Potassium-competitive acid blockers and gastroesophageal reflux disease

Table 1 Main differences in the mechanisms of action between proton pump inhibitors and potassium-competitive acid blockers[12]

Proton pump inhibitors	Potassium-competitive acid blockers
Prodrug requires transformation to the active form, sulphenamide	Direct action on the H+/K+ ATPase after protonation
Sulphenamide binds covalently to H+/K+-ATPase	P-CABs bind competitively to the K+ binding site of H+/K+-ATPase
Irreversible binding to the proton pump	Reversible binding to the proton pump
The full effect after repeated doses	The full effect after the first dose
PK affected by genetic polymorphism	PK not affected by genetic polymorphism
PD effect more significant during the daytime	PD effect lasting for both the daytime and nocturnal hours
Meal-dependent antisecretory activity	Meal-independent antisecretory activity
Concentrate in parietal cell acid space (1000-fold higher than in plasma)	Super concentrates in parietal cell acid space (100000-fold higher than in plasma)
Duration of effect related to the half-life of the sulphenamide-enzyme complex	Duration of effect related to the half-life of the drug in plasma

P-CAB: Potassium-competitive acid blocker; PD: Pharmacodynamic; PK: Pharmacokinetic.

Table 2 Clinical studies regarding the efficacy of potassium-competitive acid blocker in gastroesophageal reflux disease treatment

Ref.	Country/region	Study design	Patients, n	Diagnosis	Treatment groups	Duration of treatment, wk	Clinical outcomes
Ashida et al[42]	Japan	Multicenter, randomized, double-blind	732	EE	LPZ 30 mg; VPZ 5 mg; VPZ 10 mg; VPZ 20 mg; VPZ 40 mg	8	All VPZ regimens were non-inferior to LPZ 30 mg treatment. The proportions of healed EE subjects were 87.3%, 86.4%, 100%, 96.0%, and 87.0% with VPZ 5, 10, 20, 40 mg, and LPZ 30 mg, respectively
Ashida et al[43]	Japan	Multicenter, randomized, double-blind	607	EE	LPZ 15 mg; VPZ 10 mg; VPZ 20 mg	24	The EE recurrence rates were 16.8%, 5.1%, and 2.0% with LPZ 15 mg, VPZ 10 mg, and VPZ 20 mg, respectively, over the 24-wk maintenance period
Shinozaki et al[47]	Japan	Retrospective cohort	55	NERD = 30; EE = 25	VPZ 10 mg	4	The VPZ 10 mg for 1-mo alleviated GERD symptoms in 89% and were sustained in 82% after 1 yr without further therapy
Oshima et al[48]	Japan	Randomized placebo control	32	EE	LPZ 30 mg; VPZ 20 mg	2	The heartburn was relieved earlier with VPZ than with LPZ, and it was completely relieved in 31.3% and 12.5% of patients on day 1 with VPZ and LPZ, respectively
Akiyama et al[49]	Japan	Retrospective cohort with prospective study	13	PPI-refractory GERD	PPIs switch to VPZ 20 mg	8	The median gastric acid exposure times of the VPZ 20 mg were lower than the median gastric acid exposure times of the PPI treatment in both daytime and nocturnal observations. The VPZ 20 mg outperforms PPIs in stomach acid suppression, EAE control, symptom alleviation, and esophagitis healing in patients with PPI-refractory GERD
Mizuno et al[50]	Japan	Open-label, single-center, prospective study	50	PPI-refractory RE	PPIs switch to VPZ 20 mg for 4 wk and VPZ 10 mg	48	VPZ 10 mg prevented the recurrence of esophageal mucosal breaks in 43 of 50 (86.0%) patients. VPZ 10 mg is clinically efficacious for the long-term maintenance of healed RE
Xiao et al[51]	China, South Korea, Taiwan, Malaysia	Phase III, double-blind, multicenter study	481	EE	LPZ 30 mg; VPZ 20 mg	8	The 8-wk EE healing rates in the VPZ and LPZ groups were 92.4% and 91.3%, respectively. VPZ 20 mg was not inferior to LPZ 30 mg in EE healing at 8 wk
Okanobu et al[52]	Japan	Randomized control study	73	EE	VPZ 10 mg; VPZ 20 mg	Each dose for 4 wk and VPZ 10 mg for 8 wk	VPZ 10 mg had the same result as VPZ 20 mg in mucosal healing and symptom reduction at 4 wk and throughout the trial
Matsuda et al[53]	Japan	Multicenter, randomized, cross-over study	122	Erosive GERD	VPZ 10 mg; LPZ 15 mg	Every 2nd day for 4 wk and cross-over for more 4 wk	GERD symptoms were significantly reduced with VPZ 10 mg every other day, as measured by the FSSG and the gastrointestinal symptom rating scale
Lee et al[54]	South Korea	Randomized, double-blind, parallel-group comparison study	302	EE	TPZ 50 mg; TPZ 100 mg; EPZ 40 mg	4 and 8	At week 8, the cumulative healing rates for TPZ 50 mg, TPZ 100 mg, and EPZ 40 mg were 98.9%, 98.9%, and 98.9%, respectively
Kim et al[55]	South Korea	Phase III, double-blind, placebo-controlled, multicenter study	324	NERD	TPZ 50 mg; TPZ 100 mg; placebo	4	The proportions of heartburn-free days and full-resolution rates of heartburn were significantly higher in both TPZ groups than in the placebo group
Lee et al[56]	South Korea	Phase III, multicenter, randomized, double-blind trial	260	EE	FPZ 40 mg; EPZ 40 mg	8	FPZ 40 mg was non-inferior to EPZ 40 mg. FPZ 40 mg provided better symptom relief in patients with moderate to severe heartburn, with the effect lasting throughout the night

EAE: Esophageal acid exposure; EE: Erosive esophagitis; EPZ: Esomeprazole; FPZ: Fexuprazan; FSSG: Frequency scale for the symptoms of gastroesophageal reflux disease; GERD: Gastroesophageal reflux disease; LPZ: Lansoprazole; NERD: Non-erosive reflux disease; PPI: Proton pump inhibitor; RE: Reflux esophagitis; TPZ: Tegoprazan; VPZ: Vonoprazan.