Development of Pelubiprofen Tromethamine with Improved Gastrointestinal Safety and Absorption

Pelubiprofen (PEL), which is a commercialized non-steroidal anti-inflammatory drug (NSAID), is associated with the risk of gastrointestinal (GI) adverse events following long-term exposure and has poor water-soluble properties. Here, a new pelubiprofen tromethamine (PEL-T) with improved solubility, permeability, GI safety, and absorption, compared to PEL, has been developed. The nuclear magnetic resonance spectroscopy (NMR), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FT-IR) results confirmed that the PEL-T was well formed. The powder of PEL-T showed the presence of additional 6H protons at δ 3.66–3.61 in the 1H NMR spectrum, and shifted the sharp endothermic peaks at 129 °C in DSC, and the spectrum of distinct absorption peaks in FT-IR. In addition, compared with PEL, PEL-T showed a significantly improved solubility in various media and an increased permeability coefficient (Kp) in Caco-2 cells. Furthermore, compared to PEL oral administration, PEL-T was found to significantly reduce the damaged area in an acute gastric damage rat model. The pharmacokinetic study of the PEL-T powder showed higher maximum plasma concentration (Cmax) and area under the plasma concentration–time curve from 0 h to the last time point (AUCt) than those of the PEL powder. Taken together, our data suggest that PEL-T is a recommendable candidate with enhanced gastrointestinal safety and better absorption compared with commercial PEL.

O19 Secukinumab-related gastrointestinal safety in PsA and AS

Background Secukinumab is a selective interleukin-17a inhibitor (anti-IL17) and an effective treatment option for psoriatic arthritis (PsA) and ankylosing spondylitis (AS). Phase III study safety data indicate a possible risk of inflammatory bowel disease (IBD), a link which is biologically plausible as IL-17 is known to influence intestinal immunopathology. Real world data for secukinumab gastrointestinal safety are limited. We set out to describe the post-licensing experience of secukinumab in routine care, evaluating both baseline evaluation of pre-existing IBD as well as incident gastrointestinal adverse effects. Methods We undertook a retrospective cohort study. Ten centres from the South East of England participated. All records for patients commencing secukinumab at each centre between 2016-2019 were reviewed. A fully anonymised data collection form was used to collate patient information. Questions sought to answer whether IBD screening had occurred prior to secukinumab initiation. All gastrointestinal adverse events were reviewed. IBD-related adverse events after initiation were defined as: definite (biopsy confirmed, objective inflammation from biomarkers, clear temporal association, improvement on drug withdrawal), probable (as per definite, but without biopsy confirmation) or possible (gastrointestinal symptoms not fulfilling definite or probable criteria). Results Data for 306 patients were available: 124 (40.5%) with AS and 182 (59.5%) with PsA. 106 (34.6%) of patients had documented assessment for IBD prior to initiation; 7 of which already had pre-existing diagnoses of IBD. 24 (7.8%) patients experienced gastrointestinal related adverse events after starting secukinumab; 18 of which were formally investigated for bowel disease due to symptoms. Amongst patients who developed gastrointestinal symptoms, 4 (1.3%) had definite, 7 (2.3%) probable and 13 (4.2%) possible IBD. Out of the 4 with definite IBD; all were AS patients, all stopped secukinumab, three had pre-existing IBD and one (0.3%) case of de-novo IBD required surgical management for an inflammatory perianal abscess. All 7 patients with probable IBD had symptom resolution on withdrawal of secukinumab. Of these, 4/7 were PsA and 3/7 were AS. For the 13 patients that fulfilled possible IBD criteria, symptoms resolved without intervention and continued secukinumab treatment. Conclusion Absolute rates of new IBD in patients starting secukinumab are low. In addition, a majority of patients developing new gastrointestinal symptoms did not develop objective evidence of IBD or stop therapy. However, our experience suggests that in people with pre-existing IBD the risk is much higher. Only one-third of patients had documented evidence of screening for IBD at baseline. Given that only one patient developed de-novo IBD in the cohort, our experience would not support the practice of pre-screening for IBD prior to starting anti-IL17 therapy. Further research to evaluate this would be wise to focus specifically on the characteristics of AS patients, stratifying IBD risk prior to anti-IL17 initiation. Disclosures I.A. Onac: Other; Education support to attend conference from Abbvie. C. Tacu: Honoraria; Novartis Pharmaceutical UK - Speaker Fee. Other; education support- course - Novartis. B.D. Clarke: None. M. Lloyd: Other; departmental support from Novartis. V. Hajela: None. T. Batty: None. J. Thoroughgood: None. S. Smith: None. H. Irvine: None. D. Hill: None. G. Baxter: None. N. Horwood: Other; attend conferences from Lilly and Abbvie. S. Mahendrakar: Other; Education support to attend conferences from Lilly. R. Rajak: Honoraria; Honoraria for speaker: Eli Lilly, Amgen, Internis, Roche, UCB, Abbvie. Honoraria for chairing: Roche, Novartis, Eli Lilly, UCB. S. Griffith: Other; None declared. P. Kiely: Honoraria; Abbvie, BMS, Gilead, Lilly, Novartis, Sanofi. Member of speakers’ bureau; Abbvie, BMS, Lilly, Novartis, Sanofi. J.B. Galloway: Honoraria; Speaker fees, travel support and grants from Lilly, Abbvie, BMS, Celgene, Janssen, Pfizer, UCB, Sanofi.

Developing in vitro assays to transform gastrointestinal safety assessment: potential for microphysiological systems

Drug-induced gastrointestinal toxicities (DI-GITs) are among the most common adverse events in clinical trials.