Ustekinumab Pharmacokinetics and Exposure Response in a Phase 3 Randomized Trial of Patients With Ulcerative Colitis

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 assigned randomly 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, serum based on clinical effects (Mayo score), histologic features, and inflammation (measurement of C-reactive protein, fecal calprotectin, and fecal lactoferrin), as well as safety (infections, serious infections, and 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; the median trough concentration for dosing every 8 weeks was approximately 3-fold that of dosing every 12 weeks. Serum concentrations were 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 mg/mL. A steady-state trough serum concentration of 1.3 mg/mL or higher was 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.

Effectiveness of ustekinumab dose escalation in Crohn’s disease patients with insufficient response to standard‐dose subcutaneous maintenance therapy

“…While for patients treated with tumour necrosis factor (TNF)‐alpha inhibitors, therapeutic drug monitoring may provide important guidance for selection of strategy 23‐26 . The correlation of ustekinumab levels with treatment outcomes is not as robust 6,12,27 . Thus, the escalation strategy is currently empiric and nonstandardised.…”

Long-Term Obeticholic Acid Therapy Improves Histological Endpoints in Patients With Primary Biliary Cholangitis

“…Also, all the prospective studies available to date have shown no impact of immunomodulator on the trough serum level of vedolizumab 35,55 or ustekinumab. 9,56 The association of immunomodulators with biologics may also be deleterious. Combination with anti-TNF is associated with an increased risk of serious, opportunistic infections and lymphoma.…”

“…On the one hand, these drugs are less immunogenic, and it is not certain that adding an immunomodulator improves their efficacy. 5,6,[9][10][11] On the other hand, the addition of an immunomodulator may be deleterious because of increased risk of serious and opportunistic infections. 12,13 Hence, we aimed to evaluate the comparative effectiveness and safety of using vedolizumab or ustekinumab monotherapy vs in combination with an immunomodulator in patients with IBD through a systematic review and meta-analysis.…”

Predictors and Early Markers of Response to Biological Therapies in Inflammatory Bowel Diseases

“…Interestingly, in a retrospective analysis of IBD patients on maintenance therapy with vedolizumab, TLs <7.4 μg/mL, in patients experiencing LOR was associated with a significantly increased likelihood to respond to dose escalation compared to higher concentrations (OR 3.7, 95% CI 1.1-13, p = 0.04) [108]. A similar exposure-efficacy relationship has been observed for ustekinumab: early TLs (week 4 and 8) have been associated with clinical remission [109,110], decrease of faecal calprotectin [111] and biochemical remission [112], while TLs during maintenance have been correlated with clinical remission [109,110], endoscopic response [111,113] and need for optimization [114]. In a recent review, Alsoud et al [127] proposed target TLs for vedolizumab and ustekinumab.…”