Gefapixant

Biological Activity

Gefapixant (AF-219) is an orally active small molecule antagonist at human P2X3-containing receptors, with IC50s of ~30 nM versus recombinant hP2X3 homotrimers and 100-250 nM at hP2X2/3 heterotrimeric receptors. 

In vivo, in a rat model of knee osteoarthritis (14d following intra-articular administration of monoiodoacetate), Gefapixant (7d bid, orally; right) attenuates the weight bearing laterality with complete reversal of apparent hyperalgesia at the two higher doses.

Protocol

Cell Experiment
Cell lines
Preparation method
Concentrations
Incubation time

Animal Experiment
Animal models	Rats
Formulation
Dosages	6, 20, and 60 mg/kg two times a day and continues up to a week
Administration	by intraplantar or oral

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information

References

P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study.
Abdulqawi R, et al. Lancet. 2015 Mar 28;385(9974):1198-205. PMID: 25467586.

The therapeutic promise of ATP antagonism at P2X3 receptors in respiratory and urological disorders.
Ford AP, et al. Front Cell Neurosci. 2013 Dec 19;7:267. PMID: 24391544.

In pursuit of P2X3 antagonists: novel therapeutics for chronic pain and afferent sensitization.
Ford AP, et al. Purinergic Signal. 2012 Feb;8(Suppl 1):3-26. PMID: 22095157.