Tu1197 MicroRNA-4284 Regulates CXCL5 Expression and Is Down-Regulated in Colon Tissues of Pediatric Patients With Ulcerative Colitis

Abstract

AIM: Ulcerative colitis (UC) is a chronic inflammatory disease of the colon and rectum distinguished by relapsing and remitting gastrointestinal and systemic symptoms. Mesalamine (5-aminosalicylic acid; 5-ASA) has proven efficacy in the induction and maintenance of disease remission in patients with mild-to-moderate UC. This phase 1, multicenter, randomized, open-label study (NCT01130844) assessed the pharmacokinetic and safety profiles of 5-ASA and its major metabolite, acetyl-5-ASA (Ac-5-ASA), after administration of once-daily MMX mesalamine to children and adolescents with UC. METHODS: Study participants aged 5-17 years, with a UC diagnosis of ≥3 months were randomized to MMX mesalamine 30, 60, or 100 mg/kg/day (stratified by body weight) for 7 days. To achieve these doses in children, smaller-sized 300 mg and 600 mg tablets were developed for this study to augment the existing approved 1200 mg MMX mesalamine tablet. Patients were administered MMX mesalamine at home on Days 1-4 and on site on Days 5-7 when subjects attended for pharmacokinetic blood and urine sampling and for safety assessments. Plasma and urine concentrations of 5-ASA and Ac-5-ASA were determined by a validated LC/MS/MS assay. Key pharmacokinetic parameters for 5-ASA and Ac-5-ASA included maximum concentration (Cmax,ss), time of Cmax,ss (tmax), area under the curve for one dose interval (AUCss), and renal clearance (CLR), and percent of dose absorbed. RESULTS: A total of 52 patients (30F:22M with mean [standard deviation] age of 13.3 [3.06] years and median [range] time since UC diagnosis of 1.83 [0.2, 9.6] years) were randomized and treated: 21 at 30 mg/kg; 22 at 60 mg/kg; and 9 at 100 mg/kg. Steady state plasma concentrations for 5-ASA and Ac5-ASA were attained by Day 5 for all doses. On Day 7, mean AUCss and Cmax,ss for 5-ASA and Ac-5-ASA increased in a dose proportional manner between 30 and 60 mg/kg/day doses. Mean percentage of 5-ASA absorbed from MMX mesalamine was 29.4%, 27.0%, and 22.1%, for 30, 60, and 100 mg/kg/day doses, respectively. Mean CLR ranged from 5.0-6.5 L/h for 5-ASA and 10.0-16.2 L/h for Ac-5-ASA. The incidence of treatment-emergent adverse events was 19.2% overall. Events were similar among different dose and age groups, with no novel safety signals reported. CONCLUSIONS: The pharmacokinetic profile of 5-ASA and Ac-5ASA in children/adolescents with UC receiving MMX mesalamine across all dose levels was similar to the pharmacokinetic profile in historical adult data. MMX mesalamine was welltolerated at all doses and in all age groups; no new safety signals were identified.