Pharmacokinetics and Exposure Response Relationships of Ustekinumab in Patients With Crohn's Disease

Adedokun, Omoniyi J.; Xu, Zhenhua; Gasink, Christopher; Jacobstein, Douglas; Szapary, Philippe; Johanns, Jewel; Gao, Long; Davis, Hugh M.; Hanauer, Stephen B.; Feagan, Brian G.; Ghosh, Subrata; Sandborn, William J.

doi:10.1053/j.gastro.2018.01.043

Cited by 206 publications

(237 citation statements)

References 40 publications

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“…While patients in this long‐term extension were not subject to dose escalation based on drug concentrations, a previous analysis of ustekinumab serum concentrations of UNITI‐1, UNITI‐2 and through Week 44 of IM‐UNITI demonstrated a relationship between serum concentrations and efficacy . This supports the use of the every 8 weeks dose regimen or the option to dose escalate if patients who start every 12 weeks dosage fail to achieve response or lose response, as was allowed before Week 44 of IM‐UNITI.…”

Section: Discussionmentioning

confidence: 60%

Long‐term efficacy and safety of ustekinumab for Crohn's disease through the second year of therapy

Sandborn

Rutgeerts²,

Gasink³

et al. 2018

Aliment Pharmacol Ther

141

110

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SummaryBackgroundIn Phase 3 studies of ustekinumab, a fully human monoclonal IL‐12/23p40 antibody approved for moderate‐to‐severe Crohn's disease, patients entered a long‐term extension after completing 8 weeks of induction and 44 weeks of maintenance treatment. Efficacy through 92 weeks and safety through 96 weeks of IM‐UNITI maintenance are reported.Methods UNITI‐1 (TNF‐antagonist failures) and UNITI‐2 (conventional therapy failures) patients (N = 1281) entered IM‐UNITI, including 397 ustekinumab intravenous induction responders randomised to subcutaneous ustekinumab 90 mg every 12 weeks, every 8 weeks, or placebo and 884 nonrandomised patients. Dose‐adjustment to 90 mg every 8 weeks occurred in patients randomised to 90 mg every 12 weeks and placebo patients with loss of response (Weeks 8–32). All Week 44 completers could enter the long‐term extension without further dose adjustment. Placebo patients discontinued following study unblinding.ResultsA total of 718 patients (all treated) entered the long‐term extension (298 randomised and 420 not randomised). Overall, 86.5% (621/718) completed Week 96. The proportions of randomised patients in clinical remission were generally maintained from Week 44 through 92 in ustekinumab 90 mg every 12 weeks (77.4% to 72.6%), every 8 weeks (84.1% to 74.4%), and prior dose adjustment groups (63.4% to 53.5%). At Week 92, the proportions of patients in clinical remission were similar in the ustekinumab 90 mg every 12 weeks and every 8 weeks groups and lower in patients with prior dose adjustment. Proportions of patients in clinical remission at Week 92 for all treated every 8 weeks (64.4%) and every 12 weeks (64.3%) groups were lower than randomised every 8 weeks (74.4%) and every 12 weeks (72.6%) groups, but similarly maintained. Safety events (per hundred patient‐years) were similar among all placebo and ustekinumab patients (Week 0‐96), including adverse events (484.39 vs 447.76), serious adverse events (19.24 vs 18.82), and serious infections (4.09 vs 4.02). No dose effect was observed.ConclusionsSubcutaneous ustekinumab maintained clinical response and remission through Week 92. No new safety signals were observed. ClinicalTrials.gov number NCT01369355.

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Section: Discussionmentioning

confidence: 60%

Long‐term efficacy and safety of ustekinumab for Crohn's disease through the second year of therapy

Sandborn

Rutgeerts²,

Gasink³

et al. 2018

Aliment Pharmacol Ther

141

110

View full text Add to dashboard Cite

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“…Initially developed for psoriasis (where it remains first‐line), it is now also licensed for use in psoriatic arthritis and inflammatory bowel disease . Studies investigating the relationship between ustekinumab exposure and outcome are few, generally limited to descriptive or empirical analyses, and report mixed results . Understanding exposure‐response is complicated by the fact that some patients’ disease may not respond to IL‐23‐Th17 therapies, and furthermore, some may receive subtherapeutic drug exposure due to PK variability.…”

mentioning

confidence: 99%

Using Real‐World Data to Guide Ustekinumab Dosing Strategies for Psoriasis: A Prospective Pharmacokinetic‐Pharmacodynamic Study

Pan

Dand

Lonsdale

et al. 2020

Clinical Translational Sci

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Variation in response to biologic therapy for inflammatory diseases, such as psoriasis, is partly driven by variation in drug exposure. Real‐world psoriasis data were used to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the first‐line therapeutic antibody ustekinumab. The impact of differing dosing strategies on response was explored. Data were collected from a UK prospective multicenter observational cohort (491 patients on ustekinumab monotherapy, drug levels, and anti‐drug antibody measurements on 797 serum samples, 1,590 measurements of Psoriasis Area Severity Index (PASI)). Ustekinumab PKs were described with a linear one‐compartment model. A maximum effect (Emax) model inhibited progression of psoriatic skin lesions in the turnover PD mechanism describing PASI evolution while on treatment. A mixture model on half‐maximal effective concentration identified a potential nonresponder group, with simulations suggesting that, in future, the model could be incorporated into a Bayesian therapeutic drug monitoring “dashboard” to individualize dosing and improve treatment outcomes.

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“…However, it should be noted that in some of the patients the concentration of the drug was above 1.4 μg/mL. Moreover, the introduction of additional immunomodulators in the treatment regimen did not affect the concentration of ustekinumab in the serum (Adedokun et al, ). This shows the value of the personalization of treatment and confirms the individual character of each patient's response to the same form of pharmacotherapy.…”

Section: Discussionmentioning

confidence: 99%

The influence of ustekinumab on expression of STAT1 , STAT3 , STAT4 , SOCS2 , and IL17 in patients with psoriasis and in a control

Grabarek

Krzaczyński

Strzałka‐Mrozik

et al. 2019

Dermatologic Therapy

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The aim of this study was to assess changes in the expression of STAT1, STAT3, STAT4, SOCS2, and IL17 in psoriatic patients under ustekinumab treatment and in healthy volunteers. The study group consisted of 14 patients suffering from psoriasis vulgaris qualified for ustekinumab therapy (4 women, 10 men) The control group consisted of 14 healthy volunteers (7 women, 7 men), their whole blood was used as a material in this study. A quantitative reverse transcription polymerase chain assay was used to amplify analyzed genes. To indicate the differences in expression of selected genes in the test and control groups, the Kruskal–Wallis and the post hoc Dunn's test was carried out. After 40 weeks of observation of the effectiveness of ustekinumab in patients with psoriasis, the expression of STAT1, STAT3, STAT4, IL17, and SOCS2 was silenced. Statistic differences in expression were observed for STAT3 (40 vs. 0 weeks, p < .05; 0 week vs. C, p < .05) and SOCS2 (0 week vs. C, p < .05). Patients with psoriasis vulgaris have higher levels of STAT1, STAT3, STAT4, SOCS2, and IL17 expression compared to healthy individuals. On the other hand, the treatment of ustekinumab lasting 40 weeks caused a decrease in the transcriptional activity of the analyzed genes.

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Pharmacokinetics and Exposure Response Relationships of Ustekinumab in Patients With Crohn's Disease

Cited by 206 publications

References 40 publications

Long‐term efficacy and safety of ustekinumab for Crohn's disease through the second year of therapy

Long‐term efficacy and safety of ustekinumab for Crohn's disease through the second year of therapy

Using Real‐World Data to Guide Ustekinumab Dosing Strategies for Psoriasis: A Prospective Pharmacokinetic‐Pharmacodynamic Study

The influence of ustekinumab on expression of STAT1 , STAT3 , STAT4 , SOCS2 , and IL17 in patients with psoriasis and in a control

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