Ustekinumab Pharmacokinetics and Exposure Response in a Phase 3 Randomized Trial of Patients With Ulcerative Colitis: Ustekinumab PK and exposure-response in UC

Abstract: Background & Aims The efficacy of antibody-based therapeutics depends on their pharmacokinetics. The pharmacokinetic and exposure response profiles of ustekinumab, a monoclonal antibody against interleukin 12/interleukin 23, are known in patients with Crohn’s disease, yet there are few data from patients with ulcerative colitis. We characterized ustekinumab’s pharmacokinetics, exposure response, and optimal serum concentrations in patients with ulcerative colitis. Methods We collected data from 2 phase-3 trials (1 induction and 1 maintenance), in which patients with moderate to severe ulcerative colitis received an intravenous induction dose of ustekinumab (130 mg, n=320 or approximately 6 mg/kg, n=322). Responders were randomly assigned to groups that received subcutaneous maintenance ustekinumab (90 mg) every 8 weeks (n=176) or 12 weeks (n=172) or placebo (n=175). We evaluated the association between ustekinumab concentration and efficacy, based on clinical effects (Mayo score), histologic features, and inflammation (measurement of C-reactive protein, fecal calprotectin, and lactoferrin), as well as safety (infections, serious infections, or serious adverse events), during induction and maintenance therapy. Optimal serum concentrations of ustekinumab were identified using receiver operating characteristic curve analyses. Results In patients with ulcerative colitis, dose-proportional serum concentrations of ustekinumab, unaffected by prior biologic or concomitant immunomodulator therapy, reached steady state by the second maintenance dose; median trough concentration for dosing every 8 weeks was approximately 3-fold that of dosing every 12 weeks. Serum concentrations associated with clinical and histologic features of efficacy and normalization of inflammation markers. The week-8 concentration threshold for induction of response was 3.7 μg/mL. A steady-state trough serum concentration of 1.3 μg/mL or higher associated with a higher rate of clinical remission compared with patients who had lower serum concentrations. Serum concentrations of ustekinumab were not associated with infections, serious infections, or serious adverse events. Conclusions In an analysis of data from 2 phase-3 trials of patients with ulcerative colitis, we found that serum concentrations of ustekinumab are proportional to dose, unaffected by prior biologic or concomitant immunomodulator therapies, associated with clinical and histologic efficacy and markers of inflammation, and not associated with safety events at doses evaluated. Ustekinumab pharmacokinetics are consistent between patients with Crohn’s disease vs ulcerative colitis.