Effect of MMX^® mesalamine coadministration on the pharmacokinetics of amoxicillin, ciprofloxacin XR, metronidazole, and sulfamethoxazole: results from four randomized clinical trials

Abstract

Background

MMX^® mesalamine is a once daily oral 5-aminosalicylic acid formulation, effective in induction and maintenance of ulcerative colitis remission. Patients on long-term mesalamine maintenance may occasionally require concomitant antibiotic treatment for unrelated infections.

Aim

To evaluate the potential for pharmacokinetic interactions between MMX mesalamine and amoxicillin, ciprofloxacin extended release (XR), metronidazole, or sulfamethoxazole in four open-label, randomized, placebo-controlled, two-period crossover studies.

Methods

In all four studies, healthy adults received placebo once daily or MMX mesalamine 4.8 g once daily on days 1–4 in one of two treatment sequences. In studies 1 and 2, subjects also received a single dose of amoxicillin 500 mg (N=62) or ciprofloxacin XR 500 mg (N=30) on day 4. In studies 3 and 4, subjects received metronidazole 750 mg twice daily on days 1–3 and once on day 4 (N=30); or sulfamethoxazole 800 mg/trimethoprim 160 mg twice daily on days 1–3 and once on day 4 (N=44).

Results

MMX mesalamine had no significant effects on systemic exposure to amoxicillin, ciprofloxacin, or metronidazole; the 90% confidence intervals (CIs) around the geometric mean ratios (antibiotic + MMX mesalamine: antibiotic + placebo) for maximum plasma concentration (C_max) and area under the plasma concentration–time curve (AUC) fell within the predefined equivalence range (0.80–1.25). Sulfamethoxazole exposure increased by a statistically significant amount when coadministered with MMX mesalamine; however, increased exposure (by 12% in C_max at steady state; by 15% in AUC at steady state) was not considered clinically significant, as the 90% CIs for each point estimate fell entirely within the predefined equivalence range. Adverse events in all studies were generally mild.

Conclusion

MMX mesalamine may be coadministered with amoxicillin, ciprofloxacin, metronidazole, or sulfamethoxazole, without affecting pharmacokinetics or safety of these antibiotics.

ClinicalTrials.gov identifiers

NCT01442688, NCT01402947, NCT01418365, and NCT01469637.

Keywords:

• ulcerative colitis
• pharmacokinetics
• safety

Acknowledgments

The authors acknowledge the contributions of Stephannie Kollipara, MS, and Victor Vidals, MD, to this study. We are also grateful to Richard Abbott, PhD, for his excellent bioanalytical support. Research was funded by the sponsor, Shire Development LLC, Wayne, PA. Under the direction of the authors, Janetricks Chebukati, PhD, an employee of MedErgy, Yardley, PA, provided writing assistance for this manuscript. Editorial assistance in formatting, proofreading, copy editing, and fact checking was also provided by MedErgy. Representatives from Shire also reviewed and edited this manuscript for scientific accuracy. Shire Development LLC provided funding to MedErgy for support in writing and editing this manuscript. Although the sponsor was involved in the design, collection, analysis, interpretation, and fact checking of information, the content of this manuscript, the ultimate interpretation, and the decision to submit it for publication in Drug Design, Development, and Therapy was made by the authors.

Disclosure

David Pierce, retired, is a former employee of Shire and holds stock and/or stock options in Shire. Mary Corcoran, Patrick Martin, and Karen Barrett are employees of Shire and hold stock and/or stock options in Shire. Susi Inglis and Peter Preston are contractors for Shire. Thomas N Thompson and Sandra K Willsie are employees of PRA International, Lenexa, KS, USA, which was contracted by Shire to conduct this research.