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:

• ulcerative colitis
• mesalamine
• pharmacology

Supplementary materials

Figure S1 Schematic of final population pharmacokinetic structural model.

Notes: Numbers on the top left-hand corner of the boxes represent the compartment numbers for the population pharmacokinetic model in the NONMEM code. Hence, the two depot compartments were denoted as depot 1 and depot 3.
Abbreviations: ALAG₁, absorption lag time from depot 1; 5-ASA, 5-aminosalicylic acid; Ac-5-ASA, acetyl-5-aminosalicylic acid; Ka₁, absorption rate constant from depot 1; F₁, fraction of dose absorbed from depot 1; Ka₃, absorption rate constant from depot 3; ALAG₃, absorption lag time from depot 3 in addition to the lag time from depot 1; CLM, metabolic clearance of 5-ASA; CLNRM, non-renal clearance of Ac-5-ASA; CLR, renal clearance of 5-ASA; CLRM, renal clearance of Ac-5-ASA.

Figure S2 Goodness-of-fit and diagnostic plots for the final model in children and adolescents: plasma 5-ASA.

Notes: The dashed line represents the local regression (Loess) smoothing line. (A) Observed versus population predicted concentration; (B) observed versus individual predicted concentration; (C) conditional weighted residual versus population predicted concentration; (D) conditional weighted residual versus time.
Abbreviation: 5-ASA, 5-aminosalicylic acid.

Figure S3 Goodness-of-fit and diagnostic plots for the final model in children and adolescents: plasma Ac-5-ASA.

Notes: The dashed line represents the local regression (Loess) smoothing line. (A) Observed versus population predicted concentration; (B) observed versus individual predicted concentration; (C) conditional weighted residual versus population predicted concentration; (D) conditional weighted residual versus time.
Abbreviation: Ac-5-ASA, acetyl-5-aminosalicylic acid.

Table S1 Assay performance of 5-ASA and Ac-5-ASA bioanalytical quality control samples in human plasma and urine

Table S2 Parameter estimates of final 5-ASA/Ac-5-ASA population pharmacokinetic modela

Table S3 Simulated steady-state 5-ASA exposures by weight and dose group

Table S4 Simulated steady-state Ac-5-ASA pharmacokinetic parameters by dose and age group

Acknowledgments

The authors would like to thank Richard Abbott and York Bioanalytical Solutions for excellent bioanalytical support, and Susi Inglis for statistical support. Research was funded by the sponsor, Shire Development LLC. Under the direction of the authors, Jason Jung, PhD, an employee of MedErgy, 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.

Disclosure

Carmen Cuffari served as a consultant for Shire, Prometheus, and Abbott Nutritionals. David Pierce is a former employee of Shire, and holds stock in Shire and in GlaxoSmithKline. Bartosz Korczowski and Krzysztof Fyderek received grants from Shire for the study research conducted. Heather Van Heusen, Hong Wan, and Patrick Martin are employees of Shire, and hold stock and/or stock options at Shire. Stuart Hossack is an employee of Covance Clinical Research Unit Limited, which received funding from Shire for assistance with data analysis. Alena YZ Edwards is an employee of ICON Early Phase Services, which received funding from Shire for assistance with data analysis.

Authors contributions

Carmen Cuffari was involved with the study design as well as data analysis and interpretation. David Pierce was involved with study concept and design, oversight of the analysis, and interpretation of data (including oversight of pharmacokinetic details included in the manuscript). Bartosz Korczowski and Krzysztof Fyderek supervised the study conduct and were involved with data acquisition. Heather Van Heusen was involved with study concept and design; oversight of study conduct, execution, and data analyses; development of the clinical study report; and development of the protocol. Stuart Hossack was involved with non-compartmental pharmacokinetic data analysis and interpretation of data for the clinical study report. Hong Wan was involved with acquisition of data, analysis and interpretation of data, and statistical analysis. Alena YZ Edwards was involved with analysis and interpretation of data. Patrick Martin was involved with the overarching study concept, design, conduct, and reporting, and as the article guarantor, he takes responsibility for the integrity of the work as a whole, from inception to published article. All authors contributed to drafting of the manuscript or critical revision of the manuscript for important intellectual content, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.