P0639 Population pharmacokinetics of subcutaneous vedolizumab in Crohn’s disease and Ulcerative Colitis

Abstract Background Vedolizumab is a monoclonal antibody used for the treatment of inflammatory bowel disease (IBD). The pharmacokinetics (PK) of intravenously (IV) administered vedolizumab have been described previously.1 We aimed to develop a population PK model for subcutaneous (SC) vedolizumab and to evaluate whether current dose regimens are appropriate for SC dosing. Methods Data for model development were prospectively collected in a cohort of 61 patients with IBD receiving IV vedolizumab (300mg at week 0-2-6, thereafter every 4-11 weeks) who switched to SC treatment (108 mg every 2 weeks, Q2W). The PRIOR subroutine in NONMEM2 was used to develop a two-compartment population PK model for IV and SC vedolizumab including linear and non-linear clearance. The model was validated with goodness of fit plots, a visual predictive check and bootstrapping (n = 1000). Final model estimates were used to perform simulations in a virtual population (n = 10 000) with a white blood cell count of 7 x 109/L, randomly sampled serum albumin (mean = 44 g/L, SD = 3.0) and bodyweight (mean 77 kg, SD = 14), based on the distribution of the original dataset. Trough concentrations for an IV regimen of 300 mg vedolizumab once in 8 weeks were compared with SC regimens of 108 mg once in 2, 3, 4 and 5 weeks. For SC vedolizumab, we defined a target serum concentration of 26 mg/L, based on previously reported exposure-efficacy data.3 Results A patient with a bodyweight of 70 kg, serum albumin of 40 g/L and a white blood cell count of 7 x 109/L had a bioavailability of 66.8%, an absorption rate constant of 0.0938/day and a linear clearance of 0.157 L/day. The inter-individual variability for linear clearance was 22.9%. Most important predictors for linear clearance were serum albumin with a negative, and bodyweight and white blood cell count with a positive correlation. In the virtual population, 2.3-fold higher average trough concentrations were estimated for the SC-Q2W regimen (32 mg/L) compared to the IV-Q8W regimen (14 mg/L). Trough concentrations of at least 26 mg/L were achieved in 76% of virtual patients receiving SC vedolizumab every 2 weeks. Virtual patients with a serum vedolizumab concentration higher than 42 mg/L with Q2W dosing could de-escalate to Q3W, while still achieving a trough concentration of 26 mg/L (18% of virtual patients). Conclusion The development and evaluation of a population PK model for IV and SC vedolizumab was successful. This model could be used in the considerations of an extended SC dose regimen. Our results highlight the importance of defining clear targets for SC vedolizumab in clinical practice. References 1.Rosario M, Dirks NL, Gastonguay MR, et al. Population pharmacokinetics-pharmacodynamics of vedolizumab in patients with ulcerative colitis and Crohn’s disease. Aliment Pharmacol Ther. 2015;42(2):188-202. doi:10.1111/APT.13243 2.Gisleskog PO, Karlsson MO, Beal SL. Use of Prior Information to Stabilize a Population Data Analysis. J Pharmacokinet Pharmacodyn. 2002;29(6). 3.D’Haens G, Rosario M, Polhamus D, et al. Exposure–efficacy relationship of vedolizumab subcutaneous and intravenous formulations in Crohn’s disease and ulcerative colitis. Expert Review of Clinical Pharmacology. 2024;17(4):403-412. doi:10.1080/17512433.2024.2318465