Randomized clinical trial: pharmacokinetics and safety of multimatrix mesalamine for treatment of pediatric ulcerative colitis

Abstract

Background: Limited data are available on mesalamine (5-aminosalicylic acid; 5-ASA) use in pediatric ulcerative colitis (UC).

Aim: To evaluate pharmacokinetic and safety profiles of 5-ASA and metabolite acetyl-5-ASA (Ac-5-ASA) after once-daily, oral administration of multimatrix mesalamine to children and adolescents with UC.

Methods: Participants (5-17 years of age; 18-82 kg, stratified by weight) with UC received multi-matrix mesalamine 30, 60, or 100 mg/kg/day once daily (to 4,800 mg/day) for 7 days. Blood samples were collected pre-dose on days 5 and 6. On days 7 and 8, blood and urine samples were collected and safety was evaluated. 5-ASA and Ac-5-ASA plasma and urine concentrations were analyzed by non-compartmental methods and used to develop a population pharmacokinetic model.

Results: Fifty-two subjects (21 [30 mg/kg]; 22 [60 mg/kg]; 9 [100 mg/kg]) were randomized. On day 7, systemic exposures of 5-ASA and Ac-5-ASA exhibited a dose-proportional increase between 30 and 60 mg/kg/day cohorts. For 30, 60, and 100 mg/kg/day doses, mean percentages of 5-ASA absorbed were 29.4%, 27.0%, and 22.1%, respectively. Simulated steady-state exposures and variabilities for 5-ASA and Ac-5-ASA (coefficient of variation approximately 50% and 40%-45%, respectively) were similar to those observed previously in adults at comparable doses. Treatment-emergent adverse events were reported by ten subjects. Events were similar among different doses and age groups with no new safety signals identified.

Conclusion: Children and adolescents with UC receiving multimatrix mesalamine demonstrated 5-ASA and Ac-5-ASA pharmacokinetic profiles similar to historical adult data. Multimatrix mesalamine was well tolerated across all dose and age groups. ClinicalTrials.gov Identifier: NCT01130844.

Keywords: mesalamine; pharmacology; ulcerative colitis.

Figures

Figure 1

Subject flow diagram. Note:aIncluded blood and urine collection.

Figure 2

Mean (SD) plasma concentration–time profiles for (A) 5-ASA and (B) Ac-5-ASA in children and adolescents by treatment group. Abbreviations: 5-ASA, 5-aminosalicylic acid; Ac-5-ASA, acetyl-5-aminosalicylic acid; SD, standard deviation.

Figure 3

Box and whisker plots of simulated 5-ASA and Ac-5-ASA steady-state AUC in both child/adolescent and adult populations for low-dose (A [5-ASA] and C [Ac-5-ASA]) and high-dose exposures (B [5-ASA] and D [Ac-5-ASA]). Abbreviations: 5-ASA, 5-aminosalicylic acid; Ac-5-ASA, acetyl-5-aminosalicylic acid; AUCss, area under the curve for the defined interval between doses.