Abstract Background Off-label ustekinumab benefits patients with chronic pouchitis, yet its pharmacokinetics (PK) and target concentrations remain unclear. We aimed to characterize its population PK in chronic pouchitis, identify concentration thresholds predicting clinical remission (modified pouchitis disease activity index 5 and a reduction by ≥ 2 points), and propose optimized dosing regimens. Methods Twenty-two patients with chronic pouchitis were included.1 All received standard ustekinumab intravenous induction dosing (∼6 mg/kg), followed by 90mg subcutaneous maintenance dosing every eight weeks. Serum samples were collected at week (w)4, w8, w16, and w24. A popPK model was developed to characterize ustekinumab PK. A population pharmacodynamics (popPD) model using logistic regression was used to link drug concentrations and clinical remission and to identify the cutoff. Monte Carlo simulations (n = 1000) were conducted for the 22 patients comparing four induction dosing strategies: (1) standard label dosing, (2) exact 6 mg/kg, (3) 6 mg/kg rounded to the nearest 130 mg vial size, and (4) increased fixed-dose regimen (390 mg 55 kg, 520 mg 55–85 kg, 650 mg 85 kg). For each strategy, the rate of target attainment was calculated based on the identified cutoff. Results The PopPK model well captured the time course of ustekinumab concentrations (Figure 1a). Standardized to a 70-kg patient with albumin level 44 g/L, clearance (CL) was estimated at 0.348 L/day. The popPD model identified w4 drug concentrations as a predictor of clinical remission at w16, with a threshold of 15.0 mg/L (AUC 0.84; 95% CI 0.62–1.00) (Figure 1b). Simulations revealed that standard dosing achieved this target exposure in only 46.6% of patients (95% CI 46.0–47.3). An exact 6 mg/kg dosing improved this to 57.0% (95% CI 56.4–57.7), while vial-rounded dosing further increased target attainment to 60.9% (95% CI 60.3–61.6). The increased fixed-dose regimen achieved the highest target rate at 80.2% (95% CI 79.6–80.7). Notably, the vial-rounded dosing strategy provided consistent exposure across weight bands (58.6% 55 kg; 61.4% 55–85 kg; 60.4% 85 kg), mitigating underexposure in lighter patients (55 kg), who had a target rate of only 10.4% under the standard regimen (Figure 2). Conclusion Clearance of ustekinumab in patients with chronic pouchitis is 1.5–2 times higher than that in Crohn’s disease and ulcerative colitis. W4 concentrations were predictive of clinical remission at w16, with a cutoff of 15.0 mg/L. The vial-rounded induction strategy substantially improves target attainment, particularly in the lighter patients. Reference: 1 Outtier et al. Clin Gastroenterol Hepatol. 2024;22(12):2468-2474.e1 Conflict of interest: Ms. Zhang, Wei: No conflict of interest Outtier, An: No conflict of interest Dewit, Olivier: Consulting, lectures fees or travel accommodations: Abbvie, Biogen, Bristol Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Galapagos, Janssen, MSD, Mylan, Pfizer and Sandoz. Louis, Edouard: Education and Reserach Grants for my department: Abbvie, Takeda, Johnson and Johnson, Pfizer, Fresenius-Kabi, Celltrion, EG pharma, Sandoz, Falk Personal Fees for conferences, advisory boards and consultancy: Abbvie, Takeda, Ferring, Pfizer, Johnson and Johnson, Lilly, Galapagos, Celltrion, Arena, BMS, Falk, Biokuris, Fresenius-Kabi, Thabor Ferrante, Marc: Research grants from AbbVie, EG Pharma, Celltrion, Janssen, Pfizer, Takeda and Viatris Consultancy fees from AbbVie, AgomAb Therapeutics, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Janssen-Cilag, MRM Health, Merck Sharp and Dohme, Pfizer, Takeda and ThermoFisher Speakers’ fees from AbbVie, Biogen, Boehringer Ingelheim, Dr Falk Pharma, Ferring, Janssen-Cilag, Merck Sharp and Dohme, Pfizer, Takeda, Truvion Healthcare and Viatris Dreesen, Erwin: Erwin Dreesen received consultancy fees from Alimentiv and argenx, lecture fees from Celltrion and Galapagos, and financial support from Celltrion, Janssen, Pfizer, Prometheus Biosciences, R-Biopharm, and Sandoz, outside the submitted work, with all honoraria/fees being paid to KU Leuven and not to any personal account of Erwin Dreesen.
Zhang et al. (Thu,) studied this question.