Evaluation of the pharmacokinetic interaction between lesogaberan (AZD3355) and esomeprazole in healthy subjects

Abstract

Background: Transient 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.

Objective: To evaluate the effect of esomeprazole on the pharmacokinetics and safety of lesogaberan and vice versa.

Study design: This 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 outcome: The 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.

Results: Thirty 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.

Conclusions: There 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.

Figures

Fig. 1

Study design. = randomization.

Table I

Subject baseline characteristics (n = 30)

Fig. 2

Mean steady-state plasma concentration-time curves of lesogaberan when administered alone (n = 29) and concomitantly with esomeprazole (n = 28). Data are the combined arithmetic mean values + SD of the two following treatment groups: (i) lesogaberan 150 mg twice daily (bid) [dosed in the morning and afternoon] on days 1–6 and 150 mg once daily (od) [dosed in the morning] on day 7; and (ii) lesogaberan 150 mg bid on days 1–6 and 150 mg od on day 7, administered concomitantly with esomeprazole 40 mg od (dosed in the morning) on days 1–7. Data are from day 7.

Fig. 3

Mean steady-state plasma concentration-time curves of esomeprazole, alone (n = 29) and concomitantly with lesogaberan (n = 28). Data are the combined arithmetic mean values + SD of the two following treatment groups: (i) esomeprazole 40 mg once daily (od) [dosed in the morning] on days 1–7; and (ii) lesogaberan 150 mg twice daily (dosed in the morning and afternoon) on days 1–6 and 150 mg od (dosed in the morning) on day 7, administered concomitantly with esomeprazole 40 mg od in the morning on days 1–7. Data are from day 7.

Table II

Geometric mean ratios and 95% CIs of lesogaberan and esomeprazole area under the plasma concentration-time curve (AUC) during the dosage interval at steady-state (AUCτ), maximum plasma concentration at steady-state (Cmax), and AUC from time zero until the last quantifiable plasma concentration (AUCt) when administered concomitantly vs each alone

Table III

Summary of the secondary pharmacokinetic variables of lesogaberan and esomeprazole when administered alone and concomitantly

Table IV

Number (%) of subjects with adverse eventsa during treatment with lesogaberan and esomeprazole, either alone or concomitantly