Pharmacokinetic drug interaction and safety after coadministration of clarithromycin, amoxicillin, and ilaprazole: a randomised, open-label, one-way crossover, two parallel sequences study

Abstract

Purpose: Ilaprazole, the latest proton pump inhibitor, can be used with clarithromycin and amoxicillin as a triple therapy regimen for eradicating Helicobacter pylori. The aim of this study was to evaluate pharmacokinetic drug interactions and safety profiles after coadministration of clarithromycin, amoxicillin, and ilaprazole.

Methods: A randomised, open-label, one-way crossover, two parallel sequences study was conducted in 32 healthy subjects. In part 1, the subjects received a single dose of ilaprazole 10 mg in period 1 and clarithromycin 500 mg and amoxicillin 1000 mg twice daily for 6 days in period 2. In part 2, the subjects received clarithromycin 500 mg and amoxicillin 1000 mg once in period 1 and ilaprazole 10 mg twice daily for 6 days in period 2. In both sequences, the three drugs were coadministrated once on day 5 in period 2. Pharmacokinetic evaluations of ilaprazole (part 1), and clarithromycin and amoxicillin (part 2) were conducted.

Results: Twenty-eight subjects completed the study. For ilaprazole, the peak concentration (C_max) slightly decreased from 479 (ilaprazole alone) to 446 ng/mL (triple therapy) [Geometric least square mean ratio (90% confidence interval), 0.93 (0.70-1.22)]. The area under the concentration-time curve from 0 h to the last measurable concentration (AUC_last) slightly increased from 3301 to 3538 μg·h/mL [1.07 (0.85-1.35)]. For clarithromycin, the C_max slightly decreased from 1.87 to 1.72 μg/mL [0.90 (0.70-1.15)], and AUC_last slightly increased from 14.6 to 16.5 μg·h/mL [1.09 (0.87-1.37)]. For amoxicillin, the C_max slightly decreased from 9.37 to 8.14 μg/mL [0.86 (0.74-1.01)], and AUC_last slightly decreased from 27.9 to 26.7 μg·h/mL [0.98 (0.83-1.16)]. These changes in the PK parameters of each drug were not statistically significant.

Conclusions: The coadministration of ilaprazole, clarithromycin, and amoxicillin was tolerable and did not cause a significant PK drug interaction. Thus, a triple therapy regimen comprising ilaprazole, clarithromycin, and amoxicillin may be an option for the eradication of H. pylori. Clinicaltrials.gov number: NCT02998437.

Keywords: Amoxicillin; Clarithromycin; Drug interaction; Ilaprazole; Pharmacokinetics; Proton pump inhibitor.

Fig. 1

Study design. Notes: Subjects who were assigned to part 1 received ilaprazole 10 mg on day 1 of period 1 and clarithromycin 500 mg and amoxicillin 1000 mg from day 1 to day 6 of period 2 and ilaprazole 10 mg was concomitantly administered on day 5 of period 2. Subjects who were assigned to part 2 received both clarithromycin 500 mg and amoxicillin 1000 mg on day 1 of period 1 and ilaprazole 10 mg from day 1 to day 6 of period 2 and clarithromycin 500 mg and amoxicillin 1000 mg was concomitantly administered on day 5 of period 2

Fig. 2

Mean (SD) plasma concentration-time profiles of ilaprazole when administered as monotherapy and as part of triple therapy. a Linear scale; b semi-logarithmic scale. Abbreviations: monotherapy, administration of ilaprazole 10 mg in period 1 of treatment part 1; triple therapy, administration of ilaprazole 10 mg, clarithromycin 500 mg, and amoxicillin 1000 mg in period 2 of both treatment parts 1 and 2

Fig. 3

Mean (SD) plasma concentration-time profiles of clarithromycin when administered as dual therapy and as part of triple therapy. a Linear scale; b semi-logarithmic scale. Abbreviations: dual therapy, administration of clarithromycin 500 mg and amoxicillin 1000 mg in period 1 of treatment part 2; triple therapy, administration of ilaprazole 10 mg, clarithromycin 500 mg, and amoxicillin 1000 mg in period 2 of both treatment parts 1 and 2

Fig. 4

Mean (SD) plasma concentration-time profiles of amoxicillin when administered as dual therapy and as part of triple therapy. a Linear scale; b semi-logarithmic scale. Abbreviations: dual therapy, administration of clarithromycin 500 mg and amoxicillin 1000 mg in period 1 of treatment part 2; triple therapy, administration of ilaprazole 10 mg, clarithromycin 500 mg, and amoxicillin 1000 mg in period 2 of both treatment parts 1 and 2. Notes: Plasma amoxicillin concentrations at 48 h after study drug administration were not detected