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Background: Higher serum concentrations of vedolizumab have been associated with improved outcomes in inflammatory bowel disease. It is unclear how vedolizumab exposure is linked to endoscopic remission in Crohn disease (CD). We aimed to develop a pharmacokinetic-pharmacodynamic model linking vedolizumab exposure to endoscopic remission in CD. Methods: Data were obtained from the first 110 patients participating in a phase 4 prospective multicenter trial (LOVE-CD ClinicalTrials.gov identifier: NCT02646683), where vedolizumab was dosed at 300 mg every 8 weeks and serum concentrations and antibodies to vedolizumab were measured before each infusion. Concentration-time profiles were described by a 2-compartment model with parallel linear and nonlinear elimination. A first-order discrete-time Markov model was used to describe the relationship between pharmacokinetic exposure metrics and the probability of endoscopic remission (Simple Endoscopic Score for CD < 4). Results: Linear clearance was 0.215 L/d, and the volume of distribution of the central compartment was 4.92 L. Linear clearance was higher and vedolizumab exposure was lower in patients with lower serum albumin concentrations, in the presence of antibodies to vedolizumab, and in patients with previous exposure to other biologic therapy. A week 22 vedolizumab concentration of 20.0 mg/L was predicted to yield a 35% probability of achieving endoscopic remission at week 26. Model-based simulations suggested that endoscopic remission rates of 46.5% or 40.0% could be reached with every-4-weeks dosing in patients who were naïve or previously exposed to biologic therapy, respectively. Conclusions: Model-informed dosing of vedolizumab in CD provides a foundation for future research aiming to maximize endoscopic remission rates.

Background: Though a single nonmedical switch from the originator infliximab (IFX) to a biosimilar is considered effective and safe for most patients with inflammatory bowel disease (IBD), very limited data are available on multiple successive switches. Methods: We performed a prospective multicenter cohort study of adult IBD patients who underwent 2 switches from the originator IFX to CT-P13 to SB2 (group 1), 1 switch from CT-P13 to SB2 (group 2), and 1 switch from the originator IFX to CT-P13 (group 3). Patients were assessed at 4 and 12 months since the most recent switch for remission using clinical (physician’s assessment) and biochemical (C-reactive protein [CRP], and fecal calprotectin [FC]) measures. Patients discontinuing treatment for ineffectiveness or adverse events before month 12 were imputed as nonremitters. Results: One hundred seventy-six patients (Crohn’s disease 71%, ulcerative colitis 27.8%, IBD unclassified 1.2% group 1, 69 group 2, 80 group 3, 27) were included. At 12 months after the most recent switch 76.9% (40 of 52, group 1), 65.7% (46 of 70, group 2) and 76.9% (20 of 26, group 3) of patients were in clinical remission. Treatment persistence at 12 months was 85.0%, 87.0%, and 70.1%, respectively. There were no significant differences in the rate of clinical, CRP, FC remission, or treatment persistence at 12 months between the 3 groups. Infusion reactions occurred in 1.7% of patients (3/176), all in patients with antidrug antibodies from group 2. Conclusions: Multiple successive switching and switching between biosimilars of IFX seemed to be effective and safe.

Uvod Biološka zdravila so korenito spremenila zdravljenje kronične vnetne črevesne bolezni, saj omogočajo klinično in endoskopsko remisijo bolezni. Raziskave pri zaviralcih tumorje nekrotizirajočega dejavnika alfa (TNF-?), prvih registriranih bioloških zdravilih za to indikacijo, so pokazale, da nekateri bolniki potrebujejo višje odmerke zdravil za doseganje remisije kot drugi. Individualizirano odmerjanje na podlagi meritev serumskih koncentracij zdravil bi lahko vodilo k boljšim izidom zdravljenja. Poleg zaviralcev TNF-? sta za zdravljenje kronične vnetne črevesne bolezni registrirana tudi vedolizumab, zaviralec integrina ?4ß7, in ustekinumab, zaviralec interlevkina-12 in -23. Povezava med serumsko koncentracijo teh zdravil in izidi zdravljenja ni znana. Namen Namen raziskav je bil: - preučiti povezavo med serumskimi koncentracijami vedolizumaba in ustekinumaba ter izidi zdravljenja kronične vnetne črevesne bolezni - preučiti, ali imajo enkratne meritve serumskih koncentracij ustekinumaba enako napovedno vrednost za izide zdravljenja kot mere kumulativne izpostavljenosti zdravilu (površina pod krivuljo) - razviti farmakokinetski-farmakodinamski model za vedolizumab pri Crohnovi bolezni. Metode Opravili smo prospektivno monocentrično raziskavo pri bolnikih s kronično vnetno črevesno boleznijo, ki so začenjali zdravljenje z vedolizumabom (Crohnova bolezen [CB] in ulcerozni kolitis [UK]) oziroma ustekinumabom (CB). Serumske koncentracije vedolizumaba smo merili neposredno pred vsako infuzijo, serumske koncentracije ustekinumaba smo merili neposredno po prvi intravenski infuziji, nato pa po 2, 4 in 8 tednih. Klinično remisijo smo ocenjevali z vprašalnikom PRO-2 oziroma indeksom Harvey-Bradshaw (v raziskavi z ustekinumabom), endoskopsko remisijo pa z ileokolonoskopijo. V raziskavi z ustekinumabom smo biokemijsko remisijo opredelili s koncentracijo kalprotektina v blatu

Introduction: Ustekinumab (UST) is a human anti- IL12/23 p40 monoclonal antibody, approved for treatment of Crohn’s Disease (CD). This multicenter, non-interventional, retrospective chart review explored robust real-life data in patients receiving UST to access long-term efficacy and treatment persistence of UST treatment in the bio- naive CD population with long-standing disease. Aims & Methods: Clinical data, such as maintenance of clinical response using Harvey-Bradshaw index, combined steroid-free and biochemical clinical remission, endoscopic response/healing via the simple endoscopic score for Crohn’s disease (SES-CD), dose escalation and treatment persistence were assessed in 42 adult patients (55% female ; mean age 46 ± 15.1 years ; mean BMI 25.28 ± 4.5 kg/m2 ) with long-standing (mean duration of 10, 5 years) biologic-naive CD from 3 tertiary centers (one Slovenian and two Croatian) between January 2018 and April 2020. Data were collected before first infusion, at week (W)24, W52, as well as last follow-up. Results: At W24 84% (35/42) of CD patients had achieved clinical response and 38.1% (16/42) were in combined steroid-free and biochemical clinical remission. After an average of 16 months of treatment duration, 88.1% (37/42) of CD patients were still on UST treatment, 71.4% (30/42) had maintained clinical response and 35.7% (15/42) were in sustained steroidfree clinical remission. The number of patients requiring steroid treatment was reduced by 87%. Mean HBI decreased from 8 to 3 and SES-CD from 6 to 2. The majority [59.53%] of patients started ustekinumab as monotherapy, i.e. without concomitant immunomodulator medication. 31% of patients experienced UST dose escalation. Conclusion: UST offers an effective and persistent steroid sparing treatment option in this real-life multicenter study of bio-naive CD patients with long-standing disease.

Supplemental Material for Early vedolizumab trough levels predict combined endoscopic and clinical remission in inflammatory bowel disease by Jurij Hanžel, Nejc Sever, Ivan Ferkolj, Borut Štabuc, Nataša Smrekar, Tina Kurent, Matic Koželj, Gregor Novak, Griet Compernolle, Sophie Tops, Ann Gils and David Drobne: on behalf of Observatoire Francophone de la Sclérose en Plaques (OFSEP), Société Francophone de la Sclérose en Plaques (SFSEP), the Radiologically Isolated Syndrome Consortium (RISC) and the Pediatric Radiologically Isolated Syndrome Consortium (PARIS) in United European Gastroenterology Journal