Pilot study to assess pharmacokinetic and pharmacodynamic markers following enema-dosing with adalimumab in patients with active ulcerative colitis
In this study, we assessed pharmacokinetic (PK) and pharmacodynamic (PD) parameters following dosing with an adalimumab enema in patients with active ulcerative colitis.
Active ulcerative colitis (UC) is associated with significant morbidity and impairment to quality of life. Tumor necrosis factor alpha (TNF-α) is a key pathogenic pro inflammatory cytokine elevated
in the serum and intestinal mucosa of ulcerative colitis (UC) patients.1 The development of anti-TNF-α therapies, such as adalimumab, has revolutionized the treatment of IBD. However, the efficacy of adalimumab for UC at the currently approved dosages is suboptimal, possibly due to inadequate local drug concentrations in diseased tissue of patients with active UC and/or lack of adequate suppression of the high TNF-α burden.2,3
Topical administration has the potential to provide higher exposures of adalimumab in the target tissue, in comparison to plasma exposures, with less systemic risk. Topical administration of
adalimumab also results in pharmacologically relevant tissue levels, as suggested by the pharmacodynamic response shown in the preclinical disease model.4 These analyses provide further
support for the hypothesis that targeted topical delivery of adalimumab might provide an advantage over systemic delivery by substantially reducing TNF-α burden within the tissue.
This was a pilot study to evaluate safety and PK/PD responses of local administration of adalimumab via enema in tissue and blood. Data obtained from this study will provide further understanding of the extent of absorption, relative bioavailability, and the early safety data of adalimumab following topical administration in patients with active UC in local tissues as well as systemically.
What did we find?
Topical treatment with adalimumab may be beneficial in patients with active UC. Target engagement and modulation was demonstrated.
Monitoring tissue TNF-α, IL-6, and OSM might be useful in understanding pathway redundancy or feedback loops.
Topical administration has the potential to provide higher exposures of adalimumab in the target tissue, in comparison to plasma exposures, with less systemic risk.5
- Sparrow MP. Adalimumab in ulcerative colitis – efficacy, safety and optimization in the era of treat-to target. Expert Opin Biol Ther. 2017;17(5):613-621.
- Harris MS, Hartman D, Lemos BR, et al. AVX-470, an Orally Delivered Anti-Tumour Necrosis Factor Antibody for Treatment of Active Ulcerative Colitis: Results of a First-in-Human Trial. J Crohns Colitis. 2016;10(6):631-640.
- Yarur AJ, Jain A, Sussman DA, et al. The association of tissue anti-TNF drug levels with serological and endoscopic disease activity in inflammatory bowel disease: the ATLAS study. Gut. 2016;65(2):249-255.
- Lee SN, Singh S, Luo A, et al. A comparison of systemic versus targeted anti-TNFα antibody in treatment of colitis induced by adoptive transfer of CD44-/CD62L+ T-cells into RAG2-/- mice recipients. Poster presented at: Digestive Disease Week; May 18-21, 2019, San Diego, CA.
- Begun J, Andrews J, Chuang E, et al. Pilot study to assess pharmacokinetic and pharmacodynamic markers following enema-dosing with adalimumab in patients with active ulcerative colitis (UC). Poster presented at: American College of Gastroenterology Annual Scientific Meeting, October 21-26, 2022, Charlotte, NC.