Randomised clinical trial: Safety, tolerability, pharmacodynamics and pharmacokinetics of zastaprazan (JP‐1366), a novel potassium‐competitive acid blocker, in healthy subjects

Hwang, Inyoung; Ji, Sang Chun; Oh, Jaeseong; Kim, Hyojin; Cha, Hyunju; Kim, John; Lee, Chang-Suck; Yu, Kyung‐Sang; Lee, SeungHwan

doi:10.1111/apt.17406

Cited by 18 publications

(21 citation statements)

References 40 publications

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“…Acid‐reducing agents, such as P‐CABs and PPIs, have a clear exposure–response relationship 17,22,30 . Similarly, in this study, we observed a clear exposure–response relationship for the gastric pH parameter following the administration of various combinatorial formulations of tegoprazan (Figure S2).…”

Section: Discussionsupporting

confidence: 79%

“…Acid-reducing agents, such as P-CABs and PPIs, have a clear exposure-response relationship. 17,22,30 Similarly, in this study, we observed a clear exposure-response relationship for the gastric pH parameter following the administration of various combinatorial formulations of tegoprazan (Figure S2). Thus, it is suggested that maintaining long-term systemic exposure of tegoprazan is an essential prerequisite for achieving sufficient efficacy in preventing NAB.…”

Section: Discussionsupporting

confidence: 78%

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Pharmacokinetic and pharmacodynamic exploration of various combinations of tegoprazan immediate and delayed‐release formulations

Park

Yang

Kim

et al. 2023

Brit J Clinical Pharma

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AimsThe new modified‐release formulation of tegoprazan, a novel potassium‐competitive acid blocker, is expected to improve the management of acid‐related disease, including nocturnal acid breakthrough, by prolonging the duration of acid suppression. This study aimed to explore the pharmacokinetics (PK) and pharmacodynamics (PD) of various combinations of tegoprazan with immediate‐release (IR) and delayed‐release (DR) formulations.MethodsA three‐cohort, open‐label, randomized, single‐dose, three‐treatment, six‐sequence, three‐period crossover study was conducted. Various combinations of tegoprazan IR and DR formulations (50, 75 or 100 mg) were administered orally once per period. The 24‐h intragastric pH was monitored before and after each administration. PK blood samples were collected for up to 48 h. PK and PD were compared among treatments.ResultsEighteen healthy Korean subjects completed the study. All treatment groups showed intragastric pH above 4 approximately 1 h following tegoprazan administration. Among the various combinations, the IR and DR combination at a 1:1 ratio induced greater gastric acid suppression (%Time pH ≥ 4) than IR alone in each dose group, both for 24 h (50 mg; 59% vs. 52%, P = .2188, 95% confidence interval [CI] −6.92–22.27, 100 mg; 85% vs. 70%, P < .05, 95% CI 8.92–22.19) and at night (50 mg; 27% vs. 16%, P = .1563, 95% CI −11.79–37.71, 100 mg; 77% vs. 49%, P < .05, 95% CI 16.14–42.98), with similar systemic exposure.ConclusionsThe combinatorial tegoprazan in the IR and DR 1:1 ratio formulation was found to induce stronger gastric acid suppression throughout the day and at night, compared to the conventional IR formulation.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionsupporting

confidence: 78%

Pharmacokinetic and pharmacodynamic exploration of various combinations of tegoprazan immediate and delayed‐release formulations

Park

Yang

Kim

et al. 2023

Brit J Clinical Pharma

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“…However, a recent study showed that the pharmacokinetics and pharmacodynamics of fexuprazan were similar in healthy participants of different ethnicities (Korean, Japanese, and Caucasian). 23 Therefore, fexuprazan would have similar efficacy in people of other ethnicities. Second, to investigate the effect of fexuprazan, we included the following endoscopic findings of gastritis: erosion, edema, redness, and hemorrhage, with erosion as the main endoscopic finding analyzed.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Fexuprazan in Patients with Acute or Chronic Gastritis

et al. 2023

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Background/Aims: Fexuprazan is a novel potassium-competitive acid blocker that could be of benefit to patients with gastric mucosal injury. The aim of this study was to assess the 2-week efficacy and safety of fexuprazan in patients with acute or chronic gastritis. Methods:In this study, 327 patients with acute or chronic gastritis who had one or more gastric erosions on endoscopy and subjective symptoms were randomized into three groups receiving fexuprazan 20 mg once a day (q.d.), fexuprazan 10 mg twice a day (b.i.d.), or placebo for 2 weeks. The posttreatment assessments were the primary endpoint (erosion improvement rate), secondary endpoints (cure rates of erosion and edema and improvement rates of redness, hemorrhage, and subjective symptoms), and drug-related adverse events.Results: Among the patients, 57.8% (59/102), 65.7% (67/102), and 40.6% (39/96) showed erosion improvement 2 weeks after receiving fexuprazan 20 mg q.d., fexuprazan 10 mg b.i.d., and placebo, respectively. Both fexuprazan 20 mg q.d. and 10 mg b.i.d. showed superior efficacy to the placebo (p=0.017 and p<0.001, respectively). Likewise, both fexuprazan 20 mg q.d. and 10 mg b.i.d. also showed higher erosion healing rates than the placebo (p=0.033 and p=0.010, respectively). No difference was noted in the edema healing rate and the improvement rates for redness, hemorrhage, and subjective symptoms between the fexuprazan and placebo groups. No significant difference was noted in the incidence of adverse drug reactions.Conclusions: Fexuprazan 20 mg q.d. and 10 mg b.i.d. for 2 weeks showed therapeutic efficacy superior to that of placebo in patients with acute or chronic gastritis (ClinicalTrials.gov identifier NCT04341454).

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“…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). 9 …”

Section: P‐cab Serum Gastrin Elevationmentioning

confidence: 99%

“…Declaration of personal interests : The authors' declarations of personal and financial interests are unchanged from those in the original article 9 …”

Section: Acknowledgementsmentioning

confidence: 99%

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

Hwang

Lee

2023

Aliment Pharmacol Ther

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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).

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Randomised clinical trial: Safety, tolerability, pharmacodynamics and pharmacokinetics of zastaprazan (JP‐1366), a novel potassium‐competitive acid blocker, in healthy subjects

Cited by 18 publications

References 40 publications

Pharmacokinetic and pharmacodynamic exploration of various combinations of tegoprazan immediate and delayed‐release formulations

Pharmacokinetic and pharmacodynamic exploration of various combinations of tegoprazan immediate and delayed‐release formulations

Efficacy and Safety of Fexuprazan in Patients with Acute or Chronic Gastritis

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

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