos , Insuficiência Cardíaca/epidemiologia , Humanos , Incidência , Masculino , Neprilisina , Estudos Retrospectivos , Fatores de Tempo , Estados Unidos/epidemiologia , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
The cytosolic metalloenzyme leukotriene A4 hydrolase (LTA4H) is the final and rate-limiting enzyme in the biosynthesis of pro-inflammatory leukotriene B4 (LTB4). Preclinical studies have validated this enzyme as an attractive drug target in chronic inflammatory diseases. Despite several attempts, no LTA4H inhibitor has reached the market, yet. Herein, we disclose the discovery and preclinical profile of LYS006, a highly potent and selective LTA4H inhibitor. A focused fragment screen identified hits that could be cocrystallized with LTA4H and inspired a fragment merging. Further optimization led to chiral amino acids and ultimately to LYS006, a picomolar LTA4H inhibitor with exquisite whole blood potency and long-lasting pharmacodynamic effects. Due to its high selectivity and its ability to fully suppress LTB4 generation at low exposures in vivo, LYS006 has the potential for a best-in-class LTA4H inhibitor and is currently investigated in phase II clinical trials in inflammatory acne, hidradenitis suppurativa, ulcerative colitis, and NASH.
Assuntos
Aminobutiratos/uso terapêutico , Anti-Inflamatórios/farmacologia , Inibidores Enzimáticos/uso terapêutico , Epóxido Hidrolases/antagonistas & inibidores , Piridinas/uso terapêutico , Aminobutiratos/síntese química , Aminobutiratos/farmacocinética , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Artrite Experimental/tratamento farmacológico , Cães , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Inflamação/tratamento farmacológico , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Piridinas/síntese química , Piridinas/farmacocinética , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
In order to better explain and predict the dissolution characteristics of binary drug delivery systems (BDDSs), the dissolution behaviors of co-crystal (CC) and co-amorphous (CA) systems of sacubitril (SCB) and valsartan (VST) were evaluated in vitro and in vivo by thermodynamic and kinetic methods. The CCs of SCB and VST were prepared into a CA state through rotary evaporation. Solid-state properties were systematically evaluated. Herein, based on the results from previous studies of single-phase systems, we used thermodynamic methods to evaluate the increase in drug dissolution rate after BDDSs change from the crystalline to the amorphous state. After comparing the predicted and measured dissolution rate enhancement of the CC and CA systems, this paper attempts to explain the dissolution rate characteristics of the BDDSs. We then evaluated the bioavailability of two BDDSs in beagle dogs to confirm that there was no discrepancy in vivo with the results obtained in vitro. The results exhibited that there is strong intermolecular interaction between SCB and VST and good physical stability for the CA system. Compared with the CC, the bioavailability of SCB and VST in the CA system increased by 313.9% and 130.5%, respectively. The predicted dissolution rate ratio between CC and CA systems and their actual intrinsic dissolution rates differed by only a factor of 2.5, demonstrating the good correlation between the predicted and measured values. In the future, this method could be expanded to a variety of new samples and exciting drug prospects.
Assuntos
Aminobutiratos/administração & dosagem , Antagonistas de Receptores de Angiotensina/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Sistemas de Liberação de Medicamentos , Tetrazóis/administração & dosagem , Termodinâmica , Valsartana/administração & dosagem , Aminobutiratos/química , Aminobutiratos/farmacocinética , Antagonistas de Receptores de Angiotensina/química , Antagonistas de Receptores de Angiotensina/farmacocinética , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacocinética , Disponibilidade Biológica , Compostos de Bifenilo , Cães , Combinação de Medicamentos , Estabilidade de Medicamentos , Cinética , Preparações Farmacêuticas , Difração de Pó , Solubilidade , Tetrazóis/química , Tetrazóis/farmacocinética , Valsartana/química , Valsartana/farmacocinéticaRESUMO
An LC-tandem mass spectrometry method was developed and validated for the simultaneous quantitation of fimasartan and sacubitrilat using positive ion mode. The protein precipitation method was employed for the extraction of fimasartan, sacubitrilat and alprazolam (internal standard) from rat heparinized plasma. Baseline separation of the analytes was accomplished using an ACE-5, C18 (4.6 × 50 mm) column and gradient elution of mobile phase A (5 mm ammonium formate and 0.1% formic acid in purified water) and B (acetonitrile:methanol, 80:20; v/v). All peaks of interest were eluted within a 5-min runtime. The quantitation was achieved in the selected reaction monitoring mode. The developed method was validated as per US Food and Drug Administration guidelines and met the pre-defined acceptance criteria. The method showed linearity from 5 to 10,000 ng/mL. The accuracy/precision of intra- and inter-batch assays was 96.64%/2.05% to 109.17%/13.70% and 100.74%/3.76% to 106.39%/9.75% for fimasartan and 100.02%/1.49% to 113.80%/9.38% and 100.75%/2.31% to 108.40%/7.74% for sacubitrilat, respectively, in rat plasma. Fimasartan and sacubitrilat remained stable in rat plasma at different experimental conditions up to 21 days. The developed method was sensitive, selective and applied successfully to monitor plasma concentrations of fimasartan and sacubitrilat in an oral rat pharmacokinetic study.
Assuntos
Aminobutiratos/sangue , Compostos de Bifenilo/sangue , Cromatografia Líquida/métodos , Pirimidinas/sangue , Espectrometria de Massas em Tandem/métodos , Tetrazóis/sangue , Aminobutiratos/química , Aminobutiratos/farmacocinética , Animais , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacocinética , Modelos Lineares , Masculino , Pró-Fármacos , Pirimidinas/química , Pirimidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas por Ionização por Electrospray/métodos , Tetrazóis/química , Tetrazóis/farmacocinéticaRESUMO
Grapefruit juice inhibits esterase enzyme. Therefore, a possible interaction with ester prodrugs should be taken into consideration. In this study, the influence of grapefruit juice on sacubitril (SAC) rat liver S9 activation by esterase enzyme was evaluated. An RP-HPLC method was developed and validated for estimation of SAC in rat liver S9 fraction using a C18 Cyano column as stationary phase and acetonitrile-sodium di-hydrogen phosphate buffer (0.02 m, pH 4 adjusted by o-phosphoric acid, 40:60, v/v), as mobile phase at a flow rate of 1 mL/min and UV detection at 254 nm. The method was successfully applied to an in vitro study in which SAC was incubated with rat liver S9 fraction prepared from rats that had previously ingested grapefruit juice for a week. The calculated SAC concentration after incubation was compared with that of SAC incubated with rat liver S9 fraction from the rat control group. The statistical significance between the results of test and control incubation sets was assessed. In conclusion, the current study demonstrated that grapefruit juice decreased SAC hydrolysis, hence delaying its activation to sacubitrilat (active form) in gut lumen. Based on this food-drug interaction, it may be required that grapefruit juice should be consumed with caution in patients receiving SAC.
Assuntos
Aminobutiratos/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Citrus paradisi/química , Sucos de Frutas e Vegetais , Microssomos Hepáticos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Tetrazóis/farmacologia , Aminobutiratos/farmacocinética , Animais , Compostos de Bifenilo , Combinação de Medicamentos , Limite de Detecção , Modelos Lineares , Extratos Vegetais/farmacocinética , Ratos , Reprodutibilidade dos Testes , Tetrazóis/farmacocinética , ValsartanaRESUMO
Reptiles, the most diverse taxon of terrestrial vertebrates, might be particularly vulnerable to soil pollution. Reptiles especially lizards have been rarely evaluated in ecotoxicological studies, and there is a very limited report for effects of soil pesticide contaminants on lizards. In this study, male and female lizards (Eremias argus) were exposed to Glufosinate-ammonium (GLA) and l- Glufosinate-ammonium (L-GLA) for 60 days. Slower sprint speed, higher frequency of turning back and reduced brain index were observed in treatment groups. The accumulation of GLA in the brain of lizard was higher than that of L-GLA. Moreover, the activities of neurotoxicity-related enzymes and biomarkers of oxidative stress were also investigated. In summary, the neurotoxic effects of lizards have been observed after exposure to GLA and L-GLA. Based on the result of the Integrated Biomarker Response (IBR), males were more sensitive to contaminants than females. On the other hand, the neurotoxic pathways by GLA and L-GLA triggered were slightly different: GLA mainly acted on glutamine synthetase (GS), acetylcholinesterase (AchE) and Catalase (CAT) and L-GLA aimed at AchE, Na+/K+-ATPase, Superoxide dismutase (SOD) and Malondialdehyde (MDA). In summary, the accumulation of GLA and L-GLA in lizard's brain induced neurotoxicity by altering the levels of enzymes related to nervous system and antioxidant activity and further resulted in the decrease of brain index and locomotor performance.
Assuntos
Aminobutiratos/toxicidade , Poluição Ambiental/efeitos adversos , Lagartos/metabolismo , Locomoção/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Aminobutiratos/farmacocinética , Aminobutiratos/farmacologia , Animais , Encéfalo/enzimologia , Encéfalo/metabolismo , Ecotoxicologia , Feminino , Lagartos/fisiologia , Masculino , Síndromes Neurotóxicas/enzimologia , Estresse Oxidativo/efeitos dos fármacos , Praguicidas/metabolismo , Fatores SexuaisRESUMO
BACKGROUND: With sacubitril/valsartan treatment, B-type natriuretic peptide (BNP) concentrations increase; it remains unclear whether change in BNP concentrations is similar across all assays for its measurement. Effects of sacubitril/valsartan on atrial natriuretic peptide (ANP) concentrations in patients are unknown. Lastly, the impact of neprilysin inhibition on mid-regional pro-ANP (MR-proANP), N-terminal pro-BNP (NT-proBNP), proBNP1-108, or C-type natriuretic peptide (CNP) is not well understood. OBJECTIVES: This study sought to examine the effects of sacubitril/valsartan on results from different natriuretic peptide assays. METHODS: Twenty-three consecutive stable patients with heart failure and reduced ejection fraction were initiated and titrated on sacubitril/valsartan. Change in ANP, MR-proANP, BNP (using 5 assays), NT-proBNP (3 assays), proBNP1-108, and CNP were measured over 3 visits. RESULTS: Average time to 3 follow-up visits was 22, 46, and 84 days. ANP rapidly and substantially increased with initiation and titration of sacubitril/valsartan, more than doubling by the first follow-up visit (+105.8%). Magnitude of ANP increase was greatest in those with concentrations above the median at baseline (+188%) compared with those with lower baseline concentrations (+44%); ANP increases were sustained. Treatment with sacubitril/valsartan led to inconsistent changes in BNP, which varied across methods assessed. Concentrations of MR-proANP, NT-proBNP, and proBNP1-108 variably declined after treatment; whereas CNP concentrations showed no consistent change. CONCLUSIONS: Initiation and titration of sacubitril/valsartan led to variable changes in concentrations of multiple natriuretic peptides. These results provide important insights into the effects of sacubitril/valsartan treatment on individual patient results, and further suggest the benefit of neprilysin inhibition may be partially mediated by increased ANP concentrations.
Assuntos
Aminobutiratos , Insuficiência Cardíaca , Peptídeo Natriurético Encefálico , Neprilisina , Tetrazóis , Aminobutiratos/administração & dosagem , Aminobutiratos/farmacocinética , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/farmacocinética , Compostos de Bifenilo , Combinação de Medicamentos , Monitoramento de Medicamentos/métodos , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/análise , Peptídeo Natriurético Encefálico/sangue , Neprilisina/antagonistas & inibidores , Neprilisina/metabolismo , Fenômenos Farmacológicos , Volume Sistólico , Tetrazóis/administração & dosagem , Tetrazóis/farmacocinética , ValsartanaRESUMO
The uptake of sacubitril/valsartan since the PARADIGM study confirmed its beneficial effects on outcomes over enalapril in chronic systolic heart failure has inevitably led to potential interactions with co-prescribed medications in real-world patients. We report two cases that raise the possibility of an interaction between sacubitril/valsartan and the class Ib anti-arrhythmic mexiletine resulting in proarrhythmic effects. We discuss the pharmacokinetics of both agents and posit potential mechanistic interactions that suggest caution should be used and careful monitoring for (ventricular) arrhythmias applied in patients receiving sacubitril/valsartan and mexiletine.
Assuntos
Aminobutiratos/efeitos adversos , Antagonistas de Receptores de Angiotensina/efeitos adversos , Arritmias Cardíacas/induzido quimicamente , Mexiletina/efeitos adversos , Tetrazóis/efeitos adversos , Idoso , Aminobutiratos/farmacocinética , Antagonistas de Receptores de Angiotensina/farmacocinética , Compostos de Bifenilo , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Insuficiência Cardíaca Sistólica/tratamento farmacológico , Humanos , Masculino , Mexiletina/farmacocinética , Tetrazóis/farmacocinética , ValsartanaRESUMO
AIMS: To assess differences in diuretic dose requirements in patients treated with sacubitril/valsartan compared with enalapril in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial. METHODS AND RESULTS: Overall, 8399 patients with New York Heart Association class II-IV heart failure and reduced LVEF were randomized to sacubitril/valsartan 200 mg bid or enalapril 10 mg twice daily. Loop diuretic doses were assessed at baseline, 6, 12, and 24 months, and furosemide dose equivalents were calculated via multiplication factors (2x for torsemide and 40x for bumetanide). Percentages of participants with reductions or increases in loop diuretic dose were determined. At baseline, 80.8% of participants were taking any diuretics (n = 6290 for loop diuretics, n = 496 for other diuretics); of those, recorded dosage data for loop diuretics were available on 5487 participants. Mean baseline furosemide equivalent doses were 48.2 mg for sacubitril/valsartan and 49.6 mg for enalapril (P = 0.25). Patients treated with sacubitril/valsartan were more likely to reduce diuretic dose and less likely to increase diuretic dose relative to those randomized to enalapril at 6, 12, 24 months post-randomization, with an overall decreased diuretic use of 2.0% (P = 0.02), 4.1% (P < 0.001), and 6.1% (P < 0.001) at 6, 12, and 24 months, respectively, with similar findings in an on-treatment analysis. CONCLUSION: Treatment with sacubitril/valsartan was associated with more loop diuretic dose reductions and fewer dose increases compared with enalapril, suggesting that treatment with sacubitril/valsartan may reduce the requirement for loop diuretics relative to enalapril in patients with heart failure with reduced ejection fraction.
Assuntos
Aminobutiratos , Enalapril , Furosemida , Insuficiência Cardíaca , Volume Sistólico , Tetrazóis , Idoso , Aminobutiratos/administração & dosagem , Aminobutiratos/farmacocinética , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/farmacocinética , Disponibilidade Biológica , Compostos de Bifenilo , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Monitoramento de Medicamentos/métodos , Monitoramento de Medicamentos/estatística & dados numéricos , Enalapril/administração & dosagem , Enalapril/farmacocinética , Feminino , Furosemida/administração & dosagem , Furosemida/farmacocinética , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Conduta do Tratamento Medicamentoso/estatística & dados numéricos , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Inibidores de Simportadores de Cloreto de Sódio e Potássio/administração & dosagem , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacocinética , Tetrazóis/administração & dosagem , Tetrazóis/farmacocinética , ValsartanaRESUMO
PURPOSE: Sacubitril/valsartan (LCZ696) and nitroglycerin share the second messenger cGMP and lower blood pressure. Given the potential for co-administration of both drugs in patients with heart failure, this study was designed to investigate the potential for a pharmacodynamic drug interaction affecting blood pressure. METHODS: In this double-blind, placebo-controlled, randomised, crossover study, 40 healthy subjects received sacubitril/valsartan 200 mg bid (97/103 mg bid) or placebo for 5 days. Two hours after the morning dose of sacubitril/valsartan or placebo on day 5, subjects received intravenous nitroglycerin infusion at increasing doses up to 40 µg/min or placebo. Serial measurements of blood pressure (BP), heart rate, biomarkers and sacubitril/valsartan pharmacokinetics were conducted. RESULTS: Administration of nitroglycerin alone led to a dose- and time-dependent decrease in supine systolic BP (SBP) and diastolic BP (DBP) which was similar when nitroglycerin was co-administered with sacubitril/valsartan. At the highest dose of nitroglycerin, the mean (95% CI) decrease from baseline of SBP/DBP was 19.54 (- 21.99, - 17.09)/12.38 (- 13.85, - 10.92) mmHg for nitroglycerin alone compared to 22.63 (- 25.06, - 20.21)/12.94 (- 14.38, - 11.49) mmHg when co-administered with sacubitril/valsartan. Co-administration of sacubitril/valsartan and nitroglycerin did not result in further plasma cGMP increase compared to sacubitril/valsartan alone. The co-administration of nitroglycerin and sacubitril/valsartan was safe and well tolerated and did not impact the pharmacokinetics of sacubitril/valsartan. CONCLUSIONS: The results from this study demonstrate no pharmacodynamic drug interaction between nitroglycerin and sacubitril/valsartan in healthy subjects, suggesting that no change of dose selection and escalation recommendations or clinical monitoring during nitroglycerin administration is required.
Assuntos
Aminobutiratos/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Nitroglicerina/administração & dosagem , Tetrazóis/administração & dosagem , Administração Oral , Adulto , Aminobutiratos/farmacocinética , Biomarcadores/sangue , Compostos de Bifenilo , Estudos Cross-Over , GMP Cíclico/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Combinação de Medicamentos , Cálculos da Dosagem de Medicamento , Interações Medicamentosas , Monitoramento de Medicamentos , Feminino , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Tetrazóis/farmacocinética , ValsartanaAssuntos
Aminobutiratos/farmacocinética , Insuficiência Cardíaca/tratamento farmacológico , Tetrazóis/farmacocinética , Combinação Trimetoprima e Sulfametoxazol/farmacocinética , Antagonistas de Receptores de Angiotensina/farmacocinética , Antibacterianos/farmacocinética , Compostos de Bifenilo , Combinação de Medicamentos , Interações Medicamentosas , Insuficiência Cardíaca/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , ValsartanaRESUMO
AIMS: Sacubitril/valsartan is indicated for the treatment of heart failure and reduced ejection fraction (HFrEF). Furosemide, a loop diuretic commonly used for the treatment of HFrEF, may be coadministered with sacubitril/valsartan in clinical practice. The effect of sacubitril/valsartan on the pharmacokinetics and pharmacodynamics of furosemide was evaluated in this open label, two-period, single-sequence study in healthy subjects. METHODS: All subjects (n = 28) received 40 mg oral single-dose furosemide during period 1, followed by a washout of 2 days. In period 2, sacubitril/valsartan 200 mg (97/103 mg) was administered twice daily for 5 days and a single dose of 40 mg furosemide was coadministered on day 6. Serial plasma and urine samples were collected to determine the pharmacokinetics of furosemide and sacubitril/valsartan and the pharmacodynamics of furosemide. The point estimates and the associated 90% confidence intervals for pharmacokinetic parameters were evaluated. RESULTS: Coadministration of furosemide with sacubitril/valsartan decreased the maximum observed plasma concentration (Cmax ) [estimated geometric mean ratio (90% confidence interval): 0.50 (0.44, 0.56)], area under the plasma concentration-time curve (AUC) from time 0 to infinity [0.72 (0.67, 0.77)] and 24-h urinary excretion of furosemide [0.74 (0.69, 0.79)]. When coadministered with sacubitril/valsartan, 0-4-h, 4-8-h and 0-24-h diuresis in response to furosemide was reduced by ~7%, 21% and 0.2%, respectively, while natriuresis was reduced by ~ 28.5%, 7% and 15%, respectively. Post hoc analysis of the pivotal phase III Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) indicated that the median furosemide dose was similar at baseline and at the end of the study in the sacubitril/valsartan group. CONCLUSIONS: Sacubitril/valsartan reduced plasma Cmax and AUC and 24-h urinary excretion of furosemide, while not significantly affecting its pharmacodynamic effects in healthy subjects.
Assuntos
Aminobutiratos/farmacologia , Aminobutiratos/farmacocinética , Interações Medicamentosas , Furosemida/farmacologia , Furosemida/farmacocinética , Tetrazóis/farmacologia , Tetrazóis/farmacocinética , Adolescente , Adulto , Aminobutiratos/sangue , Aminobutiratos/urina , Antagonistas de Receptores de Angiotensina/sangue , Antagonistas de Receptores de Angiotensina/farmacocinética , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/urina , Compostos de Bifenilo , Ensaios Clínicos como Assunto/estatística & dados numéricos , Diurese/efeitos dos fármacos , Diuréticos/sangue , Diuréticos/farmacocinética , Diuréticos/farmacologia , Diuréticos/urina , Combinação de Medicamentos , Feminino , Furosemida/sangue , Furosemida/urina , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Natriurese/efeitos dos fármacos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Tetrazóis/sangue , Tetrazóis/urina , Valsartana , Adulto JovemRESUMO
Sacubitril/valsartan (LCZ696) is indicated for the treatment of patients with heart failure and reduced ejection fraction (HFrEF). Since patients with HFrEF may receive sacubitril/valsartan and sildenafil, both increasing cyclic guanosine monophosphate, the present study evaluated the pharmacokinetic and pharmacodynamic drug interaction potential between sacubitril/valsartan and sildenafil. In this open-label, three-period, single sequence study, patients with mild-to-moderate hypertension (153.8 ± 8.2 mmHg mean systolic blood pressure (SBP)) received a single dose of sildenafil 50 mg, sacubitril/valsartan 400 mg once daily for 5 days, and sacubitril/valsartan and sildenafil coadministration. When coadministered with sildenafil, the AUC and Cmax of valsartan decreased by 29% and 39%, respectively. Coadministration of sacubitril/valsartan and sildenafil resulted in a greater decrease in BP (-5/-4/-4 mmHg mean ambulatory SBP/DBP/MAP (mean arterial pressure)) than with sacubitril/valsartan alone. Both treatments were generally safe and well tolerated in this study; however, the additional BP reduction suggests that sildenafil should be administered cautiously in patients receiving sacubitril/valsartan. Unique identifier: NCT01601470.
Assuntos
Aminobutiratos/farmacologia , Aminobutiratos/farmacocinética , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/farmacocinética , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/farmacocinética , Hipertensão/tratamento farmacológico , Citrato de Sildenafila/farmacologia , Citrato de Sildenafila/farmacocinética , Tetrazóis/farmacologia , Tetrazóis/farmacocinética , Aminobutiratos/efeitos adversos , Antagonistas de Receptores de Angiotensina/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Fator Natriurético Atrial/urina , Compostos de Bifenilo , Pressão Sanguínea/efeitos dos fármacos , GMP Cíclico/urina , Método Duplo-Cego , Combinação de Medicamentos , Interações Medicamentosas , Humanos , Masculino , Pessoa de Meia-Idade , Citrato de Sildenafila/efeitos adversos , Tetrazóis/efeitos adversos , ValsartanaRESUMO
1. The potential for drug-drug interactions of LCZ696 (a novel, crystalline complex comprising sacubitril and valsartan) was investigated in vitro. 2. Sacubitril was shown to be a highly permeable P-glycoprotein (P-gp) substrate and was hydrolyzed to the active anionic metabolite LBQ657 by human carboxylesterase 1 (CES1b and 1c). The multidrug resistance-associated protein 2 (MRP2) was shown to be capable of LBQ657 and valsartan transport that contributes to the elimination of either compound. 3. LBQ657 and valsartan were transported by OAT1, OAT3, OATP1B1 and OATP1B3, whereas no OAT- or OATP-mediated sacubitril transport was observed. 4. The contribution of OATP1B3 to valsartan transport (73%) was appreciably higher than that by OATP1B1 (27%), Alternatively, OATP1B1 contribution to the hepatic uptake of LBQ657 (â¼70%) was higher than that by OATP1B3 (â¼30%). 5. None of the compounds inhibited OCT1/OCT2, MATE1/MATE2-K, P-gp, or BCRP. Sacubitril and LBQ657 inhibited OAT3 but not OAT1, and valsartan inhibited the activity of both OAT1 and OAT3. Sacubitril and valsartan inhibited OATP1B1 and OATP1B3, whereas LBQ657 weakly inhibited OATP1B1 but not OATP1B3. 6. Drug interactions due to the inhibition of transporters are unlikely due to the redundancy of the available transport pathways (LBQ657: OATP1B1/OAT1/3 and valsartan: OATP1B3/OAT1/3) and the low therapeutic concentration of the LCZ696 analytes.
Assuntos
Aminobutiratos/farmacocinética , Compostos de Bifenilo/farmacocinética , Tetrazóis/farmacocinética , Valsartana/farmacocinética , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Aminobutiratos/metabolismo , Animais , Transporte Biológico , Compostos de Bifenilo/metabolismo , Hidrolases de Éster Carboxílico/genética , Hidrolases de Éster Carboxílico/metabolismo , Linhagem Celular , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Humanos , Inativação Metabólica , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Suínos , Valsartana/metabolismoRESUMO
Sacubitril/valsartan (LCZ696), a novel angiotensin receptor-neprilysin inhibitor, was recently approved for the treatment of heart failure with reduced ejection fraction. Neprilysin degrades several peptides that modulate lipid metabolism, including natriuretic peptides. In this study, we investigated the effects of 8 weeks' treatment with sacubitril/valsartan on whole-body and adipose tissue lipolysis and lipid oxidation during defined physical exercise compared with the metabolically neutral comparator amlodipine. This was a multicenter, randomized, double-blind, active-controlled, parallel-group study enrolling subjects with abdominal obesity and moderate hypertension (mean sitting systolic blood pressure ≥130-180 mm Hg). Lipolysis during rest and exercise was assessed by microdialysis and [1,1,2,3,3-2H]-glycerol tracer kinetics. Energy expenditure and substrate oxidation were measured simultaneously using indirect calorimetry. Plasma nonesterified fatty acids, glycerol, insulin, glucose, adrenaline and noradrenaline concentrations, blood pressure, and heart rate were also determined. Exercise elevated plasma glycerol, free fatty acids, and interstitial glycerol concentrations and increased the rate of glycerol appearance. However, exercise-induced stimulation of lipolysis was not augmented on sacubitril/valsartan treatment compared with amlodipine treatment. Furthermore, sacubitril/valsartan did not alter energy expenditure and substrate oxidation during exercise compared with amlodipine treatment. In conclusion, sacubitril/valsartan treatment for 8 weeks did not elicit clinically relevant changes in exercise-induced lipolysis or substrate oxidation in obese patients with hypertension, implying that its beneficial cardiovascular effects cannot be explained by changes in lipid metabolism during exercise. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01631864.
Assuntos
Aminobutiratos , Anlodipino/administração & dosagem , Exercício Físico/fisiologia , Hipertensão , Neprilisina , Obesidade Abdominal , Tetrazóis , Tecido Adiposo/metabolismo , Aminobutiratos/administração & dosagem , Aminobutiratos/efeitos adversos , Aminobutiratos/farmacocinética , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/farmacocinética , Compostos de Bifenilo , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/administração & dosagem , Método Duplo-Cego , Combinação de Medicamentos , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/fisiologia , Masculino , Pessoa de Meia-Idade , Peptídeos Natriuréticos/metabolismo , Neprilisina/antagonistas & inibidores , Neprilisina/metabolismo , Obesidade Abdominal/diagnóstico , Obesidade Abdominal/tratamento farmacológico , Obesidade Abdominal/metabolismo , Tetrazóis/administração & dosagem , Tetrazóis/efeitos adversos , Tetrazóis/farmacocinética , Resultado do Tratamento , ValsartanaRESUMO
BACKGROUND: Sacubitril/valsartan (LCZ696) is an angiotensin receptor neprilysin inhibitor approved for the treatment of adult heart failure (HF); however, the benefit of sacubitril/valsartan in pediatric HF patients is unknown. STUDY DESIGN: This global multi-center study will use an adaptive, seamless two-part design. Part 1 will assess the pharmacokinetics/pharmacodynamics of single ascending doses of sacubitril/valsartan in pediatric (1 month to <18 years) HF patients with systemic left ventricle and reduced left ventricular systolic function stratified into 3 age groups (Group 1: 6 to <18 years; Group 2: 1 to <6 years; Group 3: 1 month to <1 year). Part 2 is a 52-week, efficacy and safety study where 360 eligible patients will be randomized to sacubitril/valsartan or enalapril. A novel global rank primary endpoint derived by ranking patients (worst-to-best outcome) based on clinical events such as death, initiation of mechanical life support, listing for urgent heart transplant, worsening HF, measures of functional capacity (NYHA/Ross scores), and patient-reported HF symptoms will be used to assess efficacy. CONCLUSION: The PANORAMA-HF study, which will be the largest prospective pediatric HF trial conducted to date and the first to use a global rank primary endpoint, will determine whether sacubitril/valsartan is superior to enalapril for treatment of pediatric HF patients with reduced systemic left ventricular systolic function.
Assuntos
Aminobutiratos/administração & dosagem , Enalapril/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Isquemia Miocárdica/complicações , Tetrazóis/administração & dosagem , Valsartana/administração & dosagem , Disfunção Ventricular Esquerda/complicações , Função Ventricular Esquerda/fisiologia , Adolescente , Aminobutiratos/farmacocinética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacocinética , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/farmacocinética , Compostos de Bifenilo , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Quimioterapia Combinada , Enalapril/farmacocinética , Feminino , Seguimentos , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/fisiopatologia , Estudos Prospectivos , Sístole , Tetrazóis/farmacocinética , Fatores de Tempo , Resultado do Tratamento , Valsartana/farmacocinética , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
Calpain overactivation has been implicated in a variety of pathological disorders including ischemia/reperfusion injury, cataract formation, and neurodegenerative diseases such as Alzheimer's disease (AD). Herein we describe our efforts leading to the identification of ketoamide-based 2-(3-phenyl-1H-pyrazol-1-yl)nicotinamides as potent and reversible inhibitors of calpain with high selectivity versus related cysteine protease cathepsins, other proteases, and receptors. Broad efficacy in a set of preclinical models relevant to AD suggests that inhibition of calpain represents an attractive approach with potential benefit for the treatment of AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Aminobutiratos/farmacologia , Calpaína/antagonistas & inibidores , Inibidores de Cisteína Proteinase/farmacologia , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Pirazóis/farmacologia , Aminobutiratos/síntese química , Aminobutiratos/farmacocinética , Animais , Catepsinas , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/farmacocinética , Cães , Hipocampo/metabolismo , Humanos , Concentração Inibidora 50 , Macaca fascicularis , Masculino , Microssomos Hepáticos/metabolismo , Niacinamida/síntese química , Niacinamida/farmacocinética , Pirazóis/síntese química , Pirazóis/farmacocinética , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Ratos Wistar , Sono REM/efeitos dos fármacos , Espectrina/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
OBJECTIVES: To assess the protein binding and pharmacokinetics of sacubitril/valsartan analytes (sacubitril, sacubitrilat, and valsartan) in an open-label, single oral dose (200 mg), parallel-group study in patients with mild and moderate hepatic impairment (Child-Pugh class A and B) and matched healthy subjects. METHODS: This study enrolled 32 subjects (n = 8 in each hepatic impairment and matched healthy subjects groups). Blood samples were collected at pre-determined time points to assess pharmacokinetics of sacubitril, sacubitrilat, and valsartan. Subjects with severe hepatic impairment were excluded as valsartan exposure is expected to be substantially increased in these patients. RESULTS: Sacubitril exposure (AUC) increased by 53% and 245% while the exposure to sacubitrilat was increased by 48% and 90% in patients with mild and moderate hepatic impairment, respectively. Sacubitril Cmax increased by 57% and 210% in mild and moderate hepatic impairment; however, for both sacubitrilat and valsartan, Cmax was unchanged. Valsartan AUC increased in patients with mild and moderate hepatic impairment by 19 - 109%, respectively. CONCLUSIONS: The increase in systemic exposures to all sacubitril/valsartan analytes correlated with the severity of liver disease. The plasma unbound fraction of sacubitrilat in patients with moderate hepatic impairment was slightly higher than in matched healthy subjects. This difference was not considered clinically significant. Safety assessments showed that sacubitril/valsartan was safe and well tolerated across all the study groups.â©.