For recombinant homotrimeric hP2X1, hP2X2, hP2X4, rP2X5, and hP2X7 channels, the IC50 values are greater than 10,000 nM, indicating that gefapixant has no inhibitory impact on any receptor that contains non-P2X3 subunits [1].

Within 14 days of intra-articular monoiodoacetate injection, gefapixant (7 days bid, oral) totally reversed overt hyperalgesia and decreased weight-bearing laterality at two higher doses in a rat model of knee osteoarthritis [2].

The aryloxy-pyrimidinediamine, Gefapixant/AF-219 (Ford et al., 2013; Smith et al., 2013) is an orally active small molecule (Mol Wt. ∼350 Daltons) antagonist at human P2X3-containing receptors. The inhibitory potency (IC50) of AF-219 has been reported as ∼30 nM versus recombinant hP2X3 homotrimers and 100–250 nM at hP2X2/3 heterotrimeric receptors, potencies very similar to those reported for recombinant rat receptors, and it displays no inhibitory impact on any non-P2X3 subunit containing receptors (IC50 values ≫ 10,000 nM at recombinant homotrimeric hP2X1, hP2X2, hP2X4, rP2X5 and hP2X7 channels). Reports from other related chemical members of this P2X3 selective pyrimidinediamine class have shown that the mechanism of inhibition is non-competitive (allosteric) and have been mixed regarding species-independency of P2X3 receptor potency estimates: AF-353 (Gever et al., 2010) shows remarkable potency congruency between human and rat recombinant P2X3 homotrimers (IC50 values of 8.7 and 8.9 nM, respectively) whereas the more potent analog AF-792 (also referred to as RO-51; developed initially as a potential prodrug for AF-353) was shown to be less potent at human versus rat P2X3 receptors in one report (Serrano et al., 2012) and yet species-independent in another (Jahangir et al., 2009). It is important to note that some selectivity for P2X3 versus P2X2/3 channels has been a common claim across several chemical classes of inhibitors (see Gum et al., 2012: e.g., AF-219 analogs, nucleotides such as TNP-ATP, benzenetricarboxylic acids such as A-317491), although in most studies values reported are not affinity determinations but IC50 estimates. Under such circumstances true selectivity cannot be categorically inferred, especially for the competitive antagonists (such as TNP-ATP and A-317491) as the IC50 is a parameter that will change with agonist concentration used and depends on agonist potency at the different trimers.[1]

Absorption, Distribution and Excretion
The absolute bioavailability of gefapixant has not been evaluated but is estimated to be ≥78%. At the recommended dose of 45 mg twice daily, steady-state is achieved within 2 days and the steady-state mean plasma AUC and Cmax are 4,144 ng∙hr/mL and 531 ng/mL, respectively. The time to peak plasma concentration (Tmax) following oral administration ranges from one to four hours. The co-administration of gefapixant with a high-fat, high-calorie meal had no effect on its AUC or Cmax.
Gefapixant is primarily eliminated via renal excretion. Following a single oral radiolabeled dose in a healthy male subject, approximately 76.4% of the administered radioactivity was recovered in the urine and 22.6% was recovered in the feces. Unchanged parent drug accounted for 64% of the recovered dose in the feces and accounted for 20% of the recovered dose in the urine.
Based on population pharmacokinetic analyses, the estimated steady-state apparent volume of distribution is 133.8 L (Vc 101 L and Vp 32.8 L) following oral twice-daily administration of gefapixant 45 mg.
Population pharmacokinetic analyses integrating data from Phase 1, 2, and 3 data showed a geometric mean apparent clearance (Cl/F) of 10.8 L/h. In clinical pharmacology studies, the observed clearance was 14.8 L/h and renal clearance was approximately 8.7 L/h.

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Metabolism / Metabolites
Gefapixant is relatively minimally metabolized. Following oral administration, only 14% of the administered dose was recovered as metabolites in the urine and feces. Unchanged parent drug is the major (87%) drug-related component in plasma, with circulating metabolites accounting for <10% each. The primary biotransformation pathways observed in gefapixant ADME studies included hydroxylation, O-demethylation, dehydrogenation, oxidation, and direct glucuronidation. Secondary biotransformation pathways included glucuronidation of O-demethylated metabolite as well as the formation of a metabolite that was O-demethylated and hydrogenated. The three most abundant circulating metabolites were: M1 (a glucuronide of O-demethylated gefapixant), M5 (a directly glucuronidated parent) and M13 (a hydroxylated metabolite.), which accounted for 1.0%, 6.3%, and 5.8%, respectively, of the total drug-related components in plasma.

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Biological Half-Life
The terminal half-life of gefapixant is 6-10 hours.

Protein Binding
Gefapixant exhibits relatively low protein binding (55%) _in vitro_, and thus drug-drug interactions resulting from protein displacement are not expected.

[1]. Anthony P. Ford, et al. The therapeutic promise of ATP antagonism at P2X3 receptors in respiratory and urological disorders. Front Cell Neurosci. 2013; 7: 267.
[2]. Ford AP, In pursuit of P2X3 antagonists: novel therapeutics for chronic pain and afferent sensitization. Purinergic Signal. 2012 Feb;8(Suppl 1):3-26.
[3]. Martin Nguyen A, et al. Validation of a visual analog scale for assessing cough severity in patients with chronic cough. Ther Adv Respir Dis. 2021 Jan-Dec;15:17534666211049743

It has been estimated that 5-10% of adults globally suffer from chronic cough, which is defined as a cough lasting longer than eight weeks. A subset of these patients remain symptomatic despite thorough investigation and treatment, termed refractory chronic cough (RCC) if they have a cough that does not respond to conventional treatment or unexplained chronic cough (UCC) when no diagnosable cause for the cough can be determined. Existing treatments for chronic cough have been associated with considerable side effects, in particular opioids such as [codeine] or [dextromethorphan]. Gefapixant is a novel antagonist of the P2X3 receptor that works to reduce the cough reflex in patients with chronic cough. It received approval in both Japan and Switzerland in 2022 for the treatment of adult patients with RCC and UCC, and received subsequent approval in the EU in September 2023 for the same indications. It is the first therapy to be approved for the treatment of RCC or UCC in the EU.

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Drug Indication
Gefapixant is indicated in adult patients for the treatment of refractory or unexplained chronic cough.
Lyfnua is indicated in adults for the treatment of refractory or unexplained chronic cough.

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Mechanism of Action
Gefapixant is a selective antagonist of P2X3 receptors, with some activity against the P2X2/3 receptor subtype. P2X3 receptors are ATP-gated ion channels found on sensory C fibers of the vagus nerve in the airways. Under inflammatory conditions, ATP is released from airway mucosal cells where it can subsequently bind to P2X3 receptors on C fibers. The activation of vagal C fibers is perceived as an urge to cough and initiates a cough reflex. Gefapixant inhibits the binding of ATP to P2X3 receptors, thereby reducing excessive C fiber activation by extracellular ATP and dampening the subsequent cough reflex.

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Pharmacodynamics
Gefapixant exerts its therapeutic effects via suppressing the cough reflex initiated by sensory C fibers of the vagus nerve. In clinical studies, patients experienced a significant reduction in 24-hour cough frequency compared to placebo - this reduction was apparent by Week 4 and persisted throughout the remainder of the primary efficacy period. As renal excretion is the primary route of elimination for gefapixant, patients with severe renal impairment (eGFR < 30 mL/min/1.73m²) may require dose adjustment to maintain appropriate systemic exposures.

C14H19N5O4S

353.39676117897

353.115

C, 47.58; H, 5.42; N, 19.82; O, 18.11; S, 9.07

1015787-98-0

Gefapixant citrate;2310299-91-1

24764487

Typically exists as White to off-white solid at room temperature

1.4±0.1 g/cm3

606.3±65.0 °C at 760 mmHg

320.5±34.3 °C

0.0±1.7 mmHg at 25°C

1.615

0.73

3

9

5

24

512

0

S(C1=CC(=C(C=C1OC)C(C)C)OC1=CN=C(N)N=C1N)(N)(=O)=O

HLWURFKMDLAKOD-UHFFFAOYSA-N

InChI=1S/C14H19N5O4S/c1-7(2)8-4-10(22-3)12(24(17,20)21)5-9(8)23-11-6-18-14(16)19-13(11)15/h4-7H,1-3H3,(H2,17,20,21)(H4,15,16,18,19)

5-(2,4-diaminopyrimidin-5-yl)oxy-2-methoxy-4-propan-2-ylbenzenesulfonamide

AF-219; Gefapixant [USAN]; Benzenesulfonamide, 5-[(2,4-diamino-5-pyrimidinyl)oxy]-2-methoxy-4-(1-methylethyl)-; RO4926219; RG-1646; Ro-4926219;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~5 mg/mL (~14.15 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.07 mM) (saturation unknown) in 10% DMSO + 90% PBS (add these co-solvents sequentially from left to right, and one by one), clear solution.

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Solubility in Formulation 2: ≥ 0.5 mg/mL (1.41 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 5.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 3: ≥ 0.5 mg/mL (1.41 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 5.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 4: ≥ 0.5 mg/mL (1.41 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 5.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)