Editorial: deja vu all over again – let the P‐CAB wars begin. Authors' reply

Abstract

We appreciate Dr. Metz's insightful comments on the development and clinical use of various potassium-competitive acid blockers (P-CABs). While P-CABs are considered as potential substitutes for proton pump inhibitors (PPIs), there are concerns regarding the risk of hypergastrinaemia in patients on long-term P-CABs.Vonoprazan, the first P-CAB to be approved in Japan, causes marked increase in serum gastrin compared with PPIs including esomeprazole and lansoprazole. Vonoprazan 20 mg once-daily increased gastrin level to over 500 pg/mL after 1 week and to about 300 pg/mL after 8 weeks, which were over 2-fold and about 1.5-fold greater than with esomeprazole and lansoprazole, respectively (Table 1). 1,2 One possible explanation for this phenomenon could be binding selectivity to gastric H + /K + ATPase. The discharge of vonoprazan into the lumen is inhibited by both its deep binding site on the proton pump and an electrostatic barrier that is formed at the pump's inlet. 3 This may result in slow dissociation and prolonged inhibition of gastric acid secretion, which contribute to the elevated gastrin level. 4 In contrast, other P-CABs such as tegoprazan and fexuprazan have shown comparable increases in serum gastrin levels to esomeprazole, despite their more potent inhibition of gastric acid secretion. [5][6][7][8] Tegoprazan increased serum gastrin level to about 200 pg/mL after administration of 200 mg once-daily for 1 week, while esomeprazole 40 mg increased serum gastrin to about 200 pg/mL. Similarly, fexuprazan increased serum gastrin level to about 200 and 150 pg/mL after administration of 40 mg once-daily for 1 and 8 weeks, respectively, while esomeprazole 40 mg increased serum gastrin to about 200 and 150 pg/mL, respectively. In our publication, maximum dosage of zastaprazan in multiple administration (40 mg once-daily) increased mean serum gastrin level to 211.4 pg/mL (SD 89.7) after 1 week, which was comparable to esomeprazole (253.1 ± 170.3 pg/mL; Table 1). 9These data on serum gastric elevation are limited due to the study population (mostly healthy subjects) and short-term usage.Therefore, further studies are needed to elucidate quantitatively the degree of reflex hypergastrinaemia with P-CABs, especially through long-term studies with head-to-head comparison to PPIs.While there are concerns about the risk of hypergastrinaemia associated with P-CABs, it is not clear whether this occurs with all P-CABs. It is important to exercise caution regarding the potential risk of hypergastrinaemia in the clinical use of P-CABs until more data become available. AUTH O R CO NTR I B UTI O N SInyoung Hwang: Conceptualization (equal); data curation (equal); writing -original draft (equal). SeungHwan Lee: Conceptualization (equal); data curation (equal); project administration (lead); supervision (lead); writing -original draft (equal); writing -review and editing (lead).