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Evaluation of pharmacokinetic interactions between amoxicillin, clarithromycin, and the potassium-competitive acid blocker YH4808 in healthy subjects.

ABSTRACT: YH4808 is a novel potassium-competitive acid blocker that was developed as a therapeutic agent for gastric acid-related diseases; it may replace proton pump inhibitors, which are widely used in combination with amoxicillin and clarithromycin for Helicobacter pylori eradication. We compared the pharmacokinetic (PK) profiles and safety of amoxicillin, clarithromycin, and YH4808 used as monotherapies or in combination for evaluating potential drug interactions. An open-label, randomized, single-dose, Latin-square (4 × 4) crossover study was conducted in 32 healthy Korean volunteers. Subjects were randomly assigned to one of the 4 treatment sequences that consisted of 4 periods separated by 21-day washout intervals. PK parameters of YH4808, amoxicillin and clarithromycin administered in combination were compared with those of the respective monotherapies. The geometric mean ratios of the maximum concentration (Cmax) and the area under the time-concentration curve from time zero to time of the last quantifiable concentration (AUClast) of YH4808 increased during the triple therapy by 48.6% and 29.1%, respectively. Similarly, the Cmax and AUClast of M3 (active metabolite of YH4808) increased by 23.3% and 16.0%, respectively. The Cmax and AUClast of clarithromycin increased by 27.4% and 30.5%, and those of 14-hydroxyclarithromycin were increased by 23.1% and 32.4%, respectively. The corresponding amoxicillin values decreased during the triple therapy by 21.5% and 15.6%, respectively. There was no clinically significant change in safety assessment related to either monotherapies or triple therapy. In conclusion, amoxicillin, clarithromycin and YH4808 administered as triple therapy did not exhibit significant PK interactions and were not associated with safety issues. Trial Registration:ClinicalTrials.gov Identifier: NCT01921647.

SUBMITTER: Lee WY

PROVIDER: S-EPMC7136080 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Evaluation of pharmacokinetic interactions between amoxicillin, clarithromycin, and the potassium-competitive acid blocker YH4808 in healthy subjects.

Lee Woo Yul WY Oh EunSil E Cui Mengqi M Kim Choon Ok CO Lim Yeji Y Kim Hunam H Park Hyeonsoo H Yoon Sukyong S Park Min Soo MS Hong Taegon T

Translational and clinical pharmacology 20200331 1

YH4808 is a novel potassium-competitive acid blocker that was developed as a therapeutic agent for gastric acid-related diseases; it may replace proton pump inhibitors, which are widely used in combination with amoxicillin and clarithromycin for <i>Helicobacter pylori</i> eradication. We compared the pharmacokinetic (PK) profiles and safety of amoxicillin, clarithromycin, and YH4808 used as monotherapies or in combination for evaluating potential drug interactions. An open-label, randomized, sin ...[more]

PMID: 32274381

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Project description:BackgroundTransient lower esophageal sphincter relaxations (TLESRs) have been identified as a primary cause of reflux events in patients with gastroesophageal reflux disease (GERD). GABA(B) receptor agonists such as lesogaberan (AZD3355) have been shown to inhibit TLESRs in healthy subjects and patients with GERD, and, therefore, offer a novel therapeutic add-on strategy to acid suppression for the management of GERD. As lesogaberan is being developed as an add-on treatment for the management of patients with GERD who have a partial response to proton pump inhibitor (PPI) therapy, it is important to rule out any clinically important pharmacokinetic drug-drug interaction between lesogaberan and PPIs.ObjectiveTo evaluate the effect of esomeprazole on the pharmacokinetics and safety of lesogaberan and vice versa.Study designThis was an open-label, randomized, three-way crossover study. The study was open to healthy adult male and female subjects. The study subjects received treatment with, in random order, lesogaberan (150 mg twice daily [dose interval 12 hours]), esomeprazole (40 mg once daily), and a combination of both, during 7-day treatment periods.Main outcomeThe presence or absence of pharmacokinetic interactions between lesogaberan and esomeprazole was assessed by measuring the steady-state area under the plasma concentration-time curves during the dosing interval (AUC(τ)) and the maximum observed plasma concentration (C(max)) for lesogaberan and esomeprazole.ResultsThirty male subjects (mean age 23.2 years, 97% Caucasian) were randomized to treatment and 28 subjects completed the study (one subject was lost to follow-up, and one subject discontinued due to an adverse event). The 95% confidence intervals of the geometric mean ratios for AUC(τ) and C(max) of lesogaberan and esomeprazole administered alone and concomitantly were within the recognized boundaries of bioequivalence (0.8-1.25). No new safety concerns were raised during this study. The number of patients with adverse events during treatment with lesogaberan alone (n = 17) and concomitantly with esomeprazole (n = 18) were comparable but higher than with esomeprazole alone (n = 10). Paresthesia (episodic, mild, and transient), pharyngitis, and flatulence were the most frequently reported adverse events.ConclusionsThere was no observed pharmacokinetic interaction between lesogaberan and esomeprazole when concomitantly administered to healthy subjects, and concomitant therapy was well tolerated. TRIAL REGISTRATION NUMBER (clinicaltrials.gov): NCT00684190.

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Dataset Information

Evaluation of pharmacokinetic interactions between amoxicillin, clarithromycin, and the potassium-competitive acid blocker YH4808 in healthy subjects.

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Evaluation of pharmacokinetic interactions between amoxicillin, clarithromycin, and the potassium-competitive acid blocker YH4808 in healthy subjects.

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