Mechanism of resistance to Gefapixant Citrate

Gefapixant Citrate (Gefapixant Citrate) is a selective P2X3 receptor antagonist, mainly used to treat refractory or unexplained chronic cough. Its core mechanism of action is different from traditional central antitussives or anti-infective drugs. It reduces cough reflex sensitivity by inhibiting ATP-mediated signaling on peripheral sensory nerve endings. Therefore, the so-called "drug resistance" is not completely equivalent to gene mutation resistance in antibiotics or targeted tumor drugs, but is more caused by the adaptability of neural pathways and the pathological heterogeneity of chronic cough.

In clinical observation, some patients' cough symptoms improved significantly when they were initially treated with Gemfapixen, but as treatment continued, symptom control may gradually weaken. This phenomenon may be related to compensatory activation of neural pathways. After the P2X3 receptor is inhibited for a long time, other receptors or pathways involved in the cough reflex, such as P2X2/3 heterologous receptors and other purinergic receptors, may be passively enhanced, thereby weakening the overall effect of the drug. At the same time, chronic cough itself is highly heterogeneous, and the pathological mechanisms of different patients vary greatly, including differences in the degree of airway inflammation, nerve remodeling, and central sensitization levels. This is also one of the reasons for the decline in efficacy in some patients.

In addition, persistent triggers of chronic cough may also affect the effectiveness of medications. For example, if gastroesophageal reflux, environmental allergens, chronic rhinitis, or airway irritation are not effectively controlled, overall cough symptoms may recur even if peripheralP2X3 receptors are inhibited. Overseas experts pointed out that this type of "functional resistance" is different from real drug failure. Its core lies in the complexity of the disease and the plasticity of neural networks.

In general, the problem of drug resistance to Gemfapixin is mainly reflected in the adaptive changes of the neural regulatory network and the diversity of pathological mechanisms, rather than simple receptor mutations or drug failure.

Reference materials:https://ec.europa.eu/health/documents/community-register/2023/20230915160172/anx_160172_en.pdf