P0761IL-23p19-inhibitor pharmacokinetics across immune-mediated inflammatory diseases: insights from a systematic review

Background IL-23p19 inhibitors are increasingly used to treat immune-mediated inflammatory disorders (IMIDs), particularly inflammatory bowel disease (IBD). Interindividual variability (IIV) in pharmacokinetics (PK), which can be explained by patient-specific factors, contribute to variable treatment responses, as shown for IL-23p19 inhibitors in psoriasis. However, a comprehensive overview of their PK parameters is lacking, limiting understanding of population variability and covariate effects. This systematic review aimed to assess the PK of IL-23p19 inhibitors in IBD and other IMIDs. Methods A systematic literature search was performed in PubMed and Embase. Studies were screened by two independent researchers. Quality was assessed using the Cochrane risk-of-bias 2 tool and the Clinical Pharmacokinetic Study Checklist. Results A total of 21 studies were identified of which nine focused on risankizumab, three on tildrakizumab, six on guselkumab and three on mirikizumab. Two studies addressed Crohn’s disease (CD) and three addressed ulcerative colitis (UC), with PK data available for risankizumab (CD:1,392; UC:1,394) and mirikizumab (UC:1,362 adults, 26 paediatrics). Notably, only one study focused on a distinct IBD population, specifically mirikizumab for paediatric UC. Optimal dosing strategies (particularly in paediatric and refractory populations) remained largely undefined. Our analysis revealed the following key PK findings. First, for risankizumab, dose-normalized maximum concentration and area under the concentrationtime curve over a dosing interval, along with central and peripheral volume of distribution and clearance were generally similar across CD and UC (Fig 1A, C-D). Second, paediatric patients with UC who received mirikizumab showed an IIV in SC bioavailability of 77.6% (95%CI 24.7–119.0). Third, patients with CD and UC demonstrated increased risankizumab trough levels over successive dosing intervals, while an opposite trend was observed across dosing regimens for other IMIDs (Fig. 1B). Covariate analysis revealed that albumin in UC and body weight in CD were relevant covariates to risankizumab PK. No covariates were reported to have a clinically meaningful effect on guselkumab or mirikizumab PK in IBD. Conclusion This systematic review highlights limited availability of PK data and the absence of sub-phenotype-specific studies for IL-23p19 inhibitors in IBD. Data on covariates influencing drug exposure in IBD are also scarce. Key findings are summarized in the graphical abstract (Fig. 2). These findings highlight the need for further research to better define PK parameters and influencing covariates, enabling personalized dosing strategies for IL-23p19 inhibitors in IBD. Conflict of interest: Pool, Ilse A.: No conflicts. de Groot, Alise D. E.: A.R.B. received speaker’s fees from AbbVie and Ferring, outside the submitted work. Keizer, Ron J.: R.J.K is an employee and stockholder of InsightRX, a company that develops precision dosing software. Dijkstra, Gerard: Grant: Royal DSM Personal Fees: Consultancy fee from Astra-Zeneca and Speakers fee from Abbvie Mian, Paola: None Dr. Bourgonje, Arno R.: A.R.B. received speaker’s fees from AbbVie and Ferring, outside the submitted work.