RESUMO
AIMS: We report on investigations exploring the P2X3-receptor antagonist filapixant's effect on taste perception and cough-reflex sensitivity and describe its pharmacokinetics, including its CYP3A4-interaction potential. METHODS: In a randomized, placebo-controlled, double-blind study, 3 × 12 healthy men (18-45 years) were assigned (3:1) to filapixant (20, 80 or 250 mg by mouth) or placebo twice daily over 2 weeks. A single dose of midazolam (1 mg), a CYP3A4 substrate, was administered with and without filapixant. Assessments included a taste-strips test, a taste questionnaire, cough challenge with adenosine triphosphate, adverse event reports and standard safety assessments. RESULTS: Taste disturbances were observed mainly in the 250-mg group: six of nine participants (67%) in this group reported hypo- or dysgeusia in the questionnaire; eight participants (89%) reported taste-related adverse events. Five participants (56%) had a decrease in overall taste-strips-test scores ≥2 points (point estimate -1.1 points, 90% confidence interval [-3.3; 1.1]). Cough counts increased with adenosine triphosphate concentration but without major differences between treatments. Filapixant exposure increased proportionally to dose. Co-administration of filapixant had no clinically relevant effect on midazolam pharmacokinetics. Area under the concentration-time curve ratios and 90% confidence intervals were within 80-125%. No serious or severe adverse events were reported. CONCLUSIONS: Overall, filapixant was safe and well tolerated, apart from mild, transient taste disturbances. Such disturbances occurred more frequently than expected based on (in vitro) receptor-selectivity data, suggesting that other factors than P2X3:P2X2/3 selectivity might also play an important role in this context. The cough-challenge test showed no clear treatment effect. Filapixant has no clinically relevant CYP3A4 interaction potential.
Assuntos
Citocromo P-450 CYP3A , Relação Dose-Resposta a Droga , Interações Medicamentosas , Midazolam , Antagonistas do Receptor Purinérgico P2X , Humanos , Masculino , Adulto , Citocromo P-450 CYP3A/metabolismo , Antagonistas do Receptor Purinérgico P2X/administração & dosagem , Antagonistas do Receptor Purinérgico P2X/farmacocinética , Antagonistas do Receptor Purinérgico P2X/efeitos adversos , Antagonistas do Receptor Purinérgico P2X/farmacologia , Método Duplo-Cego , Adulto Jovem , Midazolam/farmacocinética , Midazolam/administração & dosagem , Midazolam/efeitos adversos , Adolescente , Voluntários Saudáveis , Pessoa de Meia-Idade , Tosse/induzido quimicamente , Paladar/efeitos dos fármacos , Receptores Purinérgicos P2X3/efeitos dos fármacos , Receptores Purinérgicos P2X3/metabolismoRESUMO
BACKGROUND AND OBJECTIVES: Chronic refractory cough is a challenging condition that requires a thorough evaluation and management approach. P2X3 receptors that are ATP-dependent play an important part in nerve fiber sensitization and pathological pain pathways. We conducted this systematic review and meta-analysis to determine the long-term safety and efficacy of P2X3 receptor antagonist drugs in chronic cough. METHODS: We systematically searched PubMed, Scopus, Web of Science, and Embase to identify all relevant published studies through January 15, 2023 that assessed P2X3 antagonists in chronic cough. The protocol was registered in the PROSPERO database with ID: CRD42023422408. Efficacy outcomes were awake (daytime) cough frequency, night cough frequency, 24-h cough frequency, Cough Severity Diary, and total Leicester Cough Questionnaire score. We used the random-effect model to pool the data using RStudio and CMA software. RESULTS: A total of 11 randomized controlled trials comprising 1350 patients receiving a p2x3 antagonist compared to the placebo group were included in this meta-analysis. A significant decrease in 24-h cough frequency (MD = -4.99, 95% CI [-7.15 to -2.82], P < 0.01), awake (daytime) cough frequency (MD = -7.18, 95% CI [-9.98 to 4.37], P < 0.01), and total Leicester Cough Questionnaire score (MD = 1.74, 95% CI [1.02 to 2.46], P < 0.01) exhibited between the P2X3 antagonist and placebo groups. The frequency of the night cough showed an insignificant difference between the two groups. According to the safety, drug-related adverse events, dysgeusia, hypogeusia, and ageusia significantly increased between the P2X3 antagonist and placebo groups. CONCLUSION: P2X3 receptor antagonists are promising drugs for treating chronic cough by significantly reducing the frequency, severity, and quality. Some potential side effects may include drug-related adverse events such as hypogeusia, ageusia, and dysgeusia.
Assuntos
Ageusia , Antagonistas do Receptor Purinérgico P2X , Humanos , Antagonistas do Receptor Purinérgico P2X/efeitos adversos , Ageusia/induzido quimicamente , Ageusia/tratamento farmacológico , Disgeusia/induzido quimicamente , Disgeusia/tratamento farmacológico , Doença Crônica , Ensaios Clínicos Controlados Aleatórios como Assunto , Tosse/tratamento farmacológicoRESUMO
Chronic low-grade inflammation contributes to the development of several diseases, including cardiovascular disease. Adequate strategies to target inflammation in cardiovascular disease are in their infancy and remain an avenue of great interest. The purinergic receptor P2X7 is a ubiquitously expressed receptor that predominately mediates inflammation and cellular death. P2X7 is a ligand-gated cation channel that is activated in response to high concentrations of extracellular ATP, triggering the assembly and activation of the NLRP3 (nuclear oligomerization domain like receptor family pyrin domain containing 3) inflammasome and subsequent release of proinflammatory cytokines IL (interleukin)-1ß and IL-18. Increased P2X7 activation and IL-1ß and IL-18 concentrations have been implicated in the development of many cardiovascular conditions including hypertension, atherosclerosis, ischemia/reperfusion injury, and heart failure. P2X7 receptor KO (knockout) mice exhibit a significant attenuation of the inflammatory response, which corresponds with reduced disease severity. P2X7 antagonism blunts blood pressure elevation in hypertension and progression of atherosclerosis in animal models. IL-1ß and IL-18 inhibition has shown efficacy in clinical trials reducing major adverse cardiac events, including myocardial infarction, and heart failure. With several P2X7 antagonists available with proven safety margins, P2X7 antagonism could represent an untapped potential for therapeutic intervention in cardiovascular disorders.
Assuntos
Anti-Inflamatórios/uso terapêutico , Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Sistema Cardiovascular/efeitos dos fármacos , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Receptores Purinérgicos P2X7/efeitos dos fármacos , Animais , Anti-Inflamatórios/efeitos adversos , Fármacos Cardiovasculares/efeitos adversos , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/patologia , Humanos , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Antagonistas do Receptor Purinérgico P2X/efeitos adversos , Receptores Purinérgicos P2X7/metabolismo , Transdução de SinaisRESUMO
We evaluated the effect of gefapixant on cough reflex sensitivity to evoked tussive challenge.In this phase 2, double-blind, two-period study, patients with chronic cough (CC) and healthy volunteers (HV) were randomised to single-dose gefapixant 100â mg or placebo in a crossover fashion. Sequential inhalational challenges with ATP, citric acid, capsaicin and distilled water were performed 1, 3 and 5â h after dosing. Mean concentrations evoking ≥2 coughs (C2) and ≥5 coughs (C5) post dose versus baseline were co-primary endpoints. Objective cough frequency (coughs·h-1) over 24â h and a cough severity visual analogue scale (VAS) were assessed in CC patients. Adverse events were monitored.24 CC patients and 12 HV were randomised (mean age 61 and 38â years, respectively). The cough challenge threshold increased for ATP by 4.7-fold (C2, p≤0.001) and 3.7-fold (C5, p=0.007) for gefapixant versus placebo in CC patients; in HV, C2 and C5 increased 2.4-fold (C2, p=0.113; C5, p=0.003). The distilled water C2 and C5 thresholds increased significantly (p<0.001) by a factor of 1.4 and 1.3, respectively, in CC patients. Gefapixant had no effect on capsaicin or citric acid challenge. Median cough frequency was reduced by 42% and the least squares mean cough severity VAS was 18.0â mm lower for gefapixant versus placebo in CC patients. Dysgeusia was the most frequent adverse event (75% of HV and 67% of CC patients).ATP-evoked cough was significantly inhibited by gefapixant 100â mg, demonstrating peripheral target engagement. Cough count and severity were reduced in CC patients. Distilled water may also evoke cough through a purinergic pathway.
Assuntos
Tosse/tratamento farmacológico , Tosse/fisiopatologia , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Antitussígenos/efeitos adversos , Antitussígenos/uso terapêutico , Testes de Provocação Brônquica , Doença Crônica , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas do Receptor Purinérgico P2X/efeitos adversos , Pirimidinas/efeitos adversos , Sulfonamidas/efeitos adversos , Reino Unido , Escala Visual AnalógicaRESUMO
Chronic cough, or cough lasting >8 weeks, is often associated with underlying medical conditions (ie, asthma, gastroesophageal reflux disease, nonasthmatic eosinophilic bronchitis, and upper-airway cough syndrome). In some patients with chronic cough, treatment of these underlying conditions does not resolve the cough (refractory chronic cough [RCC]), or none of these conditions are present (unexplained chronic cough [UCC]). Despite appropriate medical evaluation, patients with RCC or UCC frequently experience cough persisting for many years, as there are currently no targeted pharmacological approaches approved for the treatment of these conditions. However, the adenosine triphosphate (ATP)-gated P2X3 receptor, a key modulator of the activation of sensory neurons central to the cough reflex, has recently garnered attention as a potential therapeutic target for the treatment of chronic cough. Gefapixant, a first-in-class, non-narcotic, selective antagonist of the P2X3 receptor, recently demonstrated efficacy and was generally well tolerated in phase 2 clinical trials in patients with RCC, validating the utility of targeting this receptor in patients with chronic cough. On the basis of these data, 2 global phase 3 trials, with combined anticipated enrolment exceeding 2000 patients and with treatment durations of up to 1 year, have been initiated. Together, these trials will further evaluate efficacy and safety of gefapixant in the control of cough in patients with RCC or UCC.
Assuntos
Tosse/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2X/farmacologia , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Animais , Antitussígenos/efeitos adversos , Antitussígenos/farmacologia , Doença Crônica , Tosse/etiologia , Tosse/fisiopatologia , Humanos , Antagonistas do Receptor Purinérgico P2X/efeitos adversos , Pirimidinas/efeitos adversos , Receptores Purinérgicos P2X3/efeitos dos fármacos , Receptores Purinérgicos P2X3/metabolismo , Sulfonamidas/efeitos adversosRESUMO
BLU-5937 is a small molecule that was shown to be a potent, selective and non-competitive P2X3 homotrimeric receptor antagonist. P2X3 receptors are ATP ion-gated channels located on primary afferent neurons. ATP released from damaged or inflamed tissues in the airways acts on P2X3 receptors of primary afferent neurons, triggering depolarization and action potentials that are transmitted centrally and interpreted as urge to cough. There are strong preclinical and clinical evidence supporting the role of P2X3 receptors in hypersensitization of the cough reflex, leading to chronic cough. By inhibiting P2X3 receptors on the primary sensory neurons, BLU-5937 would inhibit the hypersensitization of the cough reflex and, hence, the exaggerated cough experienced in chronic cough patients. BLU-5937 is being developed for the treatment of unexplained, refractory chronic cough. The high potency and selectivity of BLU-5937 for P2X3 homotrimeric receptors was demonstrated in vitro by inhibiting αß-meATP-evoked P2X3 or P2X2/3 receptor activity in cloned human hP2X3 and hP2X2/3 channels expressed in mammalian cells. The IC50 of BLU-5937 for hP2X3 homotrimeric and hP2X2/3 heterotrimeric receptors was established at 25â¯nM and >24⯵M, respectively. Furthermore, BLU-5937 (500â¯nM) was able to block αß-meATP-induced sensitization and firing activity of isolated primary nociceptors in rat dorsal root ganglions (DRGs), through P2X3 homotrimeric receptor antagonism. In a guinea pig cough model, BLU-5937 (0.3, 3 and 30â¯mg/kg, oral) significantly reduced, in a dose-dependent fashion, the histamine-induced enhancement in the number of citric acid-induced coughs. BLU-5937 (3 and 30â¯mg/kg, oral) was also shown to reduce significantly and dose-dependently the ATP-induced enhancement of citric acid-induced coughs in the guinea pig. These anti-tussive effects were obtained at a plasma concentration known to block P2X3 homotrimeric receptors, but at concentration 50-fold lower than that required to block P2X2/3 heterotrimeric receptors. These results indicate that the anti-tussive effect of BLU-5937 is primarily mediated through the inhibition of P2X3 homotrimeric receptors. In a rat behavioral taste model, BLU-5937 (10-20â¯mg/kg, IP) did not alter taste perception as compared to control animals. In the same experiment, N-00588 (10-20â¯mg/kg, IP), a weakly selective antagonist for P2X3 versus P2X2/3 receptors, had a significant inhibitory effect on taste perception. Pharmacokinetic analysis of drug plasma concentrations showed that BLU-5937 did not affect taste function at concentrations up to 30 times the IC50 for P2X3. These results suggest that N-00588 achieved systemic concentration that blocked P2X3 and P2X2/3 receptors expressed on gustatory nerve ending innervating taste buds. The lack of effect of BLU-5937, even at high doses, on taste perception may be attributed to its higher selectivity for the P2X3 versus P2X2/3 receptors on the taste buds. The safety, tolerability and pharmacokinetic profile of BLU-5937 was assessed in a battery of preclinical studies and have revealed that BLU-5937 exhibits excellent drug-like characteristics, including good oral bioavailability, low predicted clearance in human, no blood-brain barrier permeability and high safety margin versus human predicted efficacious exposure. BLU-5937 is currently in clinical phase I development stage. In conclusion, BLU-5937 was selected as a drug candidate for the treatment of chronic cough due to its high potency and selectivity for P2X3 homotrimeric receptors, strong anti-tussive effects, excellent tolerability and predicted pharmacokinetic properties in humans.
Assuntos
Antitussígenos/administração & dosagem , Tosse/tratamento farmacológico , Imidazóis/administração & dosagem , Piperidinas/administração & dosagem , Antagonistas do Receptor Purinérgico P2X/administração & dosagem , Piridinas/administração & dosagem , Receptores Purinérgicos P2X3/efeitos dos fármacos , Animais , Antitussígenos/efeitos adversos , Antitussígenos/farmacologia , Doença Crônica , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Cobaias , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacologia , Concentração Inibidora 50 , Masculino , Piperidinas/efeitos adversos , Piperidinas/farmacologia , Antagonistas do Receptor Purinérgico P2X/efeitos adversos , Antagonistas do Receptor Purinérgico P2X/farmacologia , Piridinas/efeitos adversos , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2X3/metabolismo , Percepção Gustatória/efeitos dos fármacosRESUMO
BACKGROUND: Preclinical studies suggest that P2X3 receptors are expressed by airway vagal afferent nerves and contribute to the hypersensitisation of sensory neurons. P2X3 receptors could mediate sensitisation of the cough reflex, leading to chronic cough. We aimed to investigate the efficacy of a first-in-class oral P2X3 antagonist, AF-219, to reduce cough frequency in patients with refractory chronic cough. METHODS: We did a double-blind, placebo-controlled, two-period, crossover study at one UK centre. With a computer-generated sequence, we randomly assigned patients with refractory chronic cough to AF-219, 600 mg twice a day, or to placebo (1:1), and then, after a 2 week washout, assigned patients to receive the other treatment. Patients, health-care providers, and investigators were masked to sequence assignment. We assessed daytime cough frequency (primary endpoint) at baseline and after 2 weeks of treatment using 24 h ambulatory cough recordings. The primary analysis used a mixed effects model with the intention-to-treat population. This study was registered at ClinicalTrials.gov, number NCT01432730. FINDINGS: Of 34 individuals assessed between Sept 22, 2011, and Nov 29, 2012, we randomly assigned 24 patients (mean age 54·5 years; SD 11·1). In the observed case analysis, cough frequency was reduced by 75% when patients were allocated to AF-219 compared when allocated to placebo (p=0·0003). Daytime cough frequency fell from a mean 37 coughs per h (SD 32) to 11 (8) coughs per h after AF-219 treatment versus 65 (163) coughs per h to 44 (51) coughs per h after placebo. Six patients withdrew before the end of the study because of taste disturbances, which were reported by all patients taking AF-219. INTERPRETATION: P2X3 receptors seem to have a key role in mediation of cough neuronal hypersensitivity. Antagonists of P2X3 receptors such as AF-219 are a promising new group of antitussives. FUNDING: Afferent Pharmaceuticals.
Assuntos
Antitussígenos/uso terapêutico , Tosse/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Adulto , Idoso , Antitussígenos/efeitos adversos , Doença Crônica , Ritmo Circadiano , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas do Receptor Purinérgico P2X/efeitos adversos , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Índice de Gravidade de Doença , Sulfonamidas , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: P2X3 receptor antagonists hold promising potential as a therapeutic option for patients with refractory or unexplained chronic cough, a condition lacking approved therapies. This study assessed the safety, tolerability, and pharmacokinetics (PK) of HRS-2261, a novel selective P2X3 receptor antagonist, in healthy subjects. METHODS: This randomized, double-blinded, placebo-controlled phase 1 trial of HRS-2261 consisted of three phases: the single ascending dose (SAD) study phase, the food-effect study phase, and the multiple ascending dose (MAD) study phase. In the SAD phase, healthy subjects were randomly assigned to receive a single oral dose of HRS-2261 (25, 100, 200, 400, 800, and 1200 mg) or placebo. Subjects in the 200 mg group of the SAD phase progressed directly to the food-effect phase following safety evaluation. In the MAD phase, healthy subjects were randomized to receive HRS-2261 (50, 200, and 400 mg) or placebo twice daily for 14 consecutive days. The primary endpoints were safety and tolerability. RESULTS: A total of 62 and 30 subjects were enrolled in the SAD and MAD phases, respectively, with 12 subjects from the SAD phase transitioning to the food-effect phase. The incidence and severity of adverse events (AEs) were not dose dependent, and most AEs were mild except for one moderate AE (epididymitis, which was not related to treatment) in the 400 mg group. Dysgeusia was reported in nine subjects, including two from the SAD phase, one from the food-effect phase, and six from the MAD phase. The median Tmax and geometric mean t1/2 were 0.9-2.0 h and 4.1-8.5 h in the SAD, and 2.0-2.7 h and 4.6-5.0 h on day 14 in the MAD, respectively. Drug exposures in the SAD and MAD phases were both less than dose proportional. The accumulation of the drug was slight with repeated twice-daily dosing. Food-effect study results showed that food intake did not affect the plasma exposure of HRS-2261. CONCLUSIONS: HRS-2261 demonstrated good tolerability, with a low incidence of dysgeusia. The PK profile was favorable. This study supports further development of HRS-2261 as a potential P2X3 receptor antagonist for chronic cough. TRIAL REGISTRATION NUMBER: Clinical trials.gov, identifier: NCT05274516. Trial registration date: March 10, 2022.
Assuntos
Disgeusia , Antagonistas do Receptor Purinérgico P2X , Masculino , Humanos , Antagonistas do Receptor Purinérgico P2X/efeitos adversos , Voluntários Saudáveis , Relação Dose-Resposta a Droga , Área Sob a Curva , Método Duplo-CegoRESUMO
BACKGROUND: Afferent neuronal hypersensitization via P2X3 receptor signaling has been implicated as a driver of several disorders, including refractory chronic cough, endometriosis, diabetic neuropathic pain, and overactive bladder. Eliapixant, a selective P2X3 receptor antagonist, has been in clinical development for all four disorders. OBJECTIVE: This paper describes pharmacokinetic (PK) and safety data from two phase I studies of eliapixant in healthy Japanese and Chinese participants and compares those data within the two populations and with previous multiple dose data from Caucasian participants. METHODS: Two separate phase I, single-center, randomized, placebo-controlled studies were conducted with healthy male participants. The Japanese study was single-blind and the Chinese study was double-blind. Eliapixant was administered as an oral amorphous solid dispersion immediate-release tablet in strengths of 25 mg, 75 mg, and 150 mg. PK characteristics after a single dose (SD) and at steady state (multiple dose [MD], twice daily), adverse events (AEs), and tolerability were evaluated. A post hoc comparison of PK characteristics after SD of eliapixant in Japanese and Chinese participants, and after MD of eliapixant in Japanese, Chinese, and Caucasian participants, was performed. RESULTS: Overall, 36/39 participants enrolled in the Japanese/Chinese studies, respectively (mean [standard deviation] age 25.4 [6.5] and 26.7 [5.0] years, respectively). After SD administration, maximum plasma concentration (Cmax) was higher among Japanese than Chinese participants in the 25 mg and 75 mg dose groups, but comparable in the 150 mg dose group. The area under the concentration-time curve (AUC) was comparable between Japanese and Chinese participants in the 25 mg and 75 mg dose groups, but lower among Japanese participants in the 150 mg group. Half-lives after SD and MD administration were also comparable in Japanese and Chinese participants. The post hoc analysis included 26 Japanese, 30 Chinese, and 50 Caucasian participants. Comparable exposure (Cmax,md and AUC[0-12]md) was observed after MD administration of eliapixant in Chinese and/or Japanese compared with Caucasian participants (geometric mean inter-ethnic ratios close to 1). The trough plasma concentration after eliapixant 150 mg MD, which was assumed to be relevant to eliapixant efficacy, was comparable across all ethnicity groups. Most AEs reported in the Japanese (eliapixant 75 mg SD, n = 2; eliapixant 150 mg MD, n = 2) and Chinese participants (eliapixant 25 mg SD, n = 7; eliapixant 75 mg SD, n = 6; eliapixant 150 mg SD, n = 7; eliapixant 150 mg MD, n = 9; placebo SD, n = 5; placebo MD, n = 1) were of mild intensity. Higher incidences of AEs in the Chinese population were likely due to differing standards of AE reporting between investigators. CONCLUSION: Eliapixant was well tolerated by Japanese and Chinese participants. The inter-ethnic evaluation demonstrated similar PK characteristics across Japanese, Chinese, and Caucasian participants. REGISTRATION: ClinicalTrials.gov identifier numbers: NCT04265781 and NCT04802343.
Assuntos
Antagonistas do Receptor Purinérgico P2X , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Administração Oral , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Voluntários Saudáveis , Japão , Antagonistas do Receptor Purinérgico P2X/farmacocinética , Antagonistas do Receptor Purinérgico P2X/administração & dosagem , Antagonistas do Receptor Purinérgico P2X/efeitos adversos , Método Simples-Cego , População Branca , População do Leste AsiáticoRESUMO
Gefapixant (MK-7264, RO4926219, AF-219) is a first-in-class P2X3 antagonists being developed to treat refractory or unexplained chronic cough. The initial single- and multiple-dose safety, tolerability, and pharmacokinetics of gefapixant at doses ranging from 7.5 to 1800 mg were assessed in four clinical trials. Following single-dose administration of 10-450 mg, the pharmacokinetic (PK) profile of gefapixant in plasma and urine demonstrated low inter-subject variability and a dose-proportional exposure. Following administration of multiple doses twice daily, the plasma exposures were dose-proportional at doses ranging from 7.5 to 50 mg and less than dose-proportional at doses ranging from 100 to 1800 mg. The time to mean peak drug concentration ranged from 2 to 3 h post-dose, and steady state was achieved by 7 days after dosing, with an accumulation ratio of approximately 2, comparing data from day 1 to steady state. The mean apparent terminal half-life ranged from 8.2 to 9.6 h. Gefapixant was primarily excreted unmodified in urine. Gefapixant was well tolerated following single-dose administration up to 1800 mg and multiple doses up to 1800 mg twice daily; there were no serious adverse events (AEs) reported. The most common AE reported was dysgeusia. The PK profile supports a twice-daily dosing regimen.
Assuntos
Antagonistas do Receptor Purinérgico P2X , Humanos , Masculino , Adulto , Feminino , Pessoa de Meia-Idade , Adulto Jovem , Antagonistas do Receptor Purinérgico P2X/farmacocinética , Antagonistas do Receptor Purinérgico P2X/administração & dosagem , Antagonistas do Receptor Purinérgico P2X/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Voluntários Saudáveis , Adolescente , Esquema de Medicação , Meia-Vida , Sulfonamidas/farmacocinética , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Pirimidinas/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , BenzenossulfonamidasRESUMO
JNJ-54175446 is a selective purine P2X7 receptor (P2X7R) antagonist that attenuates microglial IL-1ß/IL-18 release. In healthy volunteers, JNJ-54175446 suppressed peripheral interleukin (IL)-1ß release, and attenuated dexamphetamine-induced improvements of mood and (visuo)motor performance in a human dexamphetamine-challenge paradigm. In depression, P2X7R inhibition may dampen immune-related dysregulation of mood. These results suggest that the impact of P2X7R inhibition is most prominent in situations where mood regulation is disrupted. Total sleep deprivation (TSD) results in an acute emotional perturbation, which yields a transient antidepressant effect. In the current study, TSD was applied as a behavioral challenge to investigate whether such effects could be modulated by JNJ-54175446. This was a double-blind, placebo-controlled, randomized study to assess the safety and pharmacokinetics of JNJ-54175446 and explore its effects in patients with single episode and recurrent major depressive disorder (MDD) (N = 69) and baseline total Inventory of Depressive Symptomatology Clinician Rated (IDS-C) > 30. Patients were randomized to receive JNJ-54175446 throughout the 10-day treatment period, placebo for days 1-3 followed by JNJ-54175446 or placebo throughout. All patients underwent 36 h of TSD starting on day three until the evening of day four. The early start group was hypothesized to experience a reduced effect from TSD whilst the late starting group was hypothesized to experience prolonged effects from the TSD. JNJ-54175446 was well-tolerated and adverse events were mild to moderate. JNJ-54175446 reduced IL-1ß release by LPS-stimulated peripheral white blood cells in the presence of the P2X receptor agonist benzyl adenosine triphosphate (BzATP). JNJ-54175446 did not have a significant effect on mood as assessed using the Hamilton Depression Rating Scale, 17 items (HDRS17) and the Self-rated Quick Inventory of Depressive Symptoms (QIDS-SR). However, JNJ-54175446 blunted an acute reduction of anhedonia that occurred as a result of TSD, assessed by the Snaith-Hamilton Pleasure Scale (SHAPS) and the Probabilistic Instrumental Learning Task (PILT).
Assuntos
Transtorno Depressivo Maior , Humanos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/diagnóstico , Antagonistas do Receptor Purinérgico P2X/efeitos adversos , Receptores Purinérgicos P2X7 , Sistema Nervoso Central , Privação do Sono , DextroanfetaminaRESUMO
OBJECTIVES: The P2X(7) purinergic receptor antagonist AZD9056 was evaluated in a phase IIa study and subsequently in a phase IIb study to assess the effects of orally administered AZD9056 on the signs/symptoms of rheumatoid arthritis (RA), with American College of Rheumatology 20% response criteria (ACR20) as the primary outcome. METHODS: Both studies were randomised, double-blind, placebo-controlled, parallel-group studies in patients with RA receiving methotrexate or sulphasalazine. Phase IIa was an ascending-dose trial in two cohorts (n=75) using AZD9056 administered daily over 4 weeks. Phase IIb included an open-label etanercept treatment group. Patients were randomised to receive treatment for 6 months with 50, 100, 200 or 400 mg AZD9056 (oral, once a day) or matching placebo (oral, once a day), or subcutaneous etanercept (50 mg once a week). RESULTS: In phase IIa, 65% of AZD9056 recipients at 400 mg/day responded at the ACR20 level compared with 27% of placebo-treated patients. A significant reduction in swollen and tender joint count was observed in the actively treated group compared with placebo, whereas no effect on acute-phase response was observed. Of 385 randomised patients in the phase IIb study, 383 received treatment. AZD9056 (all doses) had no clinically or statistically significant effect on RA relative to placebo as measured by the proportion of patients meeting the ACR20 criteria at 6 months and further supported by secondary end points. In both studies AZD9056 was well tolerated up to 400 mg/day. CONCLUSIONS: AZD9056 does not have significant efficacy in the treatment of RA, and the P2X(7) receptor does not appear to be a therapeutically useful target in RA. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00520572.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2X/administração & dosagem , Adulto , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas do Receptor Purinérgico P2X/efeitos adversos , Adulto JovemRESUMO
Gefapixant (MK-7264, AF-219), a first-in-class P2X3 antagonist, is being developed as oral treatment for refractory or unexplained chronic cough. Based on in vitro data, gefapixant exerts inhibitory activity on the organic anion transporter (OAT) P1B1 transporter. Therefore, a drug-drug interaction study evaluating the potential effects of gefapixant on the OATP1B1 drug transporter, using pitavastatin as a sensitive probe substrate, was conducted. An open-label, 2-period, fixed-sequence study in 20 healthy adults 18 to 55 years old was conducted. In period 1, a 1-mg oral dose of pitavastatin was administered to each participant. After a ≥4-day washout, in period 2 participants received a 45-mg oral dose of gefapixant twice daily on days 1 through 4. On day 2 of period 2, pitavastatin was coadministered with the morning dose of gefapixant. Pitavastatin exposures following single-dose administration with and without multiple doses of gefapixant were similar: geometric mean ratio (90% confidence interval) of pitavastatin area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞ ) (pitavastatin + gefapixant/pitavastatin alone) was 0.97 (0.93-1.02). The ratio of pitavastatin lactone AUC0-∞ to pitavastatin AUC0-∞ was also comparable between treatments. Administration of gefapixant and pitavastatin was generally well tolerated, with no safety findings of concern. These results support that gefapixant has a low potential to inhibit the OATP1B1 transporter.
Assuntos
Antagonistas do Receptor Purinérgico P2X , Receptores Purinérgicos P2X3 , Adolescente , Adulto , Humanos , Pessoa de Meia-Idade , Preparações Farmacêuticas , Antagonistas do Receptor Purinérgico P2X/efeitos adversos , Pirimidinas , Quinolinas , Sulfonamidas , Adulto JovemRESUMO
Gefapixant, a P2X3 receptor antagonist, has demonstrated efficacy in patients with refractory or unexplained chronic cough. We investigated the effect of renal impairment (RI) on the pharmacokinetics (PK) of gefapixant 50 mg in an open-label, single-dose study enrolling participants with moderate (n = 6) or severe (n = 6) RI, end-stage renal disease (ESRD; n = 6) under hemodialysis (HD) and non-HD conditions, and healthy matched controls (n = 6). Serial plasma and urine samples for gefapixant concentrations were collected at selected time points over 72 and 48 hours after dosing, respectively. Linear regression analysis predicted a 1.87-, 2.79-, and 3.76-fold higher exposure (area under the plasma concentration-time curve) for participants with mild, moderate, and severe RI, respectively, than that for healthy matched control participants. Categorical analysis exhibited a 2.98-, 4.43-, and 4.74-fold higher exposure for participants with moderate RI, severe RI, and ESRD, respectively, than that for healthy matched control participants. Apparent oral clearance and renal clearance was lower in participants with various degrees of RI, by 66% to 90%, compared with healthy matched control participants, explaining the increased gefapixant exposure with increasing degrees of renal impairment. Gefapixant area under the plasma concentration-time curve and maximum plasma concentration decreased by ≈25% under HD conditions compared to non-HD conditions. Single-dose administration of gefapixant was generally well tolerated in this study. The data from this trial informed the enrollment of phase 3 clinical trials that evaluated the efficacy and safety of gefapixant in >2000 participants with refractory or unexplained chronic cough. Those efficacy and safety data, combined with analysis of population pharmacokinetics from across the entire development program, will be used to evaluate the magnitude of the renal impairment effect in the refractory or unexplained chronic cough population and to determine any dose adjustment recommendations.
Assuntos
Falência Renal Crônica , Insuficiência Renal , Doença Crônica , Tosse/induzido quimicamente , Tosse/tratamento farmacológico , Humanos , Falência Renal Crônica/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2X/efeitos adversos , Pirimidinas , Receptores Purinérgicos P2X3 , Insuficiência Renal/induzido quimicamente , SulfonamidasRESUMO
BACKGROUND AND OBJECTIVE: There is no licensed treatment for refractory chronic cough; off-label therapies have limited efficacy and can produce adverse effects. Excessive adenosine triphosphate signaling via P2X3 receptors is implicated in refractory chronic cough, and selective P2X3 receptor antagonists such as eliapixant (BAY 1817080) are under investigation. The objective of the study was to investigate the safety and tolerability of ascending repeated oral doses of eliapixant in healthy volunteers. METHODS: We conducted a repeated-dose, double-blind, randomized, placebo-controlled study in 47 healthy male individuals. Subjects received repeated twice-daily ascending oral doses of eliapixant (10, 50, 200, and 750 mg) or placebo for 2 weeks. The primary outcome was frequency and severity of adverse events. Other outcomes included pharmacokinetics and evaluation of taste disturbances, which have occurred with the less selective P2X3 receptor antagonist gefapixant. RESULTS: Peak plasma concentrations of eliapixant were reached 3-4 h after administration of the first and subsequent doses. With multiple dosing, steady-state plasma concentrations were reached after ~ 6 days, and plasma concentrations predicted to achieve ≥ 80% P2X3 receptor occupancy (the level required for efficacy) were reached at 200 and 750 mg. Increases in plasma concentrations with increasing doses were less than dose proportional. After multiple dosing, mean plasma concentrations of eliapixant showed low peak-trough fluctuations and were similar for 200- and 750-mg doses. Eliapixant was well tolerated with a low incidence of taste-related adverse events. CONCLUSIONS: Eliapixant (200 and 750 mg) produced plasma concentrations that cover the predicted therapeutic threshold over 24 h, with good safety and tolerability. These results enabled eliapixant to progress to clinical trials in patients with refractory chronic cough. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov: NCT03310645 (initial registration: 16 October, 2017).
There are few effective treatments for patients with a long-term (chronic) cough. It is thought that chronic cough is caused by nerves becoming oversensitive, wrongly causing a cough when there is no need. We tested a new drug called eliapixant in 47 healthy men. Eliapixant reduces the excessive nerve signaling responsible for chronic cough. We looked for side effects of eliapixant and measured how it behaves in the body. In particular we looked for side effects relating to the sense of taste because gefapixant, a similar drug to eliapixant, can affect taste. Participants took one of four eliapixant doses or a placebo twice daily for 2 weeks. The highest levels of eliapixant in the blood were seen 34 h after taking the drug, and stable concentrations were seen after about 6 days. At the two highest doses, eliapixant reached concentrations in the body that should be high enough to work in patients with chronic cough. Side effects were generally similar between eliapixant and placebo. Taste-related side effects were mild and went away without needing treatment. The positive results of this study meant that eliapixant could be tested in patients with chronic cough.
Assuntos
Antagonistas do Receptor Purinérgico P2X , Receptores Purinérgicos P2X3 , Doença Crônica , Tosse/induzido quimicamente , Tosse/tratamento farmacológico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Masculino , Antagonistas do Receptor Purinérgico P2X/efeitos adversosRESUMO
Gefapixant (MK-7264) is a first-in-class, selective antagonist of the P2X3 purinergic receptor currently being investigated as a therapeutic agent for the treatment of refractory or unexplained chronic cough. In non-clinical studies, gefapixant was eliminated primarily by renal excretion of the parent drug. The objective of this study was to assess the disposition of gefapixant in humans. The absorption, metabolism, and excretion profiles of gefapixant were assessed after oral administration of a single dose of [14 C]gefapixant to six healthy adult males. Following a single-oral [14 C]gefapixant dose to healthy adult males, the mass balance was achieved, with 98.9% of the administered radioactivity recovered in urine and feces. Elimination of gefapixant occurred primarily via renal excretion of the intact drug (64%); metabolism was a minor pathway of elimination of gefapixant (12% and 2% recovered in urine and feces, respectively). Single-dose administration of [14 C]gefapixant 50 mg was generally well tolerated in healthy adult males. The fraction of the anticipated therapeutic oral dose of gefapixant absorbed is estimated to be at least 78%. Gefapixant is expected to be the major circulating drug-related material in plasma, and the majority of the dosed drug will be excreted unchanged in urine.
Assuntos
Antagonistas do Receptor Purinérgico P2X/farmacocinética , Pirimidinas/farmacocinética , Sulfonamidas/farmacocinética , Administração Oral , Adulto , Radioisótopos de Carbono , Humanos , Masculino , Antagonistas do Receptor Purinérgico P2X/administração & dosagem , Antagonistas do Receptor Purinérgico P2X/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Receptores Purinérgicos P2X3/efeitos dos fármacos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Adulto JovemRESUMO
BACKGROUND: Gefapixant is a P2X3 receptor antagonist that has shown promise for the treatment of refractory and unexplained chronic cough. The aim of this study was to evaluate the efficacy of gefapixant compared with placebo after 12 weeks of treatment for refractory chronic cough or unexplained chronic cough. METHODS: We did a 12-week, phase 2b, randomised, double-blind, placebo-controlled study in patients with refractory chronic cough or unexplained chronic cough aged 18-80 years who were recruited from 44 primarily outpatient pulmonologist or allergist sites in the UK and the USA. Eligible patients had refractory or unexplained chronic cough lasting 1 year or longer, no radiographic chest abnormality, and 40 mm or more on a 100-mm cough severity visual analogue scale at enrolment. Patients were randomly assigned to receive placebo or one of three doses (7·5 mg, 20 mg, or 50 mg) of oral gefapixant twice daily, every day, for 84 days; visits to investigative sites were on days 1, 28, 42, 56, 70, 84, and 85. The randomisation schedule was computer generated using a permuted block algorithm by Advance Research Associates (Santa Clara, CA, USA). Patients and all personnel involved in the conduct and interpretation of the study were masked to treatment assignment. The primary endpoint was placebo-adjusted change from baseline in awake cough frequency after 12 weeks, assessed in the full analysis set, which is a subset of the intention-to-treat population. Adverse events were monitored and safety was evaluated in all patients receiving one or more doses of study drug. This trial is registered with ClinicalTrials.gov, NCT02612610. FINDINGS: Between Dec 21, 2015, and July 26, 2016, 253 patients were randomly assigned to placebo (n=63), gefapixant 7·5 mg (n=64), gefapixant 20 mg (n=63), or gefapixant 50 mg (n=63) twice daily. The mean age of patients was 60·2 (SD 9·9) years and 193 (76%) were women. At 12 weeks, patients' geometric mean awake cough frequency was 18·2 coughs per h (geometric SD 3·1) with placebo, and 14·5 coughs per h (3·7) with 7·5 mg, 12·0 coughs per h (4·2) with 20 mg, and 11·3 coughs per h (2·8) with 50 mg gefapixant. Estimated percentage change relative to placebo was -22·0% (-41·8 to 4·6; p=0·097) with 7·5 mg, -22·2% (-42·0 to 4·3; p=0·093) with 20 mg, and -37·0% (95% CI -53·3 to -14·9; p=0·0027) with 50 mg gefapixant. Dysgeusia was the most common adverse event, occurring in three (5%) patients given placebo, six (10%) given 7·5 mg gefapixant, 21 (33%) given 20 mg gefapixant, and 30 (48%) given 50 mg gefapixant. INTERPRETATION: Targeting purinergic receptor P2X3 with gefapixant at a dose of 50 mg twice daily significantly reduced cough frequency in patients with refractory chronic cough or unexplained chronic cough after 12 weeks of treatment compared with placebo. Further development of gefapixant is warranted for the treatment of chronic cough. FUNDING: Afferent Pharmaceuticals (acquired by Merck & Co., Inc., Kenilworth, NJ, USA).
Assuntos
Doença Crônica/tratamento farmacológico , Tosse/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2X/administração & dosagem , Pirimidinas/administração & dosagem , Sulfonamidas/administração & dosagem , Adulto , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Disgeusia/induzido quimicamente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas do Receptor Purinérgico P2X/efeitos adversos , Pirimidinas/efeitos adversos , Sulfonamidas/efeitos adversos , Reino Unido , Estados Unidos , Adulto JovemRESUMO
BACKGROUND: This is the first report of the pharmacodynamic (PD) effects of the selective, potent and brain-penetrant P2X7 receptor (P2X7R) antagonist JNJ-54175446. Activation of the P2X7R, an adenosine triphosphate-gated ion channel, leads to the production of pro-inflammatory cytokines, which have been linked to neuroinflammation and play a role in the pathogenesis of mood disorders. Previous clinical studies with JNJ-54175446 demonstrated peripheral target engagement of JNJ-54175446 by assessing ex vivo lipopolysaccharide (LPS)-stimulated cytokine production. Blood-brain barrier penetration and a clear dose-receptor occupancy relationship was demonstrated using positron emission tomography. AIMS: The objectives of this double-blind, placebo-controlled, translational study were to assess the safety and tolerability of administering multiple doses of JNJ-54175446 and to explore its PD effects using a dexamphetamine challenge. METHODS: Subjects (N = 64) were randomised to either JNJ-54175446 (50-450 mg; n = 48) or placebo (n = 16) and underwent a baseline oral 20 mg dexamphetamine challenge followed by 11 consecutive days q.d. dosing with JNJ-54175446/placebo and a randomised crossover dexamphetamine/placebo challenge. RESULTS: At all doses tested, JNJ-54175446 was well tolerated and suppressed the ex vivo LPS-induced release of cytokines. At doses ⩾100 mg, JNJ-54175446 attenuated dexamphetamine-induced increases in locomotion and enhanced the mood-elevating effects of dexamphetamine, suggesting that a dose that is approximately twice as high is needed to obtain a central PD response compared to the dose needed for maximum peripheral occupancy. CONCLUSION: Overall, the observed pharmacological profile of JNJ-54175446 in the dexamphetamine challenge paradigm is compatible with a potential mood-modulating effect.
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Estimulantes do Sistema Nervoso Central/farmacologia , Dextroanfetamina/farmacologia , Antagonistas do Receptor Purinérgico P2X/farmacologia , Piridinas/farmacologia , Triazóis/farmacologia , Adolescente , Adulto , Estimulantes do Sistema Nervoso Central/administração & dosagem , Transtorno Depressivo Maior/tratamento farmacológico , Dextroanfetamina/administração & dosagem , Método Duplo-Cego , Eletroencefalografia , Humanos , Inflamação/tratamento farmacológico , Masculino , Antagonistas do Receptor Purinérgico P2X/administração & dosagem , Antagonistas do Receptor Purinérgico P2X/efeitos adversos , Antagonistas do Receptor Purinérgico P2X/farmacocinética , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/farmacocinética , Pesquisa Translacional Biomédica , Triazóis/administração & dosagem , Triazóis/efeitos adversos , Triazóis/farmacocinética , Adulto JovemRESUMO
Gliomas are the most prevalent tumours of the central nervous system and present with high morbidity and mortality. The most common and most aggressive form of glioma is glioblastoma multiforme, of which patients have a median survival time of only 12 to 15â¯months. Current treatment options are limited and have a small impact on clinical outcome and prognosis. There is accumulating evidence that microglia, the immunocompetent cells of the central nervous system, and the purinergic P2X7 receptor (P2X7R) may contribute to tumour progression and pathology. Importantly, P2X7R on both tumour cells and infiltrating microglia is overexpressed in animal and human glioma cultures. Factors released by glioma cells and P2X7R activation recruit microglia into the largely immunosuppressive tumour microenvironment where they have been demonstrated to contribute to either tumour proliferation or tumour suppression. It is likely that P2X7R mediates a range of microglia effector functions in the glioma setting, potentially increasing tumour growth and proliferation. This review evaluates current evidence on the roles of microglia and P2X7R in glioma pathogenesis. Understanding the nature, mechanisms and outcomes of microglia and P2X7R activation in gliomas is necessary for the development of more therapies with increased efficacy and specificity.
Assuntos
Neoplasias do Sistema Nervoso Central/etiologia , Glioma/etiologia , Microglia/imunologia , Proteínas de Neoplasias/fisiologia , Receptores Purinérgicos P2X7/fisiologia , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/imunologia , Neoplasias do Sistema Nervoso Central/imunologia , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/terapia , Anergia Clonal , Citocinas/fisiologia , Glioma/imunologia , Glioma/patologia , Glioma/terapia , Humanos , Tolerância Imunológica , Metaloproteinase 2 da Matriz/fisiologia , Proteínas de Neoplasias/imunologia , Agonistas do Receptor Purinérgico P2X/uso terapêutico , Antagonistas do Receptor Purinérgico P2X/efeitos adversos , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Ratos , Receptores Purinérgicos P2X7/imunologia , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologiaRESUMO
Damage associated molecular patterns (DAMPs) are intracellular molecules released from infected or injured cells to activate inflammatory and reparatory responses. One of the most ancient and conserved DAMPs is extracellular ATP that exerts its phlogistic activity mainly through activation of the P2X7 receptor (P2X7R). The P2X7R is an ATP gated ion channel, expressed by most immune cells, including the monocyte-derived cell lineages, T and B lymphocytes and their precursors. Here we give an overview of recent and established literature on the role of P2X7R in septic and sterile inflammation. P2X7R ability in restraining intracellular bacteria and parasite infection by modulation of the immune response are described, with particular focus on Mycobacteria and Plasmodium. Emerging literature on the role of P2X7 in viral infections such as HIV-1 is also briefly covered. Finally, we describe the numerous intracellular pathways related to inflammation and activated by the P2X7R, including the NLRP3 inflammasome, NF-kB, NFAT, GSK3ß and VEGF, and discuss the involvement of P2X7R in chronic diseases. The possible therapeutic applications of P2X7R antagonists are also described.