RESUMEN

We aimed to characterize the population pharmacokinetics (PK) of vedolizumab for acute graft-versus-host disease prophylaxis in adults undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) and assess potential clinically relevant covariates. Dosing, patient characteristics, and PK from a phase 1b, open-label, dose-finding study of vedolizumab 75 mg initial dose escalated to 300 mg and a phase 3 study of vedolizumab 300 mg in patients receiving allo-HSCT were analyzed using a two-compartment population PK model with linear elimination. Covariates included age, race, weight, sex, albumin, lymphocyte count, GvHD type, and concomitant medications. Weight, albumin, and lymphocyte count were time-varying covariates. Model selection was driven by goodness-of-fit criteria, precision of parameter estimates, and visual predictive checks. In 193 patients undergoing allo-HSCT, vedolizumab PK were well described by a two-compartment, linear PK model. Using reference covariate values, final parameter estimates (95% confidence intervals [CI]) were: clearance, 0.148 (0.136, 0.162) L/day; central volume of distribution, 3.12 (3.03, 3.21) L; intercompartmental clearance, 0.500 (0.408, 0.612) L/day; and peripheral volume of distribution, 3.95 (3.52, 4.44) L. Weight and albumin were the most important predictors of vedolizumab PK, with clearance decreasing by ≈20% for low body weight/high albumin and increasing by ≈30% for high body weight/low albumin. There was an inverse relationship between vedolizumab clearance and age, but no detectable effect for lymphocyte count or GvHD type. Post hoc analyses did not detect any relationship between vedolizumab PK and concomitant medications. In summary, the covariates studied did not have a clinically meaningful effect on the PK of vedolizumab.

Asunto(s)

Anticuerpos Monoclonales Humanizados , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Modelos Biológicos , Trasplante Homólogo , Humanos , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Adulto , Enfermedad Injerto contra Huésped/prevención & control , Masculino , Femenino , Persona de Mediana Edad , Adulto Joven , Anciano , Adolescente , Fármacos Gastrointestinales/farmacocinética , Fármacos Gastrointestinales/uso terapéutico , Fármacos Gastrointestinales/administración & dosificación , Relación Dosis-Respuesta a Droga

RESUMEN

BACKGROUND: The optimal infliximab dose intensification strategy to address loss of response associated with subtherapeutic infliximab trough levels remains uncertain, as does whether post-intensification trough and treatment targets should influence this decision. OBJECTIVES: This pharmacokinetic simulation study aimed to identify infliximab dose intensification strategies capable of achieving post-intensification infliximab trough thresholds associated with clinical and objective treatment targets in Crohn's disease and ulcerative colitis. METHODS: A validated pharmacokinetic infliximab model, applied to 200 simulated patients, identified those with subtherapeutic (< 3.00 mg/L) trough levels after 30 weeks of standard (5 mg/kg 8-weekly) dosing, and subsequently applied 10 dose intensification strategies over a further 32 weeks. The proportion of simulations achieving 32-week post-intensification infliximab trough levels associated with endoscopic remission (ulcerative colitis > 7.50 mg/L, Crohn's disease > 9.70 mg/L) was the primary outcome, with perianal fistula healing (Crohn's disease > 10.10 mg/L) and clinical improvement (ulcerative colitis > 3.70 mg/L, Crohn's disease > 7.00mg/L) evaluated as secondary outcomes. All outcomes were stratified by intensity of dose intensification, with standard (≤ 10 mg/kg 8-weekly or 5 mg/kg 4-weekly; n = 5) and intensive (> 10 mg/kg 8-weekly or 5 mg/kg 4-weekly; n = 5) dosing strategies defined, respectively. RESULTS: The median pre-intensification infliximab trough level was 0.91 mg/L (interquartile range 1.37). Intensive dosing strategies were more likely to achieve infliximab trough concentrations associated with endoscopic remission (ulcerative colitis 36.48% vs. 10.80%, Crohn's disease 25.98 vs. 4.68%), perianal fistula healing (24.52% vs. 4.36%) and clinical improvement (ulcerative colitis 61.90% vs. 34.86%, Crohn's disease 40.32 vs. 12.08%) than standard intensification strategies (all p < 0.01). When controlling for cumulative (mg/kg) infliximab dose over 32 weeks, strategies that concurrently dose increased and interval shortened achieved the highest infliximab trough levels (all p < 0.01). CONCLUSION: This simulation-based analysis highlights the potential of using post-intensification infliximab trough thresholds associated with aspirational treatment targets in Crohn's disease and ulcerative colitis to guide choice of infliximab dose intensification strategy. Intensive dose intensification strategies, particularly those that concurrently dose increase and interval shorten, appear to achieve higher infliximab levels than standard dose intensification strategies. This may be particularly important in the pursuit of stringent endpoints, such as endoscopic remission and fistula healing, which have been consistently associated with higher infliximab trough levels. These findings require validation across real-world cohorts.

Asunto(s)

Colitis Ulcerosa , Enfermedad de Crohn , Infliximab , Infliximab/farmacocinética , Infliximab/administración & dosificación , Infliximab/uso terapéutico , Humanos , Enfermedad de Crohn/tratamiento farmacológico , Colitis Ulcerosa/tratamiento farmacológico , Fármacos Gastrointestinales/farmacocinética , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/uso terapéutico , Relación Dosis-Respuesta a Droga , Simulación por Computador , Adulto , Masculino , Resultado del Tratamiento , Femenino , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico

Asunto(s)

Enfermedad de Crohn , Glomerulonefritis por IGA , Infliximab , Humanos , Enfermedad de Crohn/tratamiento farmacológico , Infliximab/efectos adversos , Infliximab/uso terapéutico , Infliximab/administración & dosificación , Glomerulonefritis por IGA/tratamiento farmacológico , Masculino , Adulto , Femenino , Factores de Tiempo , Fármacos Gastrointestinales/efectos adversos , Fármacos Gastrointestinales/uso terapéutico , Fármacos Gastrointestinales/administración & dosificación , Persona de Mediana Edad

RESUMEN

BACKGROUND: A few prospective cohort studies support the safety of switching from intravenous to subcutaneous administration of vedolizumab during maintenance therapy in patients with inflammatory bowel disease. Real-life data on switching after intravenous induction therapy are lacking. OBJECTIVE: The aim was to obtain real-world data on subcutaneous vedolizumab treatment in patients with inflammatory bowel disease after switching from intravenous vedolizumab induction or maintenance therapy, and to evaluate treatment persistence, safety, and changes in disease activity and serum vedolizumab concentrations. METHODS: We performed a retrospective registry-based study of inflammatory bowel disease patients who received subcutaneous vedolizumab therapy in two tertiary centres. RESULTS: Altogether, 103 patients (26 Crohn's disease and 77 ulcerative colitis) switching from intravenous maintenance therapy (group 1) and 44 patients (14 and 30, respectively) switching from intravenous induction therapy (group 2) were included. At 6 months from baseline, 90.3% of the patients in group 1 and 90.9% of the patients in group 2 continued on subcutaneous vedolizumab. After the switch in group 1, disease activity remained stable. In group 2, clinical disease activity decreased significantly in ulcerative colitis patients ( P  = 0.002). The median serum vedolizumab concentration was 34.00 µg/ml during subcutaneous maintenance therapy in group 1, which was significantly higher than the median concentration during intravenous therapy (17.00 µg/ml, P  < 0.001), but remained unchanged in group 2 after the switch (31.50 µg/ml). CONCLUSION: Based on these data, subcutaneous vedolizumab treatment is well-tolerated and the treatment persistence remains high after switching from intravenous to subcutaneous vedolizumab therapy.

Asunto(s)

Anticuerpos Monoclonales Humanizados , Colitis Ulcerosa , Enfermedad de Crohn , Fármacos Gastrointestinales , Quimioterapia de Mantención , Sistema de Registros , Humanos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Femenino , Masculino , Adulto , Estudios Retrospectivos , Colitis Ulcerosa/tratamiento farmacológico , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/sangre , Fármacos Gastrointestinales/uso terapéutico , Fármacos Gastrointestinales/farmacocinética , Persona de Mediana Edad , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/sangre , Inyecciones Subcutáneas , Resultado del Tratamiento , Sustitución de Medicamentos , Infusiones Intravenosas , Administración Intravenosa , Adulto Joven , Factores de Tiempo

RESUMEN

BACKGROUND: Remarkable progress over the last decade has equipped clinicians with many options in the treatment of inflammatory bowel disease. Clinicians now have the unique opportunity to provide individualized treatment that can achieve and sustain remission in many patients. However, issues of primary non-response (PNR) and secondary loss of response (SLOR) to non-tumour necrosis factor inhibitor (TNFi) therapies remains a common problem. Specific issues include the choice of optimization of therapy, identifying when dose optimization will recapture response, establishing optimal dose for escalation and when to switch therapy. AIM: To explores the issues of PNR and SLOR to non-TNFi therapies. METHODS: This review explores the current evidence and literature to elucidate management options in cases of PNR/SLOR. It will also explore potential predictors for response following SLOR/PNR to therapies including the role of therapeutic drug monitoring (TDM). RESULTS: In the setting of PNR and loss of response to alpha-beta7-integrin inhibitors and interleukin (IL)-12 and IL-23 inhibitors dose optimization is a reasonable option to capture response. For Janus kinase inhibitors dose optimization can be utilized to recapture response with loss of response. CONCLUSION: The role of TDM in the setting of advanced non-TNFi therapies to identify patients who require dose optimization and as a predictor for clinical remission is not yet established and this remains an area that should be addressed in the future.

Asunto(s)

Monitoreo de Drogas , Enfermedades Inflamatorias del Intestino , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/inmunología , Monitoreo de Drogas/métodos , Fármacos Gastrointestinales/uso terapéutico , Fármacos Gastrointestinales/administración & dosificación , Inhibidores de las Cinasas Janus/uso terapéutico , Inhibidores de las Cinasas Janus/administración & dosificación , Insuficiencia del Tratamiento , Inducción de Remisión/métodos , Resultado del Tratamiento , Sustitución de Medicamentos

RESUMEN

INTRODUCTION: Hepatic encephalopathy (HE) is a severe neuropsychiatric complication of liver diseases characterized by neuroinflammation. The efficacies of nonabsorbable rifaximin (RIF) and lactulose (LAC) have been well documented in the treatment of HE. [18F]PBR146 is a translocator protein (TSPO) radiotracer used for in vivo neuroinflammation imaging. This study investigated anti-neuroinflammation effect of RIF or/and LAC in chronic HE rats by [18F]PBR146 micro-PET/CT. METHODS: Bile duct ligation (BDL) operation induced chronic HE models, and this study included Sham+normal saline (NS), BDL+NS, BDL+RIF, BDL+LAC, and BDL+RIF+LAC groups. Behavioral assessment was performed to analyze the motor function, and fecal samples were collected after successfully established the chronic HE model (more than 28 days post-surgery). In addition, fecal samples collection and micro-PET/CT scans were performed sequentially. And we also collected the blood plasma, liver, intestinal, and brain samples after sacrificing the rats for further biochemical and pathological analyses. RESULTS: The RIF- and/or LAC-treated BDL rats showed similar behavioral results with Sham+NS group, while the treatment could not reverse the biliary obstruction resulting in sustained liver injury. The RIF or/and LAC treatments can inhibit IFN-γ and IL-10 productions. The global brain uptake values of [18F]PBR146 in BDL+NS group was significantly higher than other groups (p < .0001). The brain regions analysis showed that the basal ganglia, hippocampus, and cingulate cortex had radiotracer uptake differences among groups (all p < .05), which were consistent with the brain immunohistochemistry results. Sham+NS group was mainly enriched in Christensenella, Coprobacillus, and Pseudoflavonifractor. BDL+NS group was mainly enriched in Barnesiella, Alloprevotella, Enterococcus, and Enterorhabdus. BDL+RIF+LAC group was enriched in Parabacteroides, Bacteroides, Allobaculum, Bifidobacterium, and Parasutterella. CONCLUSIONS: RIF or/and LAC had anti-neuroinflammation in BDL-induced chronic HE rats with gut microbiota alterations. The [18F]PBR146 could be used for monitoring RIF or/and LAC treatment efficacy of chronic HE rats.

Asunto(s)

Encefalopatía Hepática , Lactulosa , Ratas Sprague-Dawley , Rifaximina , Animales , Encefalopatía Hepática/tratamiento farmacológico , Encefalopatía Hepática/diagnóstico por imagen , Encefalopatía Hepática/metabolismo , Rifaximina/farmacología , Ratas , Masculino , Lactulosa/farmacología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Modelos Animales de Enfermedad , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/diagnóstico por imagen , Fármacos Gastrointestinales/farmacología , Fármacos Gastrointestinales/administración & dosificación , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Radioisótopos de Flúor , Proteínas Portadoras , Receptores de GABA-A

RESUMEN

INTRODUCTION: Several studies associate the presence of higher serum concentrations of infliximab (IFX) with fistula healing in perianal Crohn's disease (CD). This study aimed to evaluate serum IFX concentrations in patients with perianal fistulizing CD (PFCD) in the presence or absence of general, clinical, and radiological activities. METHODS: This was a cross-sectional study in patients with PFCD during maintenance treatment with IFX from two centers. Serum IFX concentrations were measured before their next infusion and anal fistulas were evaluated by clinical examination and magnetic resonance imaging (MRI), whenever possible, performed 90 days before or after serum collection. According to clinical scores, radiological activity, and disease markers, patients were classified as in remission or active disease. Mean serum IFX concentrations were compared between the groups. RESULTS: Thirty-eight patients with PFCD were included. Demographic characteristics were similar in patients with remission or active disease. The overall mean serum IFX concentration of the entire sample (n = 38) was 5.21 ± 4.75 µg/mL (median 3.63; IQR 1.44-8.82). Serum IFX levels were 6.25 ± 5.34 µg/mL (median 3.62; IQR 1.95-11.03) in the 23 (60.5%) patients in remission and 3.63 ± 3.24 µg/mL (median 3.63; IQR 1.32-6.43; p = 0.226) in the 15 (39 .5%) who presented active disease. When evaluating general, clinical, and radiological activity of PFCD, and deep remission in isolation, no statistical difference between the groups was observed (p = 0.226, p = 0.418, p = 0.126, and p = 0.232, respectively). The 13 (34.2%) patients with an optimized dose of IFX had significantly higher serum concentrations than the remaining 25 (65.8%) with a standard dose: 8.33 ± 4.41 µg/mL (median 8.36; IQR 3.82-11.20) vs. 3.59 ± 4.13 µg/mL (median 1.97; IQR 1.18-3.85) -p = 0.002. Patients in remission and with an optimized IFX dose had significantly higher serum IFX concentrations than those with a standard dose (p = 0.006), whereas no significant difference was observed among those with active disease (p = 0.083). CONCLUSION: There were no differences in IFX serum concentrations in patients with clinical or radiological active PFCD as compared with those in remission. Patients with an optimized IFX dose had significantly higher serum concentrations than those with a standard dose. Patients in remission and with an optimized IFX dose had significantly higher serum concentrations than those with a standard dose.

Asunto(s)

Enfermedad de Crohn , Fármacos Gastrointestinales , Infliximab , Imagen por Resonancia Magnética , Fístula Rectal , Humanos , Enfermedad de Crohn/sangre , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/tratamiento farmacológico , Estudios Transversales , Fístula Rectal/sangre , Fístula Rectal/etiología , Fístula Rectal/tratamiento farmacológico , Infliximab/sangre , Infliximab/uso terapéutico , Infliximab/administración & dosificación , Masculino , Femenino , Adulto , Fármacos Gastrointestinales/sangre , Fármacos Gastrointestinales/uso terapéutico , Fármacos Gastrointestinales/administración & dosificación , Persona de Mediana Edad , Adulto Joven , Índice de Severidad de la Enfermedad , Inducción de Remisión

RESUMEN

INTRODUCTION: A substantial proportion of patients with inflammatory bowel disease (IBD) on intravenous infliximab require dose intensification. Accessing additional intravenous infliximab is labour-intensive and expensive, depending on insurance and pharmaceutical reimbursement. Observational data suggest that subcutaneous infliximab may offer a convenient and safe alternative to maintain disease remission in patients requiring dose-intensified infliximab. A prospective, controlled trial is required to confirm that subcutaneous infliximab is as effective as dose-intensified intravenous infliximab, to identify predictors of disease flare and to establish the role of subcutaneous infliximab therapeutic drug monitoring. METHODS AND ANALYSIS: The DISCUS-IBD trial is an investigator-initiated, prospective, multicentre, randomised, open-label non-inferiority study comparing the rate of disease flares in participants randomised to continue dose-intensified intravenous infliximab to those switched to subcutaneous infliximab after 48 weeks. Participants are adult patients with IBD in sustained corticosteroid-free remission on any regimen of dose-intensified infliximab up to a maximum of 10 mg/kg 4-weekly intravenously. Participants allocated to intravenous infliximab will continue infliximab at the same dose-intensified regimen they were receiving at study enrolment. Subcutaneous infliximab dosing will be stratified by prior intravenous infliximab dosing. Clinical (Harvey-Bradshaw Index, partial Mayo score), biochemical (C reactive protein, faecal calprotectin), pharmacokinetic (drug-level±antidrug antibodies) and qualitative data are collected 12-weekly until study conclusion at week 48. 13 sites across Australia will participate in recruitment to reach a calculated sample size of 120 participants. ETHICS AND DISSEMINATION: Multisite ethics approval was obtained from the Health District Human Research Ethics Committee (HREC) at The Alfred Hospital under a National Mutual Acceptance (NMA) agreement (HREC/90559/Alfred-2022; Local Reference: Project 618/22, version 1.6, 2 March 2023). Findings will be reported at national and international gastroenterology meetings and published in peer-reviewed journals. DISCUS-IBD was prospectively registered with the Australian and New Zealand Clinical Trials Registry (ANZCTR) prior to commencing recruitment. TRIAL REGISTRATION NUMBER: ACTRN12622001458729.

Asunto(s)

Fármacos Gastrointestinales , Enfermedades Inflamatorias del Intestino , Infliximab , Adulto , Femenino , Humanos , Masculino , Administración Intravenosa , Australia , Monitoreo de Drogas/métodos , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Infliximab/administración & dosificación , Infliximab/uso terapéutico , Infliximab/farmacocinética , Inyecciones Subcutáneas , Estudios Multicéntricos como Asunto , Estudios Prospectivos

RESUMEN

INTRODUCTION: Infliximab (IFX) biosimilars are available to treat inflammatory bowel disease (IBD), offering cost reductions versus originator IFX in some jurisdictions. However, concerns remain regarding the efficacy and safety of originator-to-biosimilar switching. This systematic literature review evaluated safety and effectiveness of switching between IFX products in patients with IBD, including multiple switchers. METHODS: Embase, PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials were searched to capture studies (2012-2022) including patients with IBD who switched between approved IFX products. Effectiveness outcomes: disease activity; disease severity; response to treatment; patient-reported outcomes (PROs). Safety outcomes: incidence and rate of adverse events (AEs); discontinuations due to AEs, failure rate; hospitalizations; surgeries. Immunogenicity outcomes (n, %): anti-drug antibodies; patients receiving concomitant immunomodulatory medication. RESULTS: Data from 85 publications (81 observational, two randomized controlled trials) were included. Clinical effectiveness outcomes were consistent with the known profile of originator IFX with no difference after switching. There were no unexpected/serious AEs after switching, and rates of AEs were generally consistent with the known profile of IFX. CONCLUSIONS: Most studies reported that clinical, PROs, and safety outcomes for originator-to-biosimilar switching were clinically equivalent to originator responses. Limited data are available regarding multiple switches. PROTOCOL REGISTRATION: www.crd.york.ac.uk/prospero identifier is CRD42021289144.

Asunto(s)

Biosimilares Farmacéuticos , Sustitución de Medicamentos , Fármacos Gastrointestinales , Enfermedades Inflamatorias del Intestino , Infliximab , Humanos , Infliximab/efectos adversos , Infliximab/uso terapéutico , Infliximab/administración & dosificación , Biosimilares Farmacéuticos/efectos adversos , Biosimilares Farmacéuticos/uso terapéutico , Biosimilares Farmacéuticos/administración & dosificación , Biosimilares Farmacéuticos/economía , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/inmunología , Fármacos Gastrointestinales/efectos adversos , Fármacos Gastrointestinales/uso terapéutico , Fármacos Gastrointestinales/administración & dosificación , Resultado del Tratamiento

RESUMEN

AIMS: Use of infliximab (IFX) has improved outcomes in children with inflammatory bowel disease (IBD). However, a proportion of patients does not respond to IFX or loses response over time. Population pharmacokinetic (PopPK) modelling is a promising approach for IFX dose optimization, but with the increasing number of PopPK models in literature, model evaluation is essential. The aims of this study are: (i) to validate the predictive performance of existing IFX PopPK models using a cohort of children with IBD; and (ii) to perform a Bayesian estimation of the most suitable model to predict the next IFX concentrations. METHODS: PubMed was searched for IFX PopPK models in children. Selected models were rebuilt and analysed using R. Model performance was assessed through goodness-of-fit-plots, residuals against time, prediction error and prediction-corrected visual predictive checks. The validation cohort consisted of 73 children with IBD who were treated with IFX in our centre between 2017 and 2023 (340 IFX measurements). RESULTS: We identified 9 PopPK models. Model bias for individual predicted values ranged from -9.29% to 8.01% compared to bias for population predicted values. The model by Vande Casteele et al. demonstrated superior performance (individual predicted bias 2.13, population predicted bias -6.11); upon Bayesian estimation, it predicted induction trough levels with median error of 12.95% but had a median error of -69% predicting maintenance concentrations. CONCLUSION: The model by Vande Casteele et al. displayed superior performance in initial evaluations but had a high error in estimating next IFX levels and can only be used in practice to predict induction levels.

Asunto(s)

Teorema de Bayes , Fármacos Gastrointestinales , Infliximab , Modelos Biológicos , Humanos , Infliximab/farmacocinética , Infliximab/administración & dosificación , Infliximab/uso terapéutico , Infliximab/sangre , Niño , Adolescente , Masculino , Femenino , Fármacos Gastrointestinales/farmacocinética , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/sangre , Fármacos Gastrointestinales/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Preescolar , Relación Dosis-Respuesta a Droga

RESUMEN

Data from phase IIb/III and phase III studies were used to characterize the population pharmacokinetics of risankizumab and its exposure-response relationships for efficacy and safety in ulcerative colitis (UC) patients. A two-compartment model with first-order absorption and elimination accurately described risankizumab pharmacokinetics. Although certain covariates, namely, body weight, serum albumin, fecal calprotectin, sex, corticosteroid use, advanced therapy inadequate response, and pancolitis, were statistically correlated with risankizumab clearance, their impact on exposure was not clinically meaningful for efficacy or safety. Phase II exposure-response analyses demonstrated that the 1,200 mg intravenous (IV) induction dose at Weeks 0, 4, and 8 achieved near maximal response for all efficacy end points, with suboptimal efficacy from the 600 mg and little added benefit from the 1,800 mg regimens, justifying 1,200 mg IV as the induction dose in the phase III study. Phase III exposure-response analyses for efficacy during induction showed statistically significant exposure-response relationships at Week 12 following 1,200 mg IV at Weeks 0, 4, and 8, in line with phase IIb results. Exposure-response analyses for maintenance demonstrated modest improvement in Week 52 efficacy when increasing the subcutaneous dose from 180 mg to 360 mg with largely overlapping confidence intervals. Exposure-response analyses for safety indicated no apparent exposure-dependent safety events over the induction or maintenance treatment. Based on these results, the recommended dosing regimen for risankizumab in UC patients is 1,200 mg IV at Weeks 0, 4, and 8, followed by 180 mg or 360 mg subcutaneously at Week 12 and every 8 weeks thereafter.

Asunto(s)

Anticuerpos Monoclonales , Colitis Ulcerosa , Relación Dosis-Respuesta a Droga , Modelos Biológicos , Humanos , Colitis Ulcerosa/tratamiento farmacológico , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Resultado del Tratamiento , Adulto Joven , Anciano , Fármacos Gastrointestinales/farmacocinética , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/efectos adversos , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Adolescente

RESUMEN

Background/Aims: Studies on elective switching to the subcutaneous (SC) formulation of infliximab revealed comparable efficacy and safety and higher infliximab level than those exhibited by intravenous (IV) infliximab. However, no studies have reported on the effectiveness of SC switching in ulcerative colitis (UC) patients who experienced IV infliximab failure during maintenance treatment. Methods: This retrospective study included UC patients who had been switched to SC infliximab because of IV infliximab failure, between January 2021 and January 2023. Group A was defined as having clinically and biochemically active UC (secondary loss of response), and group B consisted of patients with stable symptoms but biochemically active UC. Results: Twenty-three patients met the inclusion criteria: 15 in group A and eight in group B. The serum infliximab levels significantly increased after SC switching in both groups. The electively switched group also exhibited increased infliximab levels after SC switching. Patients in group A showed improved partial Mayo score with a significant decrease in fecal calprotectin and C-reactive protein after switching. In group B, the fecal calprotectin level significantly decreased without clinical relapse after switching. A high proportion of patients (≥80%) in both groups achieved clinical and/or biochemical responses at the last follow-up. During the follow-up period, only two patients in group A discontinued SC infliximab, and only one complained of severe injection site reaction. Conclusions: In UC patients who experience IV infliximab failure during maintenance treatment, switching to SC infliximab may be a promising option because of better efficacy and safety.

Asunto(s)

Colitis Ulcerosa , Sustitución de Medicamentos , Fármacos Gastrointestinales , Infliximab , Insuficiencia del Tratamiento , Humanos , Colitis Ulcerosa/tratamiento farmacológico , Infliximab/administración & dosificación , Infliximab/farmacocinética , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Adulto , Inyecciones Subcutáneas , Sustitución de Medicamentos/métodos , Fármacos Gastrointestinales/administración & dosificación , Administración Intravenosa , Complejo de Antígeno L1 de Leucocito/análisis , Proteína C-Reactiva/análisis , Heces/química , Resultado del Tratamiento

RESUMEN

INTRODUCTION: Treatment of complex perianal fistulas in Crohn's disease remains a challenge especially after the failure of Infliximab. AIM: Update on the different therapeutic alternatives for anal fistula in Crohn's disease after failure of Infliximab. METHODS: A research in the medical literature on PubMed and Google Scholar was carried out. We included cohort studies, reviews and randomized double-blinded therapeutic trials. Case reports and fundamental research studies have been excluded. RESULTS: Anti-TNF therapy, notably Infliximab remain the therapeutic option of choice. Since Infliximab efficacy has been estimated at 60%, with a significant loss-of response rate, new therapeutic strategies have been evaluated and may offer new opportunities for the management of anal fistulas: for example, Ustekinumab could be effective after failure of anti-TNF therapy, although further studies are required. Recent guidelines suggest that injection of mesenchymal stem cells is an effective and safe treatment for complex fistulas. Other surgical options have been proposed, such as endorectal advancement flap, fibrin glue injection, anal fistula plug and ligation of the intersphincteric fistula tract, but all with limited and debatable efficacy. Given the failure rate of all these options, new strategies are currently being evaluated. CONCLUSION: Anal fistulas in Crohn's disease are a real therapeutic challenge. New medical and surgical therapies are currently being evaluated, with promising results.

Asunto(s)

Enfermedad de Crohn , Fármacos Gastrointestinales , Infliximab , Fístula Rectal , Insuficiencia del Tratamiento , Humanos , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/tratamiento farmacológico , Fístula Rectal/etiología , Fístula Rectal/tratamiento farmacológico , Fístula Rectal/terapia , Infliximab/uso terapéutico , Fármacos Gastrointestinales/uso terapéutico , Fármacos Gastrointestinales/administración & dosificación

RESUMEN

BACKGROUND AND OBJECTIVE: The influence of concomitant prednisolone on clinical outcomes and safety in infliximab-treated ulcerative colitis (UC) patients is unknown. DESIGN, SETTING, PARTICIPANTS AND OUTCOME MEASURES: A retrospective cohort study was performed, including 147 UC patients treated with infliximab at a tertiary inflammatory bowel disease (IBD) centre. Primary outcome was corticosteroid-free clinical remission (CFCR) at week 14 and week 52. Patients were grouped according to prednisolone tapering regimens: standard (≤5 mg/week), fast (>5 mg/week), direct discontinuation or no prednisolone. Patients intolerant to corticosteroids and patients stopping corticosteroids in preparation for surgery including colectomy during their initial admission were excluded. RESULTS: There was no overall association between prednisolone exposure or no exposure and CFCR at weeks 14 or 52 of infliximab. The proportion of patients with C reactive protein ≤5 mg/L was higher in the standard tapering at week 14 as compared with faster regimens or no prednisolone. In subgroup analyses, the standard tapering was associated with a higher rate of CFCR at week 14 compared with the fast-tapering regimen in patients receiving ≥40 mg prednisolone at initiation of infliximab (64.3% vs 26.3%, p=0.04) and among patients admitted with acute severe UC (66.6% vs 23.5%, p<0.05). Similar data were seen at week 52. Prednisolone did not affect infliximab trough levels but increased infection rates (10/77 vs 2/70, p=0.03), in particular C. difficile infection. CONCLUSION: In UC patients with limited disease burden, prednisolone did not affect effectiveness of infliximab. However, patients with increased disease burden seem to benefit from corticosteroid combination therapy.

Asunto(s)

Colitis Ulcerosa , Fármacos Gastrointestinales , Infliximab , Prednisolona , Inducción de Remisión , Humanos , Colitis Ulcerosa/tratamiento farmacológico , Infliximab/administración & dosificación , Infliximab/uso terapéutico , Estudios Retrospectivos , Prednisolona/administración & dosificación , Prednisolona/uso terapéutico , Masculino , Femenino , Adulto , Persona de Mediana Edad , Resultado del Tratamiento , Inducción de Remisión/métodos , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/uso terapéutico , Reducción Gradual de Medicamentos/métodos , Antiinflamatorios/administración & dosificación , Antiinflamatorios/uso terapéutico , Antiinflamatorios/efectos adversos , Proteína C-Reactiva/análisis , Proteína C-Reactiva/metabolismo , Glucocorticoides/administración & dosificación , Glucocorticoides/uso terapéutico , Glucocorticoides/efectos adversos , Quimioterapia Combinada

RESUMEN

INTRODUCTION: Medications are frequently prescribed for patients with irritable bowel syndrome (IBS) or disorders of gut brain interaction. The level of drug metabolism and modifications in drug targets determine medication efficacy to modify motor or sensory function as well as patient response outcomes. AREAS COVERED: The literature search included PubMed searches with the terms: pharmacokinetics, pharmacogenomics, epigenetics, clinical trials, irritable bowel syndrome, disorders of gut brain interaction, and genome-wide association studies. The main topics covered in relation to irritable bowel syndrome were precision medicine, pharmacogenomics related to drug metabolism, pharmacogenomics related to mechanistic targets, and epigenetics. EXPERT OPINION: Pharmacogenomics impacting drug metabolism [CYP 2D6 (cytochrome P450 2D6) or 2C19 (cytochrome P450 2C19)] is the most practical approach to precision medicine in the treatment of IBS. Although there are proof of concept studies that have documented the importance of genetic modification of transmitters or receptors in altering responses to medications in IBS, these principles have rarely been applied in patient response outcomes. Genome-wide association (GWAS) studies have now documented the association of symptoms with genetic variation but not the evaluation of treatment responses. Considerably more research, particularly focused on patient response outcomes and epigenetics, is essential to impact this field in clinical medicine.

Asunto(s)

Estudio de Asociación del Genoma Completo , Síndrome del Colon Irritable , Farmacogenética , Medicina de Precisión , Humanos , Síndrome del Colon Irritable/tratamiento farmacológico , Síndrome del Colon Irritable/genética , Medicina de Precisión/métodos , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Fármacos Gastrointestinales/farmacología , Fármacos Gastrointestinales/farmacocinética , Fármacos Gastrointestinales/administración & dosificación , Preparaciones Farmacéuticas/metabolismo , Preparaciones Farmacéuticas/administración & dosificación , Epigénesis Genética , Animales

RESUMEN

BACKGROUND: Infliximab (IFX) exposure is established as a predictive factor of pharmacokinetic (PK) origin in inflammatory bowel disease (IBD), and expert consensus is to achieve adequate exposure during induction to achieve and sustain remission. METHODS: We retrospectively evaluated the performance of a Bayesian PK tool in IBD patients starting IFX. Trough IFX serum levels collected immediately before the third (at week 6) and fourth (at week 14) infusions were evaluated from 307 IBD patients (median age=17 years, 50 % females, 83 % with Crohn's disease). Forecasted IFX concentration at the fourth infusion were estimated using serum IFX, antibodies to IFX, albumin and weight determined immediately before the third infusion using population PK calculator with Bayesian prior. The outcome variable was a clinical & biochemical remission status achieved (CRP levels below 3 mg/L in presence of clinical remission). Statistics consisted of Kaplan Meier analysis with calculation of Hazard ratio (HR), and logistic regression. RESULTS: IFX concentration above 15 µg/mL immediately before the third infusion associated with shorter time to clinical & biochemical remission than concentration below 15 µg/mL without reaching significance (163±14 days vs 200±16 days, respectively; p=0.052). However, using PK parameters at the third infusion, forecasted IFX concentrations above 10 µg/mL immediately before the fourth infusion were significantly associated with a higher rate (HR=1.6 95 %CI: 1.1 to 2.1 p<0.01) and shorter time to remission (148±18 days vs 200±13 days p<0.01). In the presence of IFX concentration above 15 µg/mL at the third infusion, there was a significant 2.5-fold higher likelihood of sustained clinical & biochemical remission status during maintenance as compared to IFX concentrations below 15 µg/mL (p<0.01). Forecasted IFX level above 10 µg/mL at fourth infusion associated with significantly 3.9-fold higher likelihood of clinical & biochemical remission as compared to forecasted IFX concentrations below 10 µg/mL (p<0.01). CONCLUSIONS: These data further support that optimized IFX concentrations during induction are associated with enhanced disease control in IBD.

Asunto(s)

Fármacos Gastrointestinales , Enfermedades Inflamatorias del Intestino , Infliximab , Inducción de Remisión , Humanos , Infliximab/farmacocinética , Infliximab/sangre , Infliximab/administración & dosificación , Infliximab/uso terapéutico , Femenino , Masculino , Estudios Retrospectivos , Adolescente , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/sangre , Fármacos Gastrointestinales/sangre , Fármacos Gastrointestinales/farmacocinética , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/uso terapéutico , Adulto , Factores de Tiempo , Adulto Joven , Teorema de Bayes , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/sangre , Persona de Mediana Edad

RESUMEN

BACKGROUND: The aim was to examine rifaximin plus lactulose efficacy in patients with cirrhosis at a risk of developing overt HE who were stratified by important baseline characteristics such as comorbid ascites or diabetes. METHODS: Pooled post hoc subgroup analysis of adults receiving rifaximin 550 mg twice daily plus lactulose or lactulose alone for 6 months in a phase 3 randomized, double-blind trial and a phase 4 open-label trial was conducted. RESULTS AND CONCLUSION: Rifaximin plus lactulose was more efficacious than lactulose alone for reducing the risk of overt HE recurrence and HE-related hospitalization in adults grouped by select baseline disease characteristics.

Asunto(s)

Quimioterapia Combinada , Fármacos Gastrointestinales , Encefalopatía Hepática , Lactulosa , Recurrencia , Rifaximina , Humanos , Rifaximina/uso terapéutico , Rifaximina/administración & dosificación , Lactulosa/uso terapéutico , Lactulosa/administración & dosificación , Masculino , Persona de Mediana Edad , Método Doble Ciego , Femenino , Fármacos Gastrointestinales/uso terapéutico , Fármacos Gastrointestinales/administración & dosificación , Encefalopatía Hepática/tratamiento farmacológico , Encefalopatía Hepática/prevención & control , Cirrosis Hepática/complicaciones , Cirrosis Hepática/tratamiento farmacológico , Adulto , Prevención Secundaria/métodos , Anciano , Resultado del Tratamiento

Asunto(s)

Colitis Ulcerosa , Fármacos Gastrointestinales , Infliximab , Humanos , Infliximab/uso terapéutico , Infliximab/administración & dosificación , Colitis Ulcerosa/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Fármacos Gastrointestinales/administración & dosificación , Dieta Vegetariana , Índice de Severidad de la Enfermedad , Terapia Combinada , Resultado del Tratamiento , Dieta a Base de Plantas

Asunto(s)

Colitis Ulcerosa , Fármacos Gastrointestinales , Infliximab , Humanos , Infliximab/uso terapéutico , Infliximab/administración & dosificación , Colitis Ulcerosa/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Fármacos Gastrointestinales/administración & dosificación , Dieta Vegetariana , Índice de Severidad de la Enfermedad , Dieta a Base de Plantas

RESUMEN

BACKGROUND: Tumor necrosis factor-α inhibitors (TNFis) are used for the treatment of inflammatory bowel disease (IBD). The aim of this study was to evaluate the association between neurological adverse events (AEs) and TNFi use. METHODS: Data of TNFis indicated for IBD were collected from the Food and Drug Administration Adverse Event Reporting System (FAERS) from the marketed date to the second quarter of 2023. The reporting odds ratio (ROR) and a Bayesian confidence propagation neural network were used to identify signals. RESULTS: A total of 4,964 neurological AEs were reported in the IBD population. Infliximab had 3 signals, including demyelination [ROR (95% CI): 1.69 (1.33,2.15)], meningitis listeria [ROR (95% CI): 5.05 (3.52,7.25)], and optic neuritis [ROR (95% CI): 1.72 (1.3,2.26)]. The signals for adalimumab were gait disturbance [ROR (95% CI): 1.43 (1.32,1.56)] and muscular weakness [ROR (95% CI): 1.4 (1.27,1.55)]. A peripheral neuropathy signal was found for adalimumab [ROR (95% CI): 1.34 (1.18,1.53)] and certolizumab pegol [ROR (95% CI): 1.49 (1.07,2.08)]. However, there were no signals among neurological AEs for golimumab. CONCLUSION: Neurological signals were detected for TNFi use, indicating that the risk of neurological AEs requires additional attention in clinical use of TNFis.

Asunto(s)

Adalimumab , Sistemas de Registro de Reacción Adversa a Medicamentos , Enfermedades Inflamatorias del Intestino , Infliximab , Enfermedades del Sistema Nervioso , Farmacovigilancia , Factor de Necrosis Tumoral alfa , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades del Sistema Nervioso/inducido químicamente , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , Adalimumab/efectos adversos , Adalimumab/administración & dosificación , Femenino , Masculino , Adulto , Infliximab/efectos adversos , Infliximab/administración & dosificación , Persona de Mediana Edad , Fármacos Gastrointestinales/efectos adversos , Fármacos Gastrointestinales/administración & dosificación , Estados Unidos , Teorema de Bayes , Adulto Joven , Anciano , Adolescente