Chemical formula: C₁₄H₁₉N₅O₄S Molecular mass: 353.4 g/mol PubChem compound: 24764487
Gefapixant is a selective antagonist of the P2X3 receptor. Gefapixant also has activity against the P2X2/3 receptor subtype. P2X3 receptors are ATP-gated ion channels found on sensory C fibres of the vagus nerve in the airways. C fibres are activated in response to inflammation or chemical irritants. ATP is released from airway mucosal cells under conditions of inflammation. Binding of extracellular ATP to P2X3 receptors is sensed as a damage signal by C fibres. Activation of C fibres, which is sensed by the patient as an urge to cough, initiates a cough reflex. Blockade of ATP signalling through P2X3 receptors reduces excessive sensory-nerve activation and excessive cough induced by extracellular ATP.
The pharmacokinetics of gefapixant were studied in healthy adults and in adults with RCC or UCC and were similar between these two populations. The steady-state mean plasma AUC and peak concentration (Cmax) are 4,144 ng∙hr/mL and 531 ng/mL with gefapixant 45 mg twice daily treatment. Steady state is achieved within 2 days, with an accumulation ratio of 1.4- to 1.5-fold.
Following oral administration of gefapixant, the time to achieve peak plasma concentrations (Tmax) ranged from 1 to 4 hours. Exposure increases are dose-proportional following multiple doses up to 300 mg twice daily. The fraction absorbed for gefapixant is at least 78%.
Relative to fasting conditions, oral administration of a single dose of gefapixant 50 mg with a standard high fat and high calorie meal had no effect on the AUC or Cmax of gefapixant. Distribution Based on population pharmacokinetic analyses, the mean steady-state apparent volume of distribution is estimated to be 138 L following oral administration of a 45 mg dose.
In vitro, gefapixant exhibits low plasma protein binding (55%) and has a blood-to-plasma ratio of 1.1. Based on preclinical studies, gefapixant has low CNS penetration.
Hepatic metabolism is a minor route of gefapixant elimination, involving oxidation and glucuronidation. Following oral administration of [14C] gefapixant, 14% of the administered dose was recovered as metabolites in the urine and faeces. Unchanged gefapixant is the major drug-related component in plasma (87%), and each circulating metabolite accounted for less than 10% of the total radioactivity detected.
Renal excretion is the major route of elimination of gefapixant and involves both passive renal filtration and active transport mechanisms. Gefapixant is recovered in urine as parent (~64%) or metabolites (~12%), and the remainder is recovered in feces as parent (~20%) or metabolites (~2%). Active renal secretion is estimated to account for ≤50% of total elimination. In vitro, gefapixant is a substrate of MATE1, MATE2K, P-gp, and BCRP transporters. Gefapixant has a terminal half-life (t½) of 6-10 hours.
Renal excretion is the major route of elimination of gefapixant. Mild or moderate renal impairment (eGFR ≥30 mL/minute/1.73 m²) does not have a clinically meaningful effect on the exposure of gefapixant.
In a population pharmacokinetic analysis including patients with refractory or unexplained chronic cough, the mean AUC and Cmax of gefapixant were predicted to increase by 89% and 54%, respectively, in patients with severe renal impairment (eGFR <30 mL/minute/1.73 m²) compared to those with normal renal function. To maintain similar systemic exposures to those with normal renal function, dose adjustment is recommended.
Hepatic metabolism is a minor route of elimination. Most of an oral dose was recovered as unchanged parent in the urine (64%) or faeces (20%). A dedicated study in subjects with hepatic impairment was not conducted, because hepatic impairment is not likely to have a clinically meaningful effect on exposure.
Based on a population pharmacokinetic analysis, age, body weight, gender, ethnicity, and race do not have a clinically meaningful effect on the pharmacokinetics of gefapixant.
Effects of other medicinal products on the pharmacokinetics of gefapixant Hepatic metabolism is a minor pathway for gefapixant elimination, and the potential for clinically meaningful drug interactions for gefapixant with co-administration of inhibitors or inducers of cytochrome P450 (CYP) or uridine 5'-diphosphoglucuronic acid glucuronosyl transferase (UGT) enzymes is low.
Concomitant use of a proton pump inhibitor, omeprazole, did not have a clinically meaningful effect on gefapixant pharmacokinetics.
Based on in vitro studies, gefapixant is a substrate of efflux transporters multidrug and toxin extrusion 1 (MATE1), MATE2K, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). In a Phase 1 clinical study, a single dose of the MATE1/MATE2K inhibitor pyrimethamine increased gefapixant AUC by 24%, an amount that is not clinically meaningful, and did not affect gefapixant Cmax.
Based on in vitro studies, the potential of gefapixant to cause CYP inhibition or induction is low, and therefore it is unlikely that gefapixant would affect the CYP-mediated metabolism of other drugs. Gefapixant is an inhibitor of MATE1, MATE2K, and organic anion-transporting polypeptide 1B1 (OATP1B1) and OATP1B3 in vitro. However, the risk of clinically meaningful drug interactions via inhibition of these transporters is low for gefapixant administered at 45 mg twice daily. The clinical relevance of in vitro inhibition of organic cation transporter 1 (OCT1) by gefapixant is not established. In a Phase 1 clinical study, multiple doses of gefapixant 45 mg did not affect exposure of the OATP1B substrate pitavastatin.
Crystalluria occurred in laboratory animals dosed with gefapixant and the majority of the urinary crystals were confirmed to be composed of gefapixant.
In a six month repeat-dose toxicity study in rats, microscopic changes in the kidney (distended tubules due to presence of crystalline material, degeneration of epithelial cells lining tubules and inflammation in the interstitium), ureter (dilatation and inflammation) and bladder (transitional cell hyperplasia) were observed at 9 times the exposure in humans at the maximum recommended human dose (MRHD).
In a nine-month repeat-dose oral toxicity study in dogs, crystals were observed in the urine and microscopic observation of focal, minimal tubular degeneration, involving occasional cortical tubules was observed in one male dog at 35 times the exposure in humans at the MRHD.
Carcinogenicity studies in rats (2-years in duration) and rasH2 transgenic mice (6-months in duration) with gefapixant showed no evidence of carcinogenic potential (no treatment related tumours) at exposures up to 9-times (rats) and 4-times (mice) the exposures at the MRHD.
Gefapixant was not genotoxic in a battery of in vitro or in vivo assays including microbial mutagenesis, chromosomal aberration in human peripheral blood lymphocytes and in the in vivo rat micronucleus test.
In animal reproduction studies, oral administration of gefapixant to pregnant rats and rabbits during the period of organogenesis showed no evidence of teratogenicity or embryo-fetal lethality at exposures (AUC) that were 6-times (rats) and 34-times (rabbits) the exposure at the MRHD. A slight reduction in rat fetal weights, which was associated with maternal toxicity, was observed at an exposure approximately 11-times the exposure at the MRHD.
Studies in pregnant rats and rabbits showed that gefapixant is transferred to the foetus through the placenta, with foetal plasma concentrations of up to 21% (rats) and 25% (rabbits) that of maternal concentrations observed on gestation day 20.
In a lactation study, gefapixant was excreted in milk of lactating rats when administered orally (up to 9-times the exposure at the MRHD) on lactation day 10, with milk concentrations 4 times that of maternal plasma concentrations observed 1-hour post dose on lactation day 10. There were no effects on fertility, mating performance or early embryonic development when gefapixant was administered to female and male rats up to 9-times the exposure at the MRHD.
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