Similar pharmacokinetics of three dosing regimens comprising two oral delayed-release mesalamine formulations in healthy adult volunteers: Randomised, open-label, parallel-group study

Niels Vande Casteele, Abhijeet Jakate, Brian McNamee, William J Sandborn, Niels Vande Casteele, Abhijeet Jakate, Brian McNamee, William J Sandborn

Abstract

Aims: Mesalamine is the first-line therapy for treating mild-to-moderate ulcerative colitis. Multiple mesalamine formulations are available, with similar safety and efficacy profiles. Mesalamine is commonly administered as divided dosing, although once-daily dosing may provide benefits for patients. We evaluated the pharmacokinetics of three dosing regimens of two oral delayed-release mesalamine formulations in healthy adult volunteers.

Methods: A randomised, open-label, parallel-group study of mesalamine pharmacokinetics following Lialda 2 × 1.2 g once daily (QD) (dose A), Asacol 6 × 400 mg QD (dose B), or Asacol 2 × 400 mg three times daily (TID) (dose C) over 7 days. Assessments included 5-aminosalicylic acid (5-ASA) and N-acetyl 5-aminosalicylic acid (N-Ac-5-ASA, primary metabolite) pharmacokinetics (Ae (%), AUC0-24 and Cmax ), safety and tolerability.

Results: All enrolled volunteers (n = 37) completed the study. Steady state was achieved for all treatments by day 4. Ratios (95% CI) of means for steady-state AUC0-24 (dose A vs B 90.3% [39.8, 204.8], dose A vs C 123.5% [55.3, 275.7], dose B vs C 136.8% [61.3, 305.5]) and Cmax (dose A vs B 106.0% [46.4, 242.2], dose A vs C 133.0% [59.1, 299.0], dose B vs C 125.5% [55.8, 282.1]) were similar for all 5-ASA treatments. Mean urinary excretion of 5-ASA plus N-Ac-5-ASA was comparable between treatments (dose A 21.3%, dose B 20.2%, dose C 17.9%). All treatment regimens were well tolerated; no safety issues were observed.

Conclusions: Plasma and urine pharmacokinetics for Asacol TID, Asacol QD, and Lialda QD are similar, suggesting similar daily systemic exposures can be obtained with either TID or QD dosing. NCT00751699.

Keywords: 5-ASA; Inflammatory bowel disease; clinical pharmacology.

Conflict of interest statement

N.V.C. has received consultancy fees from Boehringer Ingelheim, Pfizer, Takeda and UCB Pharma. A.J. is an employee of and holds stock/stock options in Allergan plc. B.M. is an employee of Allergan Biologics Ltd. W.J.S. reports personal fees from Actavis, Actogenix NV, Adherion Therapeutics, Akros Pharma, Ambrx, Am Pharma BV, Ardelyx, Arena Pharmaceuticals, Avaxia Biologics, Baxter Healthcare, Biogen, Catabasis Pharmaceuticals, Celgene, Celgene Cellular Therapeutics, Chiasma, Cosmo Pharmaceuticals, Dr August Wolff, Eisai, Eli Lilly, Ferring Pharmaceuticals, Ferring Research Institute, Forward Pharma, Galapagos, Immune Pharmaceuticals, Index Pharmaceuticals, Ironwood Pharmaceuticals, Kyowa Hakko Kirin, Lexicon Pharmaceuticals, Lipid Therapeutics GmbH, Luitpold Pharmaceuticals, MedImmune (AstraZeneca), Mesoblast, Millennium Pharmaceuticals, Nestlé, Novo Nordisk, Orexigen, Palatin, Qu Biologics, Regeneron, Ritter Pharmaceuticals, Salix Pharmaceuticals, Santarus, Seattle Genetics, Seres Health, Shire, Sigmoid Biotechnologies, Teva Pharmaceuticals, Theradiag, Theravance, TiGenix, Tillotts Pharma, Toray Industries, UCB Pharma, University of Western Ontario (owner of Robarts Clinical Trials), Vascular Biogenics, Vertex Pharmaceuticals, Warner Chilcott and Zyngenia; grants and personal fees from AbbVie, Amgen, Atlantic Pharmaceuticals, Boehringer Ingelheim, Bristol‐Myers Squibb, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Nutrition Science Partners, Pfizer, Prometheus Laboratories, Receptos and Takeda; and grants from Exact Sciences.

© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Figures

FIGURE 1
FIGURE 1
Study design. aPharmacokinetic blood collections: 0 (pre‐dose on day 1), 24 (day 2), 48 (day 3), 72 (day 4), 96 (day 5), 120 (day 6) and 144 (day 7) hours after the first dose on day 1, and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 17, 18, 19, 20, 22, 24, 30, 36 and 48 hours after the first morning dose on day 7. bPharmacokinetic urine collections: pre‐dose on day 1 and pooled over 0‐8, 8‐16 and 16‐24 hours after the first morning dose on day 7
FIGURE 2
FIGURE 2
(A) Steady‐state analysis of 5‐ASA by treatment. (B) Steady‐state analysis of N‐Ac‐5‐ASA by treatment. Day 2 is 24 hours after the first dose on day 1. Data shown as least‐squares geometric means and 95% CIs obtained from a model with independent variable ln(trough concentration) and terms for subject(treatment*sex), day, sex, treatment and treatment*day. BLQ concentrations were set to 5‐ASA 1/2 BLQ = 5 ng/mL and N‐Ac‐5‐ASA 1/2 BLQ = 10.2 ng/mL. 5‐ASA, 5‐aminosalicylic acid; BLQ, below level of quantification; CI, confidence interval; N‐Ac‐5‐ASA, N‐acetyl‐5‐aminosalicylic acid
FIGURE 3
FIGURE 3
(A) Mean plasma 5‐ASA concentration‐time profiles on day 7 following multiple‐dose oral administration of three treatment regimens of two formulations of mesalamine. (B) Mean plasma N‐Ac‐5‐ASA concentration‐time profiles on day 7 following multiple‐dose oral administration of three treatment regimens of two formulations of mesalamine. 5‐ASA, 5‐aminosalicylic acid; N‐Ac‐5‐ASA, N‐acetyl‐5‐aminosalicylic acid

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Source: PubMed

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