Intravenous Ustekinumab Reinduction Is Effective in Prior Biologic Failure Crohn’s Disease Patients Already on Every-4-Week Dosing

Sedaño, Rocío; Guizzetti, Leonardo; McDonald, Cassandra; Jairath, Vipul

doi:10.1016/j.cgh.2020.07.064

Cited by 20 publications

(18 citation statements)

References 7 publications

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“…This is broadly concordant with the findings of a retrospective real-world series, where 15/18 patients responded clinically to an additional intravenous infusion and 10/15 required escalated subcutaneous dosing in ongoing maintenance [32]. Even patients already on maximized subcutaneous dosing may benefit from an additional intravenous infusion, although none of these studies included PK assessment [33].…”

Section: Discussionsupporting

confidence: 80%

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Ustekinumab Dosing Individualization in Crohn’s Disease Guided by a Population Pharmacokinetic–Pharmacodynamic Model

et al. 2021

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Ustekinumab is a monoclonal antibody used in Crohn’s disease (CD). Dose optimization in case of non-response and the role of pharmacokinetic–pharmacodynamic (PK-PD) monitoring remain unresolved dilemmas in clinical practice. We aimed to develop a population PK-PD model for ustekinumab in CD and simulate efficacy of alternative dosing regimens. We included 57 patients and recorded their characteristics during 32 weeks after starting with ustekinumab therapy. Serum ustekinumab concentration was prospectively measured and fecal calprotectin (FC) concentration was used to monitor the disease activity. Ustekinumab PK-PD was described by a two-compartment target-mediated drug disposition model linked to an indirect response model. Lower fat-free mass, higher serum albumin, previous non-exposure to biologics, FCGR3A-158 V/V variant and lower C-reactive protein were associated with higher ustekinumab exposure. Model-based simulation suggested that 41.9% of patients receiving standard dosing achieve biochemical remission at week 32. In patients not achieving remission with standard dosing at week 16, transition to 4-weekly subcutaneous maintenance dosing with or without intravenous reinduction resulted in comparably higher remission rates at week 32 (51.1% vs. 49.2%, respectively). Our findings could be used to guide stratified ustekinumab treatment in CD, particularly in patients with unfavorable characteristics, who might benefit from early transition to 4-weekly maintenance dosing.

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Section: Discussionsupporting

confidence: 80%

“…Different approaches have been used in patients not responding or losing response to standard dosing of ustekinumab: dosing interval shortening [12][13][14][15], intravenous reinduction [32] or a combination of both [32,33]. These modifications were made at week 16 of treatment or later.…”

Section: Discussionmentioning

confidence: 99%

Ustekinumab Dosing Individualization in Crohn’s Disease Guided by a Population Pharmacokinetic–Pharmacodynamic Model

et al. 2021

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“…Unlike with anti-TNF agents the optimal management of loss of response to UST is not fully established. Shortening the interval of administration and also re-induction with iv UST have been described in patients after an initial inadequate response or secondary loss of response with good results (96)(97)(98)(99)(100)(101). However, data about the efficacy of both strategies in patients failing q8w dosing are still scarce.…”

Section: Ust Intensification Strategiesmentioning

confidence: 99%

“…Re-induction has shown to induce a significant decrease in C-reactive protein levels, with endoscopic remission in 25% of patients (42). Patients already being intensified to 4-weekly dosing can also benefit from iv re-induction, with approximately half of patients (53%) achieving clinical remission and 67% response (99). Younger patients (98) with shorter disease duration (97), no prior surgery (97), perianal disease (96), higher clinical disease activity (96,98) and corticosteroid use (96) have shown reduced response rates to these rescue strategies.…”

Section: Ust Intensification Strategiesmentioning

confidence: 99%

How to Optimize Treatment With Ustekinumab in Inflammatory Bowel Disease: Lessons Learned From Clinical Trials and Real-World Data

Gutiérrez

Rodríguez‐Lago

2021

Front. Med.

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Ustekinumab is a fully human IgG1 monoclonal antibody that has been approved for the treatment of moderate to severe Crohn's disease, and more recently moderate to severe ulcerative colitis. It binds with high affinity to the p40 subunit of human interleukin-12 and 23. This mechanism of action prevents the bioactivity of both interleukins, thus precluding their interaction with the cell surface receptor protein. The pivotal clinical trials (UNITI-1, UNITI-2 and IM-UNITI) demonstrated its clinical efficacy and safety, in naïve patients and also in those previously exposed to immunosuppressants and/or biologics. There is now an extensive experience with its use worldwide, corroborating its favorable profile even in patients with refractory disease. However, the number of medical treatment options available in inflammatory bowel disease are still limited. Hence, we should prioritize the treatments that have a greater probability of response in an individual patient. Our aim was to review and summarize all the available literature regarding the potential predictors of response to ustekinumab that can increase the success rate with this therapy in clinical practice.

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“…Collectively, these studies suggest that dose optimization does not appear to significantly impact the outcomes of primary nonresponders. Finally, seminal studies support ustekinumab reinduction as an effective strategy in CD patients with loss of response, even in the case of previous dose escalation to q4w; 82 , 83 on this matter, no data have been presented for UC patients so far.…”

Section: Methodsmentioning

confidence: 99%

Targeting IL12/23 in ulcerative colitis: update on the role of ustekinumab

Pugliese

Privitera

Fiorani

et al. 2022

Therap Adv Gastroenterol

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As our comprehension of the pathogenic mechanisms of inflammatory bowel disease (IBD) increases, the therapeutic armamentarium for its treatment can expand, and novel target therapies join the treatment pipeline. Interleukin (IL)-12 and IL23 are two key cytokines responsible for promoting and perpetuating bowel inflammation in IBD. Ustekinumab is a monoclonal antibody directed against the shared p40 subunit of both cytokines, and it was recently approved for the treatment of ulcerative colitis (UC). In the pivotal phase III UNIFI trial, ustekinumab showed a superiority over placebo in both clinical and endoscopic outcomes; furthermore, it was characterized by a favorable safety profile, with a similar rate of adverse events as compared with placebo. Recent evidence from real-life experiences have started accumulating, generally confirming the effectiveness and safety figures emerged from the registration studies. However, most of these observational studies enrolled multirefractory patients; moreover, comparative data with other target therapies are lacking, leaving physicians without clear indications about the appropriate positioning of ustekinumab in the therapeutic pipeline for UC. This review examines the basis of targeting IL12-23 in UC therapy and summarizes the data from both clinical trials and real-life studies, to highlight the main evidence already available and the research gaps that need to be filled for the optimal usage of ustekinumab in UC.

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Intravenous Ustekinumab Reinduction Is Effective in Prior Biologic Failure Crohn’s Disease Patients Already on Every-4-Week Dosing

Cited by 20 publications

References 7 publications

Ustekinumab Dosing Individualization in Crohn’s Disease Guided by a Population Pharmacokinetic–Pharmacodynamic Model

Ustekinumab Dosing Individualization in Crohn’s Disease Guided by a Population Pharmacokinetic–Pharmacodynamic Model

How to Optimize Treatment With Ustekinumab in Inflammatory Bowel Disease: Lessons Learned From Clinical Trials and Real-World Data

Targeting IL12/23 in ulcerative colitis: update on the role of ustekinumab

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