Wei Zhang 1, An Outtier 1,2, Olivier Dewit 3, Edouard Louis 4, Marc Ferrante 1,2, Erwin Dreesen 1
1 KU Leuven (Leuven, Belgium), 2 UZ Leuven (Leuven, Belgium), 3 Cliniques Universitaires Saint-Luc (Brussels, Belgium), 4 CHU Liège, Sart Tilman (Liège, Belgium)
Introduction: Pouchitis is a frequent and clinically significant complication following restorative proctocolectomy with ileal pouch–anal anastomosis in patients with ulcerative colitis and familial adenomatous polyposis [1]. When symptoms such as increased stool frequency and fluidity, rectal bleeding, urgency, incontinence, and abdominal cramping persist for more than four weeks, the condition is classified as chronic pouchitis, a challenging phenotype that often requires repeated or prolonged therapy [1,2]. Ustekinumab has shown off‑label benefit for chronic pouchitis, yet its pharmacokinetics and target exposure thresholds remain unknown.
Objective: To characterize ustekinumab population pharmacokinetics (popPK) in chronic pouchitis, quantify exposure–response, identify early concentration thresholds predictive of steroid-free outcome, and evaluate practical dosing strategies.
Methods: We analyzed data from 22 patients with chronic pouchitis treated off-label with ustekinumab [2]. All received standard intravenous induction (260 mg for bodyweight <55 kg, 390 mg for 55–85 kg, and 520 mg for >85 kg), followed by 90‑mg subcutaneous injections every eight weeks. Serum samples were collected at weeks 4, 8, 16, and 24. A popPK model was developed to describe ustekinumab disposition. Exposure–response relationships were evaluated using observed concentrations and model‑derived metrics (predicted concentrations, clearance, and area under the concentration–time curve [AUC]). Clinical outcomes were steroid‑free remission (modified Pouchitis Disease Activity Index [mPDAI] <5 and ≥2‑point reduction from baseline) and steroid‑free response (mPDAI ≥2 point reduction from baseline) at week 16 and week 24. Exposure–response relationships were quantified by logistic regression and receiver operating characteristic (ROC) analysis was performed to identify an exposure threshold. Monte Carlo simulations (n=1,000) for the 22 patients in our cohort were performed to compare four induction strategies: (1) standard label dosing, (2) 6 mg/kg, (3) 6 mg/kg rounded to the nearest 130‑mg vial (“vial-rounded”), and (4) an increased stratified regimen (390 mg <55 kg; 520 mg 55–85 kg; 650 mg >85 kg) (“label+130 mg”). Target attainment rates were calculated using the identified exposure threshold.
Results: The popPK model adequately described ustekinumab concentrations. For a typical 70-kg patient with serum albumin 44 g/L, clearance was estimated at 0.348 L/day, which was 1.5–2 times higher than values reported in Crohn’s disease and ulcerative colitis [3-6]. The observed week 4 concentration predicted steroid‑free remission at week 16 (area under the ROC curve 0.84; 95% confidence interval [CI] 0.62–1.00). A week 4 ustekinumab concentration threshold of 15.0 mg/L was identified. Under standard induction dosing, the median predicted week 4 concentration was 14.7 mg/L (95% CI, 7.4–22.7). All alternative induction strategies achieved median week 4 concentrations above 15.0 mg/L. The target attainment rate was 46.6% (95% CI 46.0–47.3) with standard dosing, compared with 57.0% (95% CI 56.4–57.7) for exact 6 mg/kg, 60.9% (95% CI 60.3–61.6) for vial‑rounded dosing, and 80.2% (95% CI 79.6–80.7) for the label+130 mg regimen. Weight‑stratified analyses showed that standard, exact 6 mg/kg, and label+130 mg strategies resulted in lower predicted week 4 concentrations and target attainment rate in patients <55 kg. For example, median week 4 concentrations were 13.1 mg/L for <55 kg versus 15.6 mg/L and 16.4 mg/L for the 55–85 kg and >85 kg groups, respectively. In contrast, vial‑rounded dosing produced more uniform exposure across weight strata (<55 kg: 16.0 mg/L, 95% CI 7.3–25.5; 55–85 kg: 16.3 mg/L, 95% CI 8.2–25.9; >85 kg: 16.1 mg/L, 95% CI 8.2–24.5). The corresponding median model‑predicted probabilities of steroid‑free remission were likewise consistent across weight bands: 25.7% (95% CI 1.4–91.9) for <55 kg, 28.2% (95% CI 1.9–93.0) for 55–85 kg, and 26.8% (95% CI 1.9–88.9) for >85 kg.
Conclusion: In chronic pouchitis, ustekinumab clearance is higher than in Crohn’s disease and ulcerative colitis. Observed week 4 concentrations were predictive of steroid‑free remission (threshold 15.0 mg/L). Vial‑rounded intravenous induction dosing (6 mg/kg rounded to the nearest 130‑mg multiple) improved week 4 target attainment and equalized exposure across weight strata, particularly benefiting lighter patients. These findings support operationally simple dosing (vial‑rounded induction).
References:
[1] Kamal et al. Frontline Gastroenterol. 2025;16:143–54
[2] Outtier et al. Clin Gastroenterol Hepatol. 2024;22(12):2468-2474.e1
[3] Wang et al. Br J Clin Pharmacol. 2022;88(1):323-335
[4] Aguiar et al. Pharmaceutics. 2021;13(10):1587
[5] Adedokun et al. Clin Ther. 2022;44(10):1336-1355
[6] Xu et al. J Clin Pharmacol. 2020;60(7):889-902. doi:10.1002/jcph.1582
Reference: PAGE 34 (2026) Abstr 11923 [www.page-meeting.org/?abstract=11923]
Poster: Clinical Applications