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Airway sensitization and irritation. Large proportions of C and A δ fiber afferents in the upper and lower airways express P2X3 receptors and can be sensitized by ATP. Activation of some of these sensory nerves by ATP liberated from epithelial and smooth muscle cells is postulated to contribute to components of airways hyperexcit- ability, giving rise to airways hypersecretion, bronchospasm, breathlessness (dyspnea), and chronic cough, all of which are undermanaged factors in chronic diseases such as COPD and asthma
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SUMMARY Despite decades of innovation and effort, the pharmaceutical needs of countless patients with chronic pain remain underserved. Effective and safe treatments must clearly come from novel approaches, yet targets and molecules selected hitherto have returned little benefit. Antagonism of P2X3 purinoceptors on pain-conveying nerves is a highly...
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... receptors are expressed by a large proportion of C- and A δ afferents that innervate the upper and lower airways arising from both placodal (nodose) and neural crest (jugular) ganglia [112, 113]. Earlier data on airways P2X3 had been mostly immunohistochemical (e.g., [114]), but more recently, data-driven arguments have surfaced [115] in favor of the proposition that afferent sensitization may drive a significant a component of key airway dysfunctions, signs, and symptoms (e.g., bronchial hyperreactivity, hypersecretion, cough, dyspnea; Fig. 7), with more attention placed on the possible role of P2X3 receptors. There are now several relevant reports that indicate P2X3 antagonism as an approach to reducing such airways sensitization. In the primary model of cough used preclinically, in which aerosolized citric acid induced cough in guinea pig, it has been shown that ATP enhances citric acid cough, and that available P2X receptor antagonists block this effect in a manner consistent with involvement of P2X3 containing receptors [116]. In the same model, cough evoked by citric acid is also augmented by co-application with histamine, and this effect can also be significantly inhibited by P2X receptor antagonism, consistent with the effect of histamine being mediated via release of ATP within the lungs [117]. The characterization of the specific P2X receptor(s) involved is a little ambiguous, hampered by lack of specific probes, but is not inconsistent with P2X3 receptor involvement. It is now established that P2X3 containing receptors are significantly involved in activation of vagal C-fibers and rapidly adapting receptors (A δ -fibers) that are believed to be central to cough initiation and sensitization [113]. Using one of the first selective P2X3, P2X2/3 antagonists, the tricarboxylic acid A-317491 (Abbott), it has been shown that ATP activation of airways afferents was indeed mediated by P2X3 containing receptors [112]. Moreover, electrophysiological recordings from jugular and nodose afferents of guinea pig airways confirm that ATP acting via P2X2/3 heterotrimers in nodose fibers leads to action potential initiation [112]. More recently, an intermediary role for ATP linking bronchoconstriction with firing of airways sensory fibers has been mechanistically investigated, and P2X3 receptors (probably via P2X2/3 heterotrimers) clearly mediate bronchospasm induced afferent nerve activation in isolated perfused lung/vagus nerve preparations from guinea pig (Fig. 8; [118]). In other investigations, it has been shown that extracellular ATP activates canine and rodent pulmonary vagal sensory fibres (A δ and C), which then leads to neurogenic bronchoconstriction and cough [119]. ATP administered by aerosol inhalation in humans induces several airways effects including cough, bronchospasm, dyspnea, and tightness in asthmatics and effects are greater than seen in healthy controls, with significantly greater potency to ATP than for adenosine and AMP, the latter indicating that the effects are not primarily mediated via degradation products of ATP [120]. Additionally, it is reported that intravenous infusion of ATP in pre-terminal cancer patients gives rise to highly distressing symptoms of breathlessness, chest tightness, and dyspnea in a large number of subjects [121]. Finally, adding further support of the potential for ATP involvement promoting respiratory disease and dysfunction, it was recently shown that the concentration of ATP is markedly elevated in the bronchoalveolar lavage fluid from COPD patients, with smoking exacerbating the ATP elevations and concentrations showing marked correlation with increased obstructive measures and symptoms [122, 123]. In this study, it was concluded that “ COPD is characterized by a strong and persistent upregulation of extracellular ATP in the airways ” and although the authors' focus was on the contribution of extracellular ATP to the pathogenesis of COPD (by promoting inflammation and tissue degradation, purportedly through P2X7 activation), the likelihood that afferent sensitization induced by available ATP heightens symptomatic manifestations, morbidity, and mortality should not be overlooked. Therefore, the management of critical airways disease characteristics and symptoms of bronchospasm, hypersecretion, cough, and dyspnea that are very poorly met with existing therapy in chronic asthma and COPD represents a possible target for P2X3 ...
Citations
... Injury-induced ATP release could activate axonal purinergic receptors, leading to the excitation of DRG neurons and transduction of nociceptive stimuli 49 . Consistently, western blotting experiments showed that P2X 3 receptors were highly expressed in peripheral afferents in both sham and SNI groups. ...
Increased low frequency cortical oscillations are observed in people with neuropathic pain, but the cause of such elevated cortical oscillations and their impact on pain development remain unclear. By imaging neuronal activity in a spared nerve injury (SNI) mouse model of neuropathic pain, we show that neurons in dorsal root ganglia (DRG) and somatosensory cortex (S1) exhibit synchronized activity after peripheral nerve injury. Notably, synchronized activity of DRG neurons occurs within hours after injury and 1-2 days before increased cortical oscillations. This DRG synchrony is initiated by axotomized neurons and mediated by local purinergic signaling at the site of nerve injury. We further show that synchronized DRG activity after SNI is responsible for increasing low frequency cortical oscillations and synaptic remodeling in S1, as well as for inducing animals’ pain-like behaviors. In naive mice, enhancing the synchrony, not the level, of DRG neuronal activity causes synaptic changes in S1 and pain-like behaviors similar to SNI mice. Taken together, these results reveal the critical role of synchronized DRG neuronal activity in increasing cortical plasticity and oscillations in a neuropathic pain model. These findings also suggest the potential importance of detection and suppression of elevated cortical oscillations in neuropathic pain states.
... The nerve fibers innervating meninges are nociceptive C-and Aδ-fibers [54][55][56] with their own repertoire of calcium, potassium and sodium channels plus nociceptive sensor proteins like P2X3 receptors [9, 26]. P2X3 receptors activated by ATP are highly expressed in nociceptive Aδ-fibers but also present in unmyelinated C-fibers [57,58]. Indeed, in vivo topical application of ATP to rat meninges induces activation of approximately half population of C-and Aδ-fibers [28]. ...
... Since the discovery of the selective expression of P2X3 receptors in sensory neurons, many research groups have focused on the development of specific antagonists aiming to inhibit painful signalling [58,[145][146][147][148][149][150]. Potentially, these selective P2X3 and P2X2/3 inhibitors may have implication for the treatment of migraine pain. ...
Migraine is a major health burden worldwide with complex pathophysiology and multifarious underlying mechanisms. One poorly understood issue concerns the early steps in the generation of migraine pain. To elucidate the basic process of migraine pain further, it seems useful to consider key molecular players that may operate synergistically to evoke headache. While the neuropeptide CGRP is an important contributor, we propose that extracellular ATP (that generally plays a powerful nociceptive role) is also a major component of migraine headache, acting in concert with CGRP to stimulate trigeminal nociceptive neurons. The aim of the present focused review is to highlight the role of ATP activating its P2X3 membrane receptors selectively expressed by sensory neurons including their nerve fiber terminals in the meninges. Specifically, we present data on the homeostasis of ATP and related purines in the trigeminovascular system and in the CNS; the basic properties of ATP signalling at peripheral and central nerve terminals; the characteristics of P2X3 and related receptors in trigeminal neurons; the critical speed and persistence of P2X3 receptor activity; their cohabitation at the so-called meningeal neuro-immune synapse; the identity of certain endogenous agents cooperating with ATP to induce neuronal sensitization in the trigeminal sensory system; the role of P2X3 receptors in familial type migraine; the current state of P2X3 receptor antagonists and their pharmacological perspectives in migraine. It is proposed that the unique kinetic properties of P2X3 receptors activated by ATP offer an interesting translational value to stimulate future studies for innovative treatments of migraine pain.
... [402] 72 Les P2X sont des récepteurs-canaux cationiques non sélectifs, ayant comme activité commune l'entrée de calcium (Ca 2+ ) et de sodium (Na + ) dans la cellule et la sortie de potassium (K + ). Etant donné que le calcium intracellulaire est un second messager, l'activation des P2X induit l'activation de plusieurs voies de signalisations liées à leurs fonctions, allant de la perception douloureuse pour P2RX2-4 [403] à la régulation de la réponse immunitaire pour P2RX7 [401], [404]- [406]. Par exemple, l'influx de calcium après la stimulation des cellules avec l'ATP, permet la translocation dans le noyau de facteurs de transcriptions impliqués dans la réponse immunitaire, comme NFAT et NF-κB et ce, de façon dépendante de P2RX7 [405]- [409]. ...
Malgré de nouvelles connaissances biologiques et des avancées thérapeutiques récentes, les cancers du poumon sont encore la première cause de décès liés au cancer alors que la fibrose pulmonaire idiopathique est incurable. Il est donc urgent d'élaborer de nouvelles approches pour aider les patients atteins de ces pathologies.P2RX7 est un récepteur canal activé par de fortes concentrations d'ATP extracellulaire (ATPe), concentrations retrouvées dans les tissus tumoraux et fibreux. Il joue un rôle majeur dans la modulation du système immunitaire par sa capacité à activer l'inflammasome NLRP3 et à libérer les cytokines IL-1β et IL-18. L'activation de P2RX7 conduit aussi à la formation de macropores à la membrane pouvant induire la mort cellulaire. Ces observations font de P2RX7 un récepteur aux capacités immunomodulatrices et antitumorales qui peuvent être exploitées. Ainsi, une collaboration avec des chimistes a permis de synthétiser une molécule nommée HEI3090 que j'ai utilisé pendant ma thèse.Durant la première partie de ma thèse, j'ai étudié l'effet de HEI3090 dans le contrôle de la croissance tumorale en utilisant deux modèles murins immunocompétents de cancer du poumon. J'ai d'abord identifié HEI3090 comme un modulateur positif de P2RX7 qui nécessite la présence d'ATPe pour potentialiser ses activités. J'ai ensuite montré que HEI3090 inhibe la croissance des tumeurs en réactivant une réponse immunitaire antitumorale, cet effet repose sur la production d'IL-18 par les cellules dendritiques. L'augmentation d'IL-18 se fait de façon NLRP3-dépendante et favorise le recrutement et la cytotoxicité des lymphocytes T CD4+ et NK ainsi que l'immunogénicité de la tumeur. De ce fait, la combinaison de HEI3090 avec des anti-PD-1 guérit 80% des souris dans le modèle de tumeurs transplantées et réduit de 60% la charge tumorale dans le modèle de carcinogenèse in situ. De plus, ces souris sont protégées d'un rechallenge tumoral grâce à la mise en place d'une réponse immunitaire mémoire CD8-dépendante. Ces résultats mettent en évidence que l'activation de P2RX7 constitue une stratégie thérapeutique prometteuse dans les cancers du poumon.Durant la deuxième partie de ma thèse, j'ai étudié la capacité de HEI3090 à contrôler le développement de fibroses pulmonaires. J'ai d'abord montré que l'expression de la voie P2RX7/IL-18/IFN-γ est diminuée chez les patients atteints de fibrose pulmonaire idiopathique (FPI), suggérant le potentiel antifibrotique de P2RX7. Ensuite, grâce au modèle murin de fibrose pulmonaire induite par inhalation de bléomycine, j'ai montré que HEI3090 empêche le développement de fibroses pulmonaires. HEI3090 cible la voie P2RX7/NLRP3/IL-18 dans les cellules immunitaires et favorise un profil immunitaire antifibrotique caractérisé par une forte production d'IFN-γ par les lymphocytes T, une diminution de production de TGFβ ainsi qu'une réduction du nombre de cellules inflammatoires. J'ai également montré que les niveaux élevés d'IL-18 plasmatique chez les patients FPI semblent prédire une meilleure survie des patients. L'ensemble de ces résultats suggère que P2RX7 est une nouvelle stratégie thérapeutique dans la FPI et nous permet de proposer que le niveau d'IL-18 plasmatique pourrait constituer un biomarqueur prédictif dans la FPI.Enfin, j'ai développé un protocole permettant d'étudier l'activation de P2RX7 in vivo basé sur la formation de macropores dans des souris sauvages et p2rx7-/-. Ce protocole permet d'étudier l'effet in vivo de molécules ciblant P2RX7, dont HEI3090. Actuellement, ces molécules ne sont étudiées qu'in vitro ou de façon indirecte in vivo. De plus, ce protocole permet d'identifier la cellule ciblée et de déterminer les doses à administrer pour une meilleure efficacité.L'ensemble de ce travail a permis de mettre en avant une stratégie thérapeutique dans deux pathologies pulmonaires mais également d'identifier un potentiel biomarqueur prédictif qui est l'IL-18.
... ATP has been demonstrated as a crucial neurotransmitter, involving visceral sensory conduction by activating heteromultimers P2X2/3 receptors or heteromultimers P2X3 receptors (Burnstock, 2001), especially the P2X3 receptor, predominantly expressed on the small-to-medium diameter DRG neurons, is widely deemed to play an important role in visceral pain and hypersensitivity (Ford, 2012). Under physiological or pathological conditions, ATP is released from epithelial cells in response to distension of hollow organs (e.g., bladder, gut, and lung) and then activates the P2X3 receptor of peripheral afferent terminals to conduct the chemical and nociceptive sensory (Burnstock, 2001). ...
Background: Clinical investigation indicates a high level of co-morbidity between bladder overactivity and irritable bowel syndrome. The cross-sensitization of afferent pathways has been demonstrated to be the main reason for the cross-organ sensitization, but the underlying mechanism is unclear.
Methods: A single dose of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) was applied to induce the colitis rat models by intracolonic administration. All rats were randomly divided into three groups: control, TNBS-3-day, and TNBS-7-day groups. Western blot and immunofluorescent staining were performed to detect the expression of the P2X3 receptor. The spontaneous contractions of the detrusor strip were measured to evaluate the detrusor contractility function. The micturition function was measured by a cystometry experiment. The intercontractile interval (ICI) and maximum bladder pressure (BP) were recorded.
Results: The distal colon from colitis showed serious tissue damage or chronic inflammation after TNBS instillation ( p < 0.01). However, there were no detectable histological changes in bladder among groups ( p > 0.05). TNBS-induced colitis significantly increased P2X3 receptor expression on the myenteric and submucosal plexus of the distal colon and urothelium of the bladder, especially at day 3 post-TNBS ( p < 0.05). Meanwhile, the expression of the P2X3 receptor on DRG neurons was increased in TNBS-induced colitis ( p < 0.01). The detrusor strip of rats exhibited detrusor overactivity after days 3 and 7 of TNBS administration ( p < 0.01), but inhibition of the P2X3 receptor had no effect ( p > 0.05). Moreover, the rats with colitis exhibited the micturition pattern of bladder overactivity, manifested by decreased ICI and increased maximum BP ( p < 0.05). Interestingly, inhibition of the P2X3 receptor by intrathecal injection of A-317491 alleviated bladder overactivity evoked by TNBS-induced colitis ( p < 0.05).
Conclusion: The upregulation of the P2X3 receptor in an afferent pathway involved in bladder overactivity evoked by TNBS-induced colonic inflammation, suggesting that the P2X3 receptor antagonist may be an available and novel strategy for the control of bladder overactivity.
... [1,3] Alternatively, P2X3 receptor expression is abundant in primary afferent neurons corresponding to its nociceptive function. [5,6] The P2Y receptors are a family of G protein-coupled receptors of which eight mammalian subtypes have been identified. [7] Two subfamilies are described as the Gq-coupled P2Y1-like (P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11) and the Gi-coupled P2Y12-like (P2Y12, P2Y13, P2Y14) receptors. ...
... [6] Due to P2 purinergic receptor involvement in various pain states, P2 receptor antagonism has been investigated for pain management in pre-clinical studies and clinical trials. [5,27] For example, P2X3 antagonist AF-315 produced dose-dependent anti-hyperalgesia in both an adjuvant-induced arthritis rat model and a rat model of knee osteoarthritis. [5] Kidney P2 purinergic receptor expression in the kidney has been reported in mice, rats, and in human primary mesangial and visceral glomerular epithelial cells (Table 1). ...
... [5,27] For example, P2X3 antagonist AF-315 produced dose-dependent anti-hyperalgesia in both an adjuvant-induced arthritis rat model and a rat model of knee osteoarthritis. [5] Kidney P2 purinergic receptor expression in the kidney has been reported in mice, rats, and in human primary mesangial and visceral glomerular epithelial cells (Table 1). [28][29][30] Purinergic signaling is well-studied in the normal function of the kidney, particularly in blood pressure regulation (Fig. 2). ...
P2 purinergic receptors are involved in the normal function of the kidney, bladder, and prostate via signaling that occurs in response to extracellular nucleotides. Dysregulation of these receptors is common in pathological states and often associated with disease initiation, progression, or aggressiveness. Indeed, P2 purinergic receptor expression is altered across multiple urologic disorders including chronic kidney disease, polycystic kidney disease, interstitial cystitis, urinary incontinence, overactive bladder syndrome, prostatitis, and benign prostatic hyperplasia. P2 purinergic receptors are likewise indirectly associated with these disorders via receptor-mediated inflammation and pain, a common characteristic across most urologic disorders. Furthermore, select P2 purinergic receptors are overexpressed in urologic cancer including renal cell carcinoma, urothelial carcinoma, and prostate adenocarcinoma, and pre-clinical studies depict P2 purinergic receptors as potential therapeutic targets. Herein, we highlight the compelling evidence for the exploration of P2 purinergic receptors as biomarkers and therapeutic targets in urologic cancers and other urologic disease. Likewise, there is currently optimism for P2 purinergic receptor-targeted therapeutics for the treatment of inflammation and pain associated with urologic diseases. Further exploration of the common pathways linking P2 purinergic receptor dysregulation to urologic disease might ultimately help in gaining new mechanistic insight into disease processes and therapeutic targeting.
... P2X3R, a subtype of the ATP-gated cation channel P2XR family, has been reported to be closely related to neuropathological diseases, such as pain and chronic cough, as it is predominantly expressed in primary sensory neurons, especially nociceptive neurons [12][13][14]. In various animal studies, the local injection of ATP into rats induced nociceptive behaviors and caused thermal and mechanical hypersensitivity [15][16][17]. ...
... Furthermore, several investigations of P2X3R functions revealed the downregulation of P2X3R expression by antisense oligonucleotides or short interfering RNA [18][19][20], and inhibition of P2X3R by selective antagonists [21,22] in animal models of neuropathic and inflammatory pain attenuated pain responses, such as allodynia and hyperalgesia. In addition to neuropathic and inflammatory pain, neuronal hypersensitivity caused by P2X3R activation plays a key role in other diseases, such as overactive bladder and airway hyperreactivity [13,23,24]. ...
Artificial intelligence (AI) has been recognized as a powerful technique that can accelerate drug discovery during the hit compound identification step. However, most simple deep learning models have been used for naive pre-filtering as the prediction result cannot be interpreted. Recently, our group developed a new deep learning model (Highlight on Target Sequence; HoTS) that can predict binding regions in a target protein sequence based on patterns learned from interactions between a target protein sequence and a ligand. In this study, we searched for new binding regions of the P2X3 receptor (P2X3R) using HoTS, and suggested a novel putative binding site of P2X3R by a cavity search on the predicted binding regions. The novel putative binding site was employed to generate pharmacophore features, and combinations of pharmacophore features were validated as queries. Two separate virtual screenings using the optimized pharmacophore query Q12 with docking-based scoring and HoTS-based prediction of ligand interactions enabled the initial selection of the compound library for in vitro screening. The screening of each set of 500 compounds from the two approaches (HoTS interaction prediction and Pharmacophore-LibDock cascade) resulted in the identification of 10 (HoTS-1 – 10) and 6 compounds (PD-1 – 6) with low micromolar IC50 values. Remarkably, the hit rate was 10-fold higher than that from the previous random screening of 8364 compound library, and the chemical structures of all identified hit compounds were distinct from those of known P2X3R antagonists, indicating that novel chemical entities could be developed for P2X3R antagonists by targeting the binding site. Overall, this study suggests the discovery of a novel putative binding site for P2X3R using the AI deep learning protocol along with in silico MD simulation and experimental screening of targeted library compounds to successfully identify 16 unique and novel hit compounds. These results may accelerate the discovery of novel chemical-class drugs for P2X3R antagonists.
... Previous research has demonstrated that the cough reflex is partially initiated by the C-fibers of the vagus nerve, and preclinical studies suggest that inhibiting the P2X3 receptor along the C-fibers blocks the cough response without interfering with the protective function of cough. [3][4][5] Thus, the P2X3 receptor has emerged as a potential therapeutic target for treatment of chronic cough. Gefapixant is a nonnarcotic, small-molecule inhibitor of the P2X3 receptor being developed for treatment of RCC or UCC. ...
Gefapixant is a P2X3‐receptor antagonist being developed for treatment of refractory or unexplained chronic cough. Four phase 1 studies were conducted in healthy participants that bridged the early‐phase gefapixant formulation (F01) to the phase 3 (F04A) and intended commercial (F04B) formulations. In addition, food and proton pump inhibitor (PPI) coadministration effects on gefapixant exposure were assessed. The gefapixant free base formulation (F01) was used in the initial early‐phase clinical studies. Adding citric acid to the F01 formulation (to generate F02) enhanced drug solubilization, resulting in similar bioavailability and mitigating food and gastric pH effects. The subsequently developed gefapixant citrate salt formulation (F04) achieved exposures that were comparable to F02 in the fed state (90%CIs of geometric mean ratios for area under the plasma concentration–time curve from time 0 extrapolated to infinity and maximum observed concentration were within 0.80 and 1.25) and were not meaningfully affected by food or PPIs (90%CIs of geometric mean ratios for area under the plasma concentration–time curve from time 0 extrapolated to infinity and maximum observed concentration were within 0.80 and 1.25). Minor compositional changes were made to generate the F04A and F04B formulations. In vitro dissolution studies were used to bridge F04 to F04A, and clinical bioequivalence was then established between F04A and F04B. These data support use of the proposed commercial gefapixant formulation without significant food and PPI effects.
... Furthermore, high levels of PEG2 are observed in UUI and is considered as a potential target for future treatment. Urinary adenosine triphosphate (ATP) is also involved in contraction and relaxation of the detrusor muscle, and in patients with OAB, it may be overexpressed or its concentration in urine may change [47,48]. Urinary b3-adrenoceptor (B3-AR) is involved in detrusor relaxation, and the Trp64Arg polymorphism in B3-AR is closely related to DO [49]. ...
Urine is no longer considered to be sterile. After the existence of the microbiome was revealed through metagenomic analysis using next-generation sequencing, the relationship between characteristics of the microbiome and diseases have been studied and published in various journals. A microbiome exists in the urinary tract and is associated with urinary tract infection, malignancy of the genitourinary tract, and lower urinary tract symptoms. Based on the urine sampling method, sampling site, culture method, and sex, the characteristics of the microbiome vary. Most of the Lactobacillus species are identified mainly in women, and various other species are identified in men. These microorganisms can cause or prevent various diseases. Variations in the microbiome are seen in those with and without disease, and an asymptomatic status does not indicate the absence of microbes. This microbiome has been implicated in a variety of lower urinary tract symptoms and diseases, in particular, overactive bladder. The microbiome differs between patients with urgency and urge urinary incontinence and healthy individuals. There are many aspects of the microbiome yet to be studied in relation to other lower urinary tract symptoms.
... 5-11 P2X3 receptor antagonists that block overactivation of these neurons could therefore offer a new approach to the management of many of these conditions. 6 Gefapixant, developed by Merck, initially established proof-ofconcept for the targeting of P2X3 in patients with RCC; however, gefapixant produces reversible and selective P2X3 and P2X2/3 receptor antagonism, 12 and taste-related adverse events (AEs) were common with this agent. [13][14][15][16][17] These taste-related AEs have since been attributed to off-target effects on the P2X2/3 heterotrimer receptor, which is involved in taste perception. ...
Aim:
Neuronal hypersensitisation due to ATP-dependent P2X3 receptor signalling plays a significant role in several disorders including chronic cough and endometriosis. This first-in-human study of eliapixant (BAY 1817080) investigated the tolerability, safety and pharmacokinetics (PK) of single doses of eliapixant, including the effect of food and co-administration with a CYP3A inhibitor on eliapixant relative bioavailability.
Methods:
In this randomised, double-blind phase I study (NCT02817100), 88 healthy male subjects received single ascending doses of immediate-release eliapixant (10-800 mg) tablets or placebo under fasted conditions, with food (low-fat continental or high-fat American breakfast) or with itraconazole (fasted state). PK parameters, dose proportionality, adverse events (AEs) and taste assessments (taste strips; dysgeusia questionnaire) were evaluated.
Results:
Eliapixant had a long half-life (23.5-58.9 hours [fasted state]; 32.8-43.8 [high-fat breakfast]; 38.9-46.0 hours [low-fat breakfast]). Less than dose-proportional increases in maximum plasma concentrations (Cmax ) and area under the concentration-time curve from time 0 to infinity (AUC[0-inf] ) were observed with ascending eliapixant doses. We observed a pronounced food effect with the high-fat breakfast (4.1-fold increased Cmax ; 2.7-fold increased AUC[0-inf] ), a smaller food effect with the low-fat breakfast and a mild-to-moderate effect of itraconazole co-administration on eliapixant (1.1-1.2-fold increased Cmax ; 1.7-fold increased AUC from 0 to 72 hours). Eliapixant was well tolerated with minimal impact on taste perception.
Conclusion:
The PK profile, particularly the long half-life, and favourable tolerability with no taste-related AEs, supports the further development of eliapixant in disorders with underlying P2X3 receptor-mediated neuronal hypersensitisation.
... 4 ATP released by damaged, stressed, or inflamed tissues in airways stimulates C fiber sensory nerves through P2X3, initiating a cough reflex. 5 Blockade of extracellular ATP signaling through P2X3 receptors reduces sensory-nerve activation and cough in pre-clinical models, [6][7][8] and data from clinical trials suggest gefapixant can have a similar effect in patients. [9][10][11] In non-clinical studies in animals, gefapixant was eliminated primarily by renal excretion of the parent drug. ...
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 [14C]gefapixant to six healthy adult males. Following a single‐oral [14C]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 [14C]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.
