title: 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).
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pediatrics, Division of Pediatric Gastroenterology and Nutrition, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Carmen
authors.initials: C
authors.lastname: Cuffari
authors.affiliation: Shire, Basingstoke, UK.
authors.forename: David
authors.initials: D
authors.lastname: Pierce
authors.affiliation: Medical College, University of Rzeszów, Rzeszów, Poland.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Korczowski
authors.affiliation: University Children's Hospital of Cracow, Cracow, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Fyderek
authors.affiliation: Shire, Wayne, PA, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Van Heusen
authors.affiliation: Covance Clinical Research Unit Limited, Leeds, UK.
authors.forename: Stuart
authors.initials: S
authors.lastname: Hossack
authors.affiliation: Shire, Wayne, PA, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wan
authors.affiliation: ICON Early Phase Services, Marlow, Buckinghamshire, UK.
authors.forename: Alena Y Z
authors.initials: AY
authors.lastname: Edwards
authors.affiliation: Shire, Wayne, PA, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Martin
mesh_terms: D000293:Adolescent; D000636:Aminosalicylic Acids / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D003093:Colitis, Ulcerative / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D019804:Mesalamine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000636:Aminosalicylic Acids; D000894:Anti-Inflammatory Agents, Non-Steroidal; C505368:acetyl-5-aminosalicylic acid; D019804:Mesalamine
keywords: mesalamine; pharmacology; ulcerative colitis