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

David Pierce, Mary Corcoran, Patrick Martin, Karen Barrett, Susi Inglis, Peter Preston, Thomas N Thompson, Sandra K Willsie, David Pierce, Mary Corcoran, Patrick Martin, Karen Barrett, Susi Inglis, Peter Preston, Thomas N Thompson, Sandra K Willsie

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 (Cmax) 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 Cmax 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.

Clinicaltrialsgov identifiers: NCT01442688, NCT01402947, NCT01418365, and NCT01469637.

Keywords: pharmacokinetics; safety; ulcerative colitis.

Figures

Figure 1
Figure 1
Study 1: Mean (SD) amoxicillin plasma concentrations versus time for amoxicillin coadministered with placebo or with MMX® mesalamine (Cosmo Technologies Ltd, Wicklow, Ireland). Treatment A consisted of placebo administered orally once daily on days 1–4 plus a single oral dose of amoxicillin 500 mg on day 4. Treatment B consisted of MMX mesalamine 4.8 g administered orally once daily on days 1–4 plus a single oral dose of amoxicillin 500 mg on day 4. Note: The error bar rises above the mean data point for treatment A and falls below the mean data point for treatment B. Abbreviations: SD, standard deviation; h, hours.
Figure 2
Figure 2
Study 2: Mean (SD) ciprofloxacin XR plasma concentrations versus time for ciprofloxacin XR coadministered with placebo or with MMX® mesalamine (Cosmo Technologies Ltd, Wicklow, Ireland). Treatment A consisted of placebo administered once daily on days 1–4 plus a single oral dose of ciprofloxacin XR 500 mg on day 4. Treatment B consisted of MMX mesalamine 4.8 g given once daily on days 1–4 plus a single oral dose of ciprofloxacin XR 500 mg on day 4. Note: The error bar rises above the mean data point for treatment A and falls below the mean data point for treatment B. Abbreviations: SD, standard deviation; XR, extended release; h, hours.
Figure 3
Figure 3
Study 3: Mean (SD) metronidazole (A) and hydroxymetronidazole (B) plasma concentrations versus time for metronidazole coadministered with placebo or with MMX® mesalamine (Cosmo Technologies Ltd, Wicklow, Ireland). Treatment A consisted of placebo administered orally once daily on days 1–4 plus metronidazole 750 mg twice daily on days 1–3 and a single dose of metronidazole 750 mg on day 4. Treatment B consisted of MMX mesalamine 4.8 g once daily on days 1–4 plus metronidazole 750 mg twice daily on days 1–3 and a single dose of metronidazole 750 mg on day 4. Note: The error bar rises above the mean data point for treatment A and falls below the mean data point for treatment B. Abbreviations: SD, standard deviation; h, hours.
Figure 4
Figure 4
Study 4: Mean (SD) sulfamethoxazole plasma concentrations versus time for sulfamethoxazole coadministered with placebo or with MMX® mesalamine (Cosmo Technologies Ltd, Wicklow, Ireland). Treatment A consisted of placebo administered orally once daily on days 1–4 plus sulfamethoxazole 800 mg/trimethoprim 160 mg twice daily on days 1–3 and a single dose of sulfamethoxazole 800 mg/trimethoprim 160 mg on day 4. Treatment B consisted of MMX mesalamine 4.8 g once daily on days 1–4 plus sulfamethoxazole 800 mg/trimethoprim 160 mg twice daily on days 1–3 and a single dose of sulfamethoxazole 800 mg/trimethoprim 160 mg on day 4. Note: The error bar rises above the mean data point for treatment A and falls below the mean data point for treatment B. Abbreviations: SD, standard deviation; h, hours.

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