RESUMEN
Introduction: Overactive bladder (OAB) is a highly prevalent condition with limited treatment options due to poor efficacy, side effects, and patient compliance. Novel drug delivery systems that can target the bladder wall may improve OAB therapy. Methods: We explored a polydopamine (PDA)-coated lactobacillus platform as a potential carrier for localized OAB treatment. Urinary microbiome profiling was performed to identify the presence of lactobacillus in healthy and OAB groups. Lactobacillus-PDA nanoparticles were synthesized and characterized by electron microscopy and spectrophotometry. A rat bladder perfusion model and human bladder smooth muscle cell spheroids were used to assess the distribution and penetration of the nanoparticles. The efficacy of the Lactobacillus-PDA system (LPS) for delivering the antimuscarinic drug solifenacin was evaluated in an OAB rat model. Results: Urinary microbiome profiling revealed lactobacillus as a dominant genus in both healthy and OAB groups. The synthesized Lactobacillus-PDA nanoparticles exhibited uniform size and optical properties. In the rat bladder perfusion model, the nanoparticles distributed throughout the bladder wall and smooth muscle without toxicity. The nanoparticles also penetrated human bladder smooth muscle cell spheroids. In the OAB rat model, LPS facilitated the delivery of solifenacin and improved treatment efficacy. Discussion: The results highlight LPS as a promising drug carrier for targeted OAB therapy via penetration into bladder tissues. This bacteriotherapy approach may overcome limitations of current systemic OAB medications. Lactobacillus, a probiotic bacterium present in the urinary tract microbiome, was hypothesized to adhere to and penetrate the bladder wall when coated with PDA nanoparticles, making it a suitable candidate for localized drug delivery.
Asunto(s)
Indoles , Lactobacillus , Microbiota , Polímeros , Vejiga Urinaria Hiperactiva , Vejiga Urinaria , Animales , Indoles/química , Indoles/farmacocinética , Vejiga Urinaria Hiperactiva/terapia , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Humanos , Polímeros/química , Microbiota/efectos de los fármacos , Ratas , Esferoides Celulares , Succinato de Solifenacina/farmacocinética , Succinato de Solifenacina/química , Succinato de Solifenacina/administración & dosificación , Modelos Animales de Enfermedad , Ratas Sprague-Dawley , Nanopartículas/química , Sistemas de Liberación de Medicamentos/métodos , Femenino , Miocitos del Músculo Liso/efectos de los fármacos , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/farmacología , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/administración & dosificación , Portadores de Fármacos/químicaRESUMEN
Clinical guidelines for COPD and asthma recommend inhaled ß-adrenergic agonists, muscarinic antagonists, and, for frequent exacerbators, inhaled corticosteroids, with the challenge of combining them into a single device. The MABA (muscarinic antagonist and ß2 agonist) concept has the potential to simplify this complexity while increasing the efficacy of both pharmacologies. In this article, we report the outcome of our solid-state driven back-up program that led to the discovery of the MABA compound CHF-6550. A soft drug approach was applied, aiming at high plasma protein binding and high hepatic clearance, concurrently with an early stage assessment of crystallinity through a dedicated experimental workflow. A new chemotype was identified, the diphenyl hydroxyacetic esters, able to generate crystalline material. Among this class, CHF-6550 demonstrated in vivo efficacy, suitability for dry powder inhaler development, favorable pharmacokinetics, and safety in preclinical settings and was selected as a back-up candidate, fulfilling the desired pharmacological and solid-state profile.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2 , Antagonistas Muscarínicos , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/farmacología , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/síntesis química , Antagonistas Muscarínicos/uso terapéutico , Antagonistas Muscarínicos/administración & dosificación , Animales , Humanos , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Agonistas de Receptores Adrenérgicos beta 2/farmacología , Agonistas de Receptores Adrenérgicos beta 2/química , Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Administración por Inhalación , Ratas , Descubrimiento de Drogas , Relación Estructura-Actividad , Masculino , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológicoRESUMEN
To assess the pharmacologically relevant and selective muscarinic receptor occupancy in the bladder mucosa, we considered not only plasma drug concentrations but also urinary drug concentrations. The purpose of this study was to predict muscarinic receptor occupancy in the human bladder mucosa based on urinary concentrations in response to clinical dosages of antimuscarinic agents used to treat overactive bladder. The calculated mean plasma or serum unbound steady state concentrations were 0.06-11 nM in clinical dosages of five antimuscarinic agents. Urinary concentrations calculated from the mean plasma or serum and renal clearance ranged between 19 nM and 2 µM, which were >10-fold higher than the Ki values for bladder muscarinic receptors excluding propiverine. Bladder mucosal muscarinic receptor occupancy estimated from the urinary concentrations and the Ki values was >90 % at a steady state in clinical dosages of five antimuscarinic agents. The bladder muscarinic receptor occupancy was higher than that in the parotid gland calculated based on the mean plasma or serum unbound concentrations and Ki values for muscarinic receptors in the parotid gland. These results suggest that sufficient and selective muscarinic receptor occupancy by antimuscarinic agents, to exert pharmacological effects, in the bladder mucosa can be predicted using urinary concentrations.
Asunto(s)
Membrana Mucosa , Antagonistas Muscarínicos , Receptores Muscarínicos , Vejiga Urinaria Hiperactiva , Vejiga Urinaria , Humanos , Antagonistas Muscarínicos/farmacocinética , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Vejiga Urinaria Hiperactiva/metabolismo , Vejiga Urinaria Hiperactiva/orina , Receptores Muscarínicos/metabolismo , Vejiga Urinaria/metabolismo , Vejiga Urinaria/efectos de los fármacos , Membrana Mucosa/metabolismo , Membrana Mucosa/efectos de los fármacos , Masculino , Femenino , Persona de Mediana Edad , Adulto , AncianoRESUMEN
Purpose: To date, aclidinium pharmacokinetic (PK) studies have focused on Caucasian populations, and no data are available for Chinese populations. We aimed to characterize the PK and safety profile of aclidinium and its metabolites (LAS34823 and LAS34850) following single and multiple (twice-daily; BID) dosing in healthy Chinese participants, and to compare PK data between Chinese and Caucasian populations. Materials and methods: In this Phase I, open-label study (NCT03276052), healthy participants from a single site in China received aclidinium bromide 400 µg via a dry powder inhaler. The Day 1 single dose was followed by a washout period of 96 hours. On Days 5 through 8, participants received BID doses. Results: Twenty healthy Chinese participants, aged 18-45 years, were enrolled. Aclidinium absorption was rapid (median time to maximum concentration [tmax] 0.08 hours post-dose following single/multiple doses). LAS34823 had a similar median tmax of 0.08 hours, whereas LAS34850 tmax occurred later (median 2.50-3.00 hours). Aclidinium, LAS34823, and LAS34850 concentrations declined in a bi-phasic manner; geometric mean half-life was 13.5 hours (single dosing) and 21.4 hours (multiple dosing), while steady state was generally achieved after 5 days' continuous dosing. Area under the concentration-time curve during a dosage interval (AUCτ) metabolite to parent ratios for LAS34823 were 2.6 (Day 1) and 2.9 (Day 9), while LAS34850 had ratios of 136.0 and 94.8, respectively. Aclidinium accumulation occurred after 5 days of BID dosing (LS mean accumulation ratio for AUCτ Day 9/Day 1: 214.1% [90% CI, 176.5, 259.6]); LAS34823 accumulation was similar, while LAS34850 accumulation was lower. Between-participant exposure variability was moderate to high for aclidinium and LAS34823, and low for LAS34850. Conclusion: Single and multiple doses of aclidinium were well tolerated in healthy Chinese participants. The safety profile of and exposure to aclidinium was consistent with previous studies conducted in Caucasian populations.
Asunto(s)
Antagonistas Muscarínicos , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Pueblos del Este de Asia , Voluntarios Sanos , Antagonistas Muscarínicos/administración & dosificación , Antagonistas Muscarínicos/efectos adversos , Antagonistas Muscarínicos/farmacocinética , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Tropanos/administración & dosificación , Tropanos/efectos adversos , Tropanos/farmacocinética , Población Blanca , Administración por Inhalación , Adolescente , Adulto Joven , Adulto , Persona de Mediana EdadRESUMEN
The extent and rate of bioavailability are fundamental measures to characterize the pharmacokinetics of drugs after oral administration. Together with bioavailability (F), the mean absorption time (MAT) can be used to define the rate of bioavailability, i.e., the rate of drug absorption. Previous results suggest that F may depend on MAT. Estimates of F and MAT were obtained from the input function (sum of two inverse Gaussian functions) used to model the oral absorption process. The estimation was performed by population analysis (nonlinear mixed-effects modeling) based on data from bioavailability studies in healthy volunteers. For trospium and ketamine, F decreased significantly with increasing MAT, while for propiverine, a significant increase was observed. Thus, the interindividual variability in F could be largely attributed to the interindividual variability in MAT. For trospium and propiverine, the relative dispersion (normalized variance) of the absorption time distribution increased significantly with MAT. For trospium and propiverine, the plot of F versus MAT provides information about the effect of gastrointestinal transit on drug absorption. In contrast, an increase in hepatic extraction with increasing MAT is responsible for the dependence of F on MAT. The F versus MAT plot is suggested as a simple diagnostic tool in evaluating the results of bioavailability studies.
Asunto(s)
Bencilatos , Hígado , Humanos , Disponibilidad Biológica , Administración Oral , Antagonistas Muscarínicos/farmacocinéticaRESUMEN
PURPOSE: The objective of the present study was to prepare stable and high bioavailability ocular atropine loaded films (ATR-films) as potential ocular drug delivery systems for the treatment of myopia. METHODS: ATR-films were prepared by the solvent casting method and the physical properties of films were evaluated including thickness, water content, light transparency, disintegration time, and mechanical properties. FT-IR, DSC, XRD, TGA, AFM, and Raman spectroscopy were performed to characterize the film. The stability test was conducted under different conditions, such as high humidity, high temperature, and strong light. The pharmacokinetic study and irritation assessment were conducted in rabbits. The efficacy of ATR-films was evaluated by refraction and ocular biometry in myopia guinea pigs. RESULT: After optimizing the formulation, the resulting ATR-film was flexible and transparent with lower water content (8.43% ± 1.25). As expected, the ATR-film was stable and hydrolysate was not detected, while the content of hydrolysate in ATR eye drops can reach up to 8.1867% (limit: < 0.2%) in the stability study. The safety assessment both in vitro and in vivo confirmed that the ATR-film was biocompatible. Moreover, the bioavailability (conjunctiva 3.21-fold, cornea 2.87-fold, retina 1.35-fold, sclera 2.05-fold) was greatly improved compared with the ATR eye drops in vivo pharmacokinetic study. The pharmacodynamic study results showed that the ATR-film can slow the progress of form-deprivation myopia (~ 100 ± 0.81D), indicating that it has a certain therapeutic effect on form-deprivation myopia. CONCLUSION: The ATR-film with good stability and high bioavailability will have great potential for the treatment of myopia.
Asunto(s)
Atropina/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Antagonistas Muscarínicos/administración & dosificación , Miopía/tratamiento farmacológico , Administración Oftálmica , Animales , Atropina/farmacocinética , Disponibilidad Biológica , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Cobayas , Humanos , Masculino , Antagonistas Muscarínicos/farmacocinética , Miopía/diagnóstico , Conejos , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Prevention or modification of acquired epilepsy in patients at risk is an urgent, yet unmet, clinical need. Following acute brain insults, there is an increased risk of mesial temporal lobe epilepsy (mTLE), which is often associated with debilitating comorbidities and reduced life expectancy. The latent period between brain injury and the onset of epilepsy may offer a therapeutic window for interfering with epileptogenesis. The pilocarpine model of mTLE is widely used in the search for novel antiepileptogenic treatments. Recent biochemical studies indicated that cholinergic mechanisms play a role in the epileptogenic alterations induced by status epilepticus (SE) in this and other models of mTLE, which prompted us to evaluate whether treatment with the muscarinic antagonist scopolamine during the latent period after SE is capable of preventing or modifying epilepsy and associated behavioral and cognitive alterations in female Sprague-Dawley rats. First, in silico pharmacokinetic modeling was used to select a dosing protocol by which M-receptor inhibitory brain levels of scopolamine are maintained during prolonged treatment. This protocol was verified by drug analysis in vivo. Rats were then treated twice daily with scopolamine over 17 days after SE, followed by drug wash-out and behavioral and video/EEG monitoring up to ~6 months after SE. Compared to vehicle controls, rats that were treated with scopolamine during the latent period exhibited a significantly lower incidence of spontaneous recurrent seizures during periods of intermittent recording in the chronic phase of epilepsy, less behavioral excitability, less cognitive impairment, and significantly reduced aberrant mossy fiber sprouting in the hippocampus. The present data may indicate that scopolamine exerts antiepileptogenic/disease-modifying activity in the lithium-pilocarpine rat model, possibly involving increased remission of epilepsy as a new mechanism of disease-modification. For evaluating the rigor of the present data, we envision a study that more thoroughly addresses the gender bias and video-EEG recording limitations of the present study.
Asunto(s)
Lesiones Traumáticas del Encéfalo/complicaciones , Epilepsia del Lóbulo Temporal/prevención & control , Fibras Musgosas del Hipocampo/efectos de los fármacos , Antagonistas Muscarínicos/farmacología , Escopolamina/farmacología , Animales , Conducta Animal/efectos de los fármacos , Cognición/efectos de los fármacos , Simulación por Computador , Electroencefalografía , Epilepsia del Lóbulo Temporal/inducido químicamente , Epilepsia del Lóbulo Temporal/etiología , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Litio , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/uso terapéutico , Ratas , Ratas Sprague-Dawley , Escopolamina/farmacocinética , Escopolamina/uso terapéutico , Convulsiones/prevención & controlRESUMEN
Selective M1 muscarinic acetylcholine receptor (mAChR) agonists are being developed as symptomatic treatment for neurodegenerative and neuropsychiatric disorders that lead to cognitive dysfunction. Demonstrating cognition-enhancing effects in early-phase clinical development in healthy subjects is difficult. A challenge with the M1 mAChR antagonist biperiden could be used to demonstrate procognitive and pharmacological effects of selective M1 mAChR agonists. The aim of this study was to develop such a model. To this end, 12 healthy elderly subjects participated in a randomized, placebo-controlled, 3-way crossover study investigating tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) effects of 2 and 4 mg biperiden. Repeated PD assessments were performed using neurocognitive tasks and electrophysiological measurements. A population PK-PD model was developed. Four milligrams of biperiden showed significant impairment of sustained attention (-2.1 percentage point in adaptive tracking [95%CI, -3.043 to -1.148], verbal memory (2-3 fewer words recalled [95%CI, -5.9 to -0.2]) and working memory (up to a 50-millisecond increase in the n-back task reaction time [95%CI, 21.854-77.882]) compared with placebo. The PK data were best fitted by a 2-compartment model and showed high interoccasion and intersubject variability. Population PK-PD analysis quantified significant concentration-effect relationships for the n-back reaction time, n-back accuracy, and adaptive tracking. In conclusion, biperiden caused M1 mAChR-related dose- and concentration-dependent temporary declines in cognitive functioning. Therefore a biperiden pharmacological challenge model can be used for proof-of-pharmacology studies and to demonstrate cognition-enhancing effects of new cholinergic compounds that are being developed.
Asunto(s)
Biperideno/farmacología , Antagonistas Muscarínicos/farmacología , Anciano , Atención/efectos de los fármacos , Biperideno/farmacocinética , Cognición/efectos de los fármacos , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Voluntarios Sanos , Humanos , Masculino , Antagonistas Muscarínicos/farmacocinética , Tiempo de Reacción/efectos de los fármacosRESUMEN
The selective ß 3-adrenoceptor agonist mirabegron, an established alternative to antimuscarinic therapy for patients with overactive bladder, induces additional effects against receptors, transporters, and hepatic enzymes. The present study aimed to elucidate the effects of mirabegron on muscarinic receptors in the rat bladder using radioligand binding and functional assays. Mirabegron (0.1-100 µM) inhibited specific [N-methyl-3H]scopolamine methyl chloride binding in the bladder and other tissues of rats in a concentration-dependent manner. Binding affinity in the bladder was similar to that in the heart and significantly higher than those in the submaxillary gland and brain. Mirabegron induced the concentration-dependent relaxation of carbachol-induced contractions in the rat isolated bladder. Further analyses using a two-site model revealed that the relative quantities of high- and low-affinity components for mirabegron were 44.5% and 55.5%, respectively. Respective pEC50 values were 7.06 and 4.97. Based on the receptor binding affinity and pharmacokinetics of mirabegron, muscarinic receptor occupancy in the human bladder for 24 hours after the administration of a single oral dose of 50 mg mirabegron was 37%-76%. The present results demonstrate for the first time that mirabegron may relax the detrusor smooth muscle not only by ß 3-adrenoceptor activation but also muscarinic receptor blockade. SIGNIFICANCE STATEMENT: Mirabegron, the first selective ß 3-adrenoceptor agonist, represents an alternative to antimuscarinic agents for management of overactive bladder (OAB). The present study aimed to clarify whether mirabegron directly binds to muscarinic receptors and affects cholinergic agonist-induced contractions in rat urinary bladder and to predict muscarinic receptor occupancy in human bladder after oral administration of mirabegron. The results demonstrated that mirabegron therapy for patients with OAB may be due not only to ß 3-adrenoceptor activation but also muscarinic receptor blockade.
Asunto(s)
Acetanilidas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 3/farmacología , Antagonistas Muscarínicos/farmacocinética , Tiazoles/farmacocinética , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Agentes Urológicos/farmacocinética , Acetanilidas/administración & dosificación , Acetanilidas/uso terapéutico , Administración Oral , Agonistas de Receptores Adrenérgicos beta 3/administración & dosificación , Agonistas de Receptores Adrenérgicos beta 3/uso terapéutico , Animales , Encéfalo/metabolismo , Masculino , Antagonistas Muscarínicos/administración & dosificación , Antagonistas Muscarínicos/uso terapéutico , Contracción Muscular , Unión Proteica , Ratas , Ratas Sprague-Dawley , Receptores Muscarínicos/metabolismo , Glándula Submandibular/metabolismo , Tiazoles/administración & dosificación , Tiazoles/uso terapéutico , Vejiga Urinaria/metabolismo , Agentes Urológicos/administración & dosificación , Agentes Urológicos/uso terapéuticoRESUMEN
Nerve agent exposure is generally treated by an antidote formulation composed of a muscarinic antagonist, atropine sulfate (ATR), and a reactivator of acetylcholinesterase (AChE) such as pralidoxime, obidoxime (OBI), methoxime, trimedoxime or HI-6 and an anticonvulsant. Organophosphates (OPs) irreversibly inhibit AChE, the enzyme responsible for termination of acetylcholine signal transduction. Inhibition of AChE leads to overstimulation of the central and peripheral nervous system with convulsive seizures, respiratory distress and death as result. The present study evaluated the efficacy and pharmacokinetics (PK) of ATR/OBI following exposure to two different VX dose levels. The PK of ATR and OBI administered either as a single drug, combined treatment but separately injected, or administered as the ATR/OBI co-formulation, was determined in plasma of naïve guinea pigs and found to be similar for all formulations. Following subcutaneous VX exposure, ATR/OBI-treated animals showed significant improvement in survival rate and progression of clinical signs compared to untreated animals. Moreover, AChE activity after VX exposure in both blood and brain tissue was significantly higher in ATR/OBI-treated animals compared to vehicle-treated control. In conclusion, ATR/OBI has been proven to be efficacious against exposure to VX and there were no PK interactions between ATR and OBI when administered as a co-formulation.
Asunto(s)
Atropina , Sustancias para la Guerra Química/toxicidad , Inhibidores de la Colinesterasa/toxicidad , Reactivadores de la Colinesterasa , Antagonistas Muscarínicos , Cloruro de Obidoxima , Compuestos Organotiofosforados/toxicidad , Acetilcolinesterasa/sangre , Acetilcolinesterasa/metabolismo , Animales , Atropina/sangre , Atropina/farmacocinética , Atropina/uso terapéutico , Encéfalo/metabolismo , Reactivadores de la Colinesterasa/sangre , Reactivadores de la Colinesterasa/farmacocinética , Reactivadores de la Colinesterasa/uso terapéutico , Modelos Animales de Enfermedad , Combinación de Medicamentos , Cobayas , Masculino , Antagonistas Muscarínicos/sangre , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/uso terapéutico , Cloruro de Obidoxima/sangre , Cloruro de Obidoxima/farmacocinética , Cloruro de Obidoxima/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Patients admitted to the hospital with COPD are commonly managed with inhaled short-acting bronchodilators, sometimes in lieu of the long-acting bronchodilators they take as outpatients. If held on admission, these long-acting inhalers should be re-initiated upon discharge; however, health-care transitions sometimes result in unintentional discontinuation. RESEARCH QUESTION: What is the risk of unintentional discontinuation of long-acting muscarinic antagonist (LAMA) and long-acting beta-agonist and inhaled corticosteroid (LABA-ICS) combination medications following hospital discharge in older adults with COPD? STUDY DESIGN AND METHODS: A retrospective cohort study was conducted by using health administrative data from 2004 to 2016 from Ontario, Canada. Adults with COPD aged ≥ 66 years who had filled prescriptions for a LAMA or LABA-ICS continuously for ≥ 1 year were included. Log-binomial regression models were used to determine risk of medication discontinuation following hospitalization in each medication cohort. RESULTS: Of the 27,613 hospitalization discharges included in this study, medications were discontinued 1,466 times. Among 78,953 patients with COPD continuously taking a LAMA or LABA-ICS, those hospitalized had a higher risk of having medications being discontinued than those who remained in the community (adjusted risk ratios of 1.50 [95% CI, 1.34-1.67; P < .001] and 1.62 [95% CI, 1.39, 1.90; P < .001] for LAMA and LABA-ICS, respectively). Crude rates of discontinuation for people taking LAMAs were 5.2% in the hospitalization group and 3.3% in the community group; for people taking LABA-ICS, these rates were 5.5% in the hospitalization group and 3.1% in the community group. INTERPRETATION: In an observational study of highly compliant patients with COPD, hospitalization was associated with an increased risk of long-acting inhaler discontinuation. These Results suggest a likely larger discontinuation problem among less adherent patients and should be confirmed and quantified in a prospective cohort of patients with COPD and average compliance. Quality improvement efforts should focus on safe transitions and patient medication reconciliation following discharge.
Asunto(s)
Broncodilatadores , Preparaciones de Acción Retardada , Administración del Tratamiento Farmacológico/normas , Alta del Paciente/normas , Transferencia de Pacientes , Enfermedad Pulmonar Obstructiva Crónica , Administración por Inhalación , Corticoesteroides/administración & dosificación , Corticoesteroides/farmacocinética , Agonistas Adrenérgicos beta/administración & dosificación , Agonistas Adrenérgicos beta/farmacocinética , Anciano , Broncodilatadores/administración & dosificación , Broncodilatadores/farmacocinética , Canadá/epidemiología , Continuidad de la Atención al Paciente , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/farmacocinética , Deprescripciones , Femenino , Humanos , Masculino , Antagonistas Muscarínicos/administración & dosificación , Antagonistas Muscarínicos/farmacocinética , Transferencia de Pacientes/métodos , Transferencia de Pacientes/normas , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/terapia , Mejoramiento de la CalidadRESUMEN
BACKGROUND: The muscarinic receptor antagonist trospium chloride (TCl) is used for pharmacotherapy of the overactive bladder syndrome. TCl is a hydrophilic positively charged drug. Therefore, it has low permeability through biomembranes and requires drug transporters for distribution and excretion. In humans, the organic cation transporters OCT1 and OCT2 and the multidrug and toxin extrusion MATE1 and MATE2-K carriers showed TCl transport. However, their individual role for distribution and excretion of TCl is unclear. Knockout mouse models lacking mOct1/mOct2 or mMate1 might help to clarify their role for the overall pharmacokinetics of TCl. METHOD: In preparation of such experiments, TCl transport was analyzed in HEK293 cells stably transfected with the mouse carriers mOct1, mOct2, mMate1, and mMate2, respectively. RESULTS: Mouse mOct1, mOct2, and mMate1 showed significant TCl transport with Km values of 58.7, 78.5, and 29.3 µM, respectively. In contrast, mMate2 did not transport TCl but showed MPP+ transport with Km of 60.0 µM that was inhibited by the drugs topotecan, acyclovir, and levofloxacin. CONCLUSION: TCl transport behavior as well as expression pattern were quite similar for the mouse carriers mOct1, mOct2, and mMate1 compared to their human counterparts.
Asunto(s)
Bencilatos/metabolismo , Proteínas de Transporte de Catecolaminas en la Membrana Plasmática/metabolismo , Nortropanos/metabolismo , Proteínas de Transporte de Catión Orgánico/metabolismo , Transportador 2 de Cátion Orgánico/metabolismo , Animales , Bencilatos/farmacocinética , Transporte Biológico , Proteínas de Transporte de Catecolaminas en la Membrana Plasmática/genética , Células HEK293 , Humanos , Cinética , Ratones Endogámicos C57BL , Ratones Noqueados , Antagonistas Muscarínicos/metabolismo , Antagonistas Muscarínicos/farmacocinética , Nortropanos/farmacocinética , Proteínas de Transporte de Catión Orgánico/genética , Transportador 2 de Cátion Orgánico/genéticaRESUMEN
The aim of this investigation was to characterize and compare the pharmacokinetics (PK) of the antimuscarinic drug solifenacin in pediatric patients with overactive bladder (OAB) or neurogenic detrusor overactivity (NDO) utilizing data from three phase III trials. LION was a placebo-controlled, 12-week trial in children (5-<12 years) and adolescents (12-<18 years) with OAB. MONKEY and MARMOSET were open-label, 52-week trials in children and adolescents or younger children (6 months-<5 years), respectively, with NDO. During the trials, solifenacin doses could be titrated to weight-adjusted pediatric equivalent doses (PEDs) of 2.5, 5, 7.5, or 10 mg day-1 . Nonlinear mixed effects modeling was used to develop population PK models to characterize the PK in patients with either OAB or NDO. Overall, 194 children and adolescents received solifenacin. At the time of PK sampling, the majority (119/164 [72.6%] patients) were receiving PED10 once daily. All population models included first-order oral absorption, a lag time, and interindividual variability. PK analysis showed that apparent clearance was similar in both patient populations. Mean apparent oral plasma clearance (CL/F), apparent volume of distribution during the terminal phase (Vz /F), and terminal half-life (t1/2 ) were higher in adolescents than in children, but median time to maximum plasma concentration (tmax ) was similar. Dose-normalized exposure results were similar for both younger and older patients with OAB or NDO. In conclusion, population PK modeling was used to successfully characterize solifenacin PK in pediatric patients with OAB or NDO. Similar solifenacin PK characteristics were observed in both populations.
Asunto(s)
Antagonistas Muscarínicos/farmacocinética , Succinato de Solifenacina/farmacocinética , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Vejiga Urinaria Hiperactiva/metabolismo , Agentes Urológicos/farmacocinética , Adolescente , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Lactante , Masculino , Antagonistas Muscarínicos/administración & dosificación , Método Simple Ciego , Succinato de Solifenacina/administración & dosificación , Vejiga Urinaria Hiperactiva/diagnóstico , Agentes Urológicos/administración & dosificaciónRESUMEN
Revefenacin inhalation solution is an anticholinergic indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease. Mass balance, pharmacokinetics, and metabolism of revefenacin were evaluated after intravenous and oral administration of [14C]-revefenacin in healthy subjects. Pharmacological activity of the major revefenacin metabolite was also assessed. Adult males (n = 9) received 20 µg intravenously of approximately 1 µCi [14C]-revefenacin and/or a single 200-µg oral solution of approximately 10 µCi [14C]-revefenacin. Mean recovery of radioactive material was 81.4% after intravenous administration (54.4% in feces; 27.1% in urine) and 92.7% after oral dosing (88.0% in feces, 4.7% in urine). Mean absolute bioavailability of oral revefenacin was low (2.8%). Intact revefenacin accounted for approximately 52.1% and 13.1% of the total radioactivity in plasma after intravenous and oral administration, respectively. Two main circulating metabolites were observed in plasma. After an intravenous dose, a hydrolysis product, THRX-195518 (M2) was observed that circulated in plasma at 14.3% of total radioactivity. After an oral dose, both THRX-195518 and THRX-697795 (M10, N-dealkylation and reduction of the parent compound) were observed at 12.5% of total circulating radioactivity. THRX-195518 was the major metabolite excreted in feces and comprised 18.8% and 9.4% of the administered intravenous and oral dose, respectively. The major metabolic pathway for revefenacin was hydrolysis to THRX-195518. In vitro pharmacological evaluation of THRX-195518 indicated that it had a 10-fold lower binding affinity for the M3 receptor relative to revefenacin. Receptor occupancy analysis suggested that THRX-195518 has minimal contribution to systemic pharmacology relative to revefenacin after inhaled administration. SIGNIFICANCE STATEMENT: The major metabolic pathway for revefenacin was hydrolysis to the metabolite THRX-195518 (M2), and both revefenacin and THRX-195518 underwent hepatic-biliary and fecal elimination after oral or intravenous administration with negligible renal excretion. Pharmacological evaluation of THRX-195518 indicated that it had a 10-fold lower binding affinity for the M3 muscarinic receptor relative to revefenacin and that THRX-195518 has minimal contribution to systemic pharmacology after inhaled administration.
Asunto(s)
Benzamidas/farmacocinética , Broncodilatadores/farmacocinética , Carbamatos/farmacocinética , Antagonistas Muscarínicos/farmacocinética , Administración por Inhalación , Administración Oral , Adulto , Benzamidas/administración & dosificación , Benzamidas/análisis , Disponibilidad Biológica , Broncodilatadores/administración & dosificación , Carbamatos/administración & dosificación , Carbamatos/análisis , Heces/química , Voluntarios Sanos , Eliminación Hepatobiliar , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Antagonistas Muscarínicos/administración & dosificación , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Soluciones , Adulto JovenAsunto(s)
Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Broncodilatadores/administración & dosificación , Antagonistas Muscarínicos/administración & dosificación , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Administración por Inhalación , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Broncodilatadores/farmacocinética , Ensayos Clínicos como Asunto/métodos , Quimioterapia Combinada , Humanos , Antagonistas Muscarínicos/farmacocinética , Enfermedad Pulmonar Obstructiva Crónica/metabolismoRESUMEN
BACKGROUND: Navafenterol (AZD8871) is a dual-pharmacology muscarinic antagonist ß2-agonist (MABA) molecule in development for the treatment of chronic obstructive pulmonary disease (COPD). The pharmacodynamics, safety and tolerability of single doses of navafenterol were investigated in patients with moderate to severe COPD. METHODS: This was a randomized, five-way complete cross-over study. Patients received single doses of navafenterol 400 µg, navafenterol 1800 µg and placebo (all double-blind) and indacaterol 150 µg and tiotropium 18 µg (both open-label active comparators). The primary pharmacodynamic endpoint was change from baseline in trough forced expiratory volume in 1 s (FEV1) on day 2. Safety and tolerability were monitored throughout. RESULTS: Thirty-eight patients were randomized and 28 (73.7%) completed the study. Navafenterol 400 µg and 1800 µg demonstrated statistically significant improvements vs placebo in change from baseline in trough FEV1 (least squares mean [95% confidence interval]: 0.111 [0.059, 0.163] L and 0.210 [0.156, 0.264] L, respectively, both P < .0001). The changes were significantly greater with navafenterol 1800 µg vs the active comparators (least squares mean treatment difference: 0.065-0.069 L, both P < .05). The frequency of treatment-emergent adverse events was similar for placebo and the active comparators (range 34.4-37.5%), slightly higher for navafenterol 400 µg (52.9%), and lowest for navafenterol 1800 µg (22.6%). CONCLUSIONS: Both doses of navafenterol demonstrated sustained bronchodilation over 24 h. Navafenterol was well tolerated and no safety concerns were raised. TRIAL REGISTRY: ClinicalTrials.gov ; No.: NCT02573155 ; URL: www.clinicaltrials.gov . Registered 9th October, 2015.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Broncoconstricción/efectos de los fármacos , Broncodilatadores/administración & dosificación , Pulmón/efectos de los fármacos , Antagonistas Muscarínicos/administración & dosificación , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Quinolinas/administración & dosificación , Triazoles/administración & dosificación , Administración por Inhalación , Agonistas de Receptores Adrenérgicos beta 2/efectos adversos , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Anciano , Broncodilatadores/efectos adversos , Broncodilatadores/farmacocinética , Estudios Cruzados , Método Doble Ciego , Inglaterra , Femenino , Volumen Espiratorio Forzado , Humanos , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Antagonistas Muscarínicos/efectos adversos , Antagonistas Muscarínicos/farmacocinética , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Quinolinas/efectos adversos , Quinolinas/farmacocinética , Recuperación de la Función , Resultado del Tratamiento , Triazoles/efectos adversos , Triazoles/farmacocinética , Capacidad VitalRESUMEN
BACKGROUND: Navafenterol (AZD8871) is a novel, long-acting, dual-pharmacology (muscarinic receptor antagonist and ß2-adrenoceptor agonist) molecule in development for chronic obstructive pulmonary disease and asthma. METHODS: These two phase I, randomised, single-blind, multiple-ascending-dose studies evaluated inhaled navafenterol and placebo (3:1 ratio) in healthy, male, non-Japanese (study A; NCT02814656) and Japanese (study B; NCT03159442) volunteers. In each study, volunteers were dosed in three cohorts, allowing gradual dose escalation from 300 µg to 600 µg to 900 µg. The primary objective was to investigate the safety and tolerability of navafenterol at steady state. Pharmacokinetics were also assessed. RESULTS: Twenty-four volunteers completed each study (navafenterol, n = 6; placebo, n = 2 in each cohort). There were no deaths, serious adverse events (AEs) or treatment-emergent AEs (TEAEs) leading to discontinuation of navafenterol. The most frequent TEAEs were vessel puncture-site bruise (placebo, n = 2; navafenterol 900 µg; n = 3) in study A and diarrhoea (placebo, n = 1; navafenterol 300 µg, n = 2; navafenterol 900 µg, n = 3) in study B. No dose-response relationship was observed for TEAEs. There was a dose-dependent increase in mean heart rate on day 16 in both studies. The pharmacokinetics of navafenterol were similar between non-Japanese and Japanese volunteers. CONCLUSIONS: Multiple ascending doses of navafenterol were well-tolerated and the safety and pharmacokinetics of navafenterol were similar in non-Japanese and Japanese volunteers. The findings support navafenterol clinical development. TRIAL REGISTRATION: ClinicalTrials.gov ; Nos.: NCT02814656 and NCT03159442; URL: www.clinicaltrials.gov .
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Broncodilatadores/administración & dosificación , Antagonistas Muscarínicos/administración & dosificación , Quinolinas/administración & dosificación , Triazoles/administración & dosificación , Administración por Inhalación , Agonistas de Receptores Adrenérgicos beta 2/efectos adversos , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Adulto , Pueblo Asiatico , Broncodilatadores/efectos adversos , Broncodilatadores/farmacocinética , Voluntarios Sanos , Humanos , Japón/etnología , Londres , Masculino , Persona de Mediana Edad , Antagonistas Muscarínicos/efectos adversos , Antagonistas Muscarínicos/farmacocinética , Quinolinas/efectos adversos , Quinolinas/farmacocinética , Método Simple Ciego , Triazoles/efectos adversos , Triazoles/farmacocinéticaRESUMEN
BACKGROUND: Navafenterol (AZD8871) is an inhaled long-acting dual-pharmacology muscarinic antagonist/ß2-adrenoceptor agonist (MABA) in development for the treatment of obstructive airways diseases. The safety, tolerability, pharmacodynamics, and pharmacokinetics of navafenterol were investigated in patients with mild asthma. METHODS: This was a randomised, single-blind, placebo-controlled, single-ascending-dose study. Patients were randomly assigned to one of two cohorts which evaluated escalating doses of navafenterol (50-2100 µg) in an alternating manner over three treatment periods. The primary pharmacodynamic endpoint was the change from pre-dose baseline in trough forced expiratory volume in 1 s (FEV1) for each treatment period. RESULTS: Sixteen patients were randomised; 15 completed treatment. Data from all 16 patients were analysed. The maximum tolerated dose was not identified, and all doses of navafenterol were well tolerated. The most frequently reported treatment-emergent adverse events (TEAEs) were headache (n = 10, 62.5%) and nasopharyngitis (n = 7, 43.8%). No TEAEs were serious, fatal, or led to discontinuation, and no dose dependency was identified. Navafenterol demonstrated a dose-ordered bronchodilatory response with a rapid onset of action (within 5 min post-dose). Doses ≥200 µg resulted in improvements in trough FEV1 (mean change from baseline range 0.186-0.463 L) with sustained bronchodilation for 24-36 h. Plasma concentrations increased in a dose-proportional manner, peaking ~ 1 h post-dose, with a derived terminal elimination half-life of 15.96-23.10 h. CONCLUSIONS: In this study navafenterol was generally well tolerated with a rapid onset of action which was sustained over 36 h. TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT02573155.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Asma/tratamiento farmacológico , Broncoconstricción/efectos de los fármacos , Broncodilatadores/administración & dosificación , Pulmón/efectos de los fármacos , Antagonistas Muscarínicos/administración & dosificación , Quinolinas/administración & dosificación , Triazoles/administración & dosificación , Administración por Inhalación , Agonistas de Receptores Adrenérgicos beta 2/efectos adversos , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Adulto , Asma/diagnóstico , Asma/fisiopatología , Broncodilatadores/efectos adversos , Broncodilatadores/farmacocinética , Inglaterra , Femenino , Volumen Espiratorio Forzado , Humanos , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Antagonistas Muscarínicos/efectos adversos , Antagonistas Muscarínicos/farmacocinética , Quinolinas/efectos adversos , Quinolinas/farmacocinética , Recuperación de la Función , Índice de Severidad de la Enfermedad , Método Simple Ciego , Resultado del Tratamiento , Triazoles/efectos adversos , Triazoles/farmacocinéticaRESUMEN
INTRODUCTION: Overactive bladder is a common problem women suffer from, with its incidence increasing with age. The mainstay of treatment is antimuscarinic medication. There is growing evidence that antimuscarinics may increase the risk of cognitive impairment, dementia, and even death. AREAS COVERED: This review explores the evidence that antimuscarinics increase the risk of cognitive impairment, dementia, and death. It evaluates how best to treat overactive bladder the older woman. EXPERT OPINION: The evidence suggests that antimuscarinics increase the risk of cognitive impairment and dementia in the older adult. Care should be taken to use an antimuscarinic that is less likely to cross the blood-brain barrier and thus reduce the risk of these significant adverse events. A patient's anticholinergic load also needs to be considered when treating this group. Other treatment options such as fluid management, bladder retraining, vaginal estrogens, mirabegron, Onabotulinum toxin A and neuromodulation can be used instead.
Asunto(s)
Disfunción Cognitiva/inducido químicamente , Antagonistas Muscarínicos/administración & dosificación , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Factores de Edad , Animales , Barrera Hematoencefálica/metabolismo , Antagonistas Colinérgicos/administración & dosificación , Antagonistas Colinérgicos/efectos adversos , Demencia/inducido químicamente , Femenino , Humanos , Antagonistas Muscarínicos/efectos adversos , Antagonistas Muscarínicos/farmacocinética , Factores de RiesgoRESUMEN
PURPOSE: The triple combination therapy budesonide/glycopyrrolate/formoterol fumarate in a metered dose inhaler (BGF MDI), formulated by using innovative co-suspension delivery technology, is a new inhaled corticosteroid/long-acting muscarinic antagonist/long-acting ß2-agonist fixed-dose combination for the maintenance treatment of COPD. For some patients, the use of an MDI may be optimized with a spacer. This Phase I study assessed the effect of a spacer on lung exposure, total systemic exposure, and safety of BGF MDI 320/36/9.6 µg in healthy subjects. METHODS: This randomized, open-label, crossover study assessed the pharmacokinetic and safety profiles of BGF MDI in healthy adult subjects who received a single dose of BGF MDI 320/36/9.6 µg (administered as 2 inhalations with 160/18/4.8 µg per actuation) in 4 regimens: without spacer and no charcoal; with spacer and no charcoal; without spacer and with charcoal; and with spacer and with charcoal. Primary objectives were to assess total systemic exposure (without charcoal) and lung exposure (with charcoal) of budesonide, glycopyrronium, and formoterol administered as BGF MDI with and without a spacer. Safety was also assessed. FINDINGS: In total, 56 subjects were randomized (mean age, 29.9 years; 60.7% male, 17.9% former smokers). For systemic exposure (without charcoal), the spacer/without spacer ratio, expressed as a percentage (intrasubject %CV) of Cmax and AUC0-tlast, respectively, was 152.0 (47.5) and 132.8 (43.6) for budesonide, 240.6 (80.2) and 154.7 (73.4) for glycopyrronium, and 165.6 (50.7) and 98.6 (53.8) for formoterol. For lung exposure (with charcoal), the spacer/without spacer ratio percentage (%CV) of Cmax and AUC0-tlast, respectively, was 183.6 (65.9) and 198.4 (71.5) for budesonide, 262.0 (91.8) and 373.9 (120.7) for glycopyrronium, and 222.9 (56.3) and 385.2 (147.0) for formoterol. Subjects who were judged to have suboptimal inhalation technique without a spacer (those in the lowest drug exposure quartile based on AUC0-tlast) had the greatest increase in both total systemic and lung exposure when a spacer was used versus no spacer. Subjects in the highest quartile had a minimal change in both total systemic and lung exposure when the spacer was used. Treatment-emergent adverse events (TEAEs) (all mild/moderate) reported by >1 subject per regimen were headache, cough, and dizziness. One subject withdrew because of TEAEs of headache and presyncope (neither considered treatment-related). IMPLICATIONS: Drug delivery can be improved for subjects with suboptimal MDI inhalation technique when using a spacer device with BGF MDI triple therapy. ClinicalTrials.gov identifier: NCT03311373.