Best Practice for Therapeutic Drug Monitoring of Infliximab: Position Statement from the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

BACKGROUND: Infliximab, an anti-tumor necrosis factor monoclonal antibody, has revolutionized the pharmacological management of immune-mediated inflammatory diseases (IMIDs). This position statement critically reviews and examines existing data on therapeutic drug monitoring (TDM) of infliximab in patients with IMIDs. It provides a practical guide on implementing TDM in current clinical practices and outlines priority areas for future research. METHODS: The endorsing TDM of Biologics and Pharmacometrics Committees of the International Association of TDM and Clinical Toxicology collaborated to create this position statement. RESULTS: Accumulating data support the evidence for TDM of infliximab in the treatment of inflammatory bowel diseases, with limited investigation in other IMIDs. A universal approach to TDM may not fully realize the benefits of improving therapeutic outcomes. Patients at risk for increased infliximab clearance, particularly with a proactive strategy, stand to gain the most from TDM. Personalized exposure targets based on therapeutic goals, patient phenotype, and infliximab administration route are recommended. Rapid assays and home sampling strategies offer flexibility for point-of-care TDM. Ongoing studies on model-informed precision dosing in inflammatory bowel disease will help assess the additional value of precision dosing software tools. Patient education and empowerment, and electronic health record-integrated TDM solutions will facilitate routine TDM implementation. Although optimization of therapeutic effectiveness is a primary focus, the cost-reducing potential of TDM also merits consideration. CONCLUSIONS: Successful implementation of TDM for infliximab necessitates interdisciplinary collaboration among clinicians, hospital pharmacists, and (quantitative) clinical pharmacologists to ensure an efficient research trajectory.

Disease-modifying treatments for patients with multiple sclerosis in Spain. / Tratamientos modificadores de la enfermedad en pacientes con esclerosis múltiple en España.

Multiple sclerosis is a chronic demyelinating disease of the central nervous system and long-term disabling. Different disease-modifying treatments are available. These patients, despite being generally young, have high comorbidity and risk of polymedication due to their complex symptomatology and disability. OBJECTIVE PRIMARY: To determine the type of disease-modifying treatment in patients seen in Spanish hospital pharmacy departments. SECONDARY OBJECTIVES: To determine concomitant treatments, determine the prevalence of polypharmacy, identify the prevalence of interactions and analyse pharmacotherapeutic complexity. METHOD: Observational, cross-sectional, multicentre study. All patients with a diagnosis of multiple sclerosis and active disease-modifying treatment who were seen in outpatient clinics or day hospitals during the second week of February 2021 were included. Modifying treatment, comorbidities and concomitant treatments were collected to determine multimorbidity pattern, polypharmacy, pharmacotherapeutic complexity (Medication Regimen Complexity Index) and drug-drug interactions. RESULTS: 1,407 patients from 57 centres in 15 autonomous communities were included. The most frequent form of disease presentation was the relapsing remitting form (89.3%). The most prescribed disease-modifying treatment was dimethyl fumarate (19.1%), followed by teriflunomide (14.0%). Of the parenteral disease-modifying treatments, the two most prescribed were glatiramer acetate and natalizumab with 11.1% and 10.8%. 24.7% of the patients had one comorbidity and 39.8% had at least 2 comorbidities. 13.3% belonged to at least one of the defined patterns of multimorbidity and 16.5% belonged to 2 or more patterns. The concomitant treatments prescribed were psychotropic drugs (35.5%); antiepileptic drugs (13.9%) and antihypertensive drugs and drugs for cardiovascular pathologies (12.4%). The presence of polypharmacy was 32.7% and extreme polypharmacy 8.1%. The prevalence of interactions was 14.8%. Median pharmacotherapeutic complexity was 8.0 (IQR: 3.3 -- 15.0). CONCLUSIONS: We have described the disease-modifying treatment of patients with multiple sclerosis seen in Spanish pharmacy services and characterised concomitant treatments, the prevalence of polypharmacy, interactions, and their complexity.

Relationship between vedolizumab serum concentrations in the induction phase and early and sustained response in the first year of treatment in patients with ulcerative colitis.

OBJECTIVE: Evidence on the usefulness of proactive monitoring of vedolizumab serum concentrations during the induction phase of treatment is limited. The objective of our study was to evaluate the effectiveness of measuring such concentrations during this phase in predicting response to  treatment in patients with ulcerative colitis with a view to determining whether  patients would benefit from early monitoring of  edolizumab serum concentrations. METHOD: This was a prospective descriptive study carried out at three public  general hospitals. It included adult patients with ulcerative colitis who were  initiated on vedolizumab at the participating hospitals from June 2019 to June  2020. Vedolizumab serum concentrations were determined  at weeks 6 and 14.  Response to treatment was biologically, clinically, and endoscopically  evaluated at weeks 6, 14, and 52. An analysis was made of the relationship  between vedolizumab serum concentrations at week 6 and early response to  treatment, and of the relationship between the vedolizumab serum  concentrations at weeks 6 and 14 and persistent response at one year. RESULTS: A total of 45 patients were included of whom 22 (49%) were considered non-responsive after one year and required intensification of treatment. The median (interquartile range) vedolizumab serum  oncentrations obtained at 6 weeks was higher in patients who obtained an  early response and in those who maintained the response at one year than  in  those who did not respond to vedolizumab [27.4 (19.0-40.8) µg/mL vs 15.6  (13.4-28.5) µg/mL; p = 0.018] and [29.9 (19.2-43.2) µg/mL vs 18.2 (15.4- 26.9) µg/mL; p = 0.022] respectively. Vedolizumab serum concentrations ≥  17.3 µg/mL at week 6 were predictive of a good early response, and  edolizumab serum concentrations ≥ 26.1 µg/mL at week 6 predicted a  sustained response at one year. No relationship was found between  edolizumab serum concentrations at week 14 and a sustained response. CONCLUSIONS: We observed a relationship between vedolizumab serum concentrations determined at week 6, and early and maintained  esponse to vedolizumab therapy in patients with ulcerative colitis, which  supports early drug monitoring during the induction phase to individualize  treatment and increase effectiveness.

OBJETIVO: La evidencia sobre la utilidad de la monitorización proactiva de las  concentraciones séricas de vedolizumab en la fase de inducción del tratamiento es limitada. El objetivo del estudio ha sido evaluar la capacidad de las concentraciones séricas de vedolizumab determinadas en esta fase para predecir la respuesta al tratamiento en pacientes con colitis ulcerosa, con  el fin de establecer si los pacientes se beneficiarían clínicamente de una  monitorización precoz.Método: Estudio descriptivo, prospectivo, realizado en tres hospitales generales públicos. Incluyó a los pacientes adultos con colitis  ulcerosa, que iniciaron tratamiento con vedolizumab en los centros  participantes desde junio de 2019 a junio de 2020. Se determinaron las  concentraciones séricas de vedolizumab en las semanas 6 y 14 de tratamiento.  La respuesta bioquímica, clínica y endoscópica se evaluó en las  semanas 6, 14 y 52. Se estudió la relación de las concentraciones séricas de  vedolizumab determinadas en la semana 6 con la respuesta temprana al  tratamiento, así como la relación de las concentraciones séricas de  vedolizumab en las semanas 6 y 14 con la persistencia de respuesta al año de  tratamiento. RESULTADOS: Se incluyeron 45 pacientes, de los que 22 (49%) se consideraron no respondedores al cabo de un año y necesitaron intensificar el  tratamiento. Las medianas (rango intercuartílico) de las concentraciones séricas de vedolizumab en la semana 6 fueron superiores,  tanto en los pacientes que presentaron respuesta temprana como en los que  mantuvieron respuesta al cabo de un año, comparadas con las de los pacientes que no respondieron a vedolizumab [27,4 (19,0-40,8) µg/ml vs  15,6 (13,4­28,5) µg/ml; p = 0,018] y [29,9 (19,2-43,2) µg/ml vs 18,2  (15,4­26,9) µg/ml; p = 0,022], respectivamente. Las concentraciones séricas  de vedolizumab ≥ 17,3 µg/ml en la semana 6 predijeron una buena respuesta  temprana, y concentraciones séricas de vedolizumab ≥ 26,1 µg/ml en la  emana 6 predijeron una respuesta mantenida al cabo de un año. No se  encontró relación entre las concentraciones séricas de vedolizumab en la  semana 14 y la respuesta mantenida. CONCLUSIONES: Se ha observado una relación entre las concentraciones séricas  de vedolizumab determinadas en la semana 6 y la  respuesta temprana y mantenida a la terapia en pacientes con colitis ulcerosa,  lo que avala la monitorización precoz durante la fase de inducción, para individualizar el tratamiento y aumentar su eficacia.

Bayes-based dosing of infliximab in inflammatory bowel diseases: Short-term efficacy.

AIMS: Therapeutic drug monitoring of infliximab can guide clinical decisions in patients with loss of response and in those who can benefit from a de-intensification. The aim of this study was to determine the impact of therapeutic drug monitoring combined with Bayesian forecasting methodology on clinical response in a real-world dataset of patients suffering from inflammatory bowel disease. METHODS: We performed a single-centre prospective study with one-group pre-test/post-test design in 108 adult inflammatory bowel disease patients treated with model-based dosing of infliximab maintenance treatment. We recorded clinical activity scores (Harvey-Bradshaw index and partial Mayo) and inflammatory biomarkers per patient. RESULTS: The initial infliximab regimen was maintained in 49 (45.4%) patients and was adjusted in 59 (54.6%) patients (34 treatment intensifications, 9 de-intensifications and 16 treatment discontinuations or therapy replacements). The median time from intervention to index measurement was 126 (103-160) days. The overall proportion of patients in clinical remission increased from 65.7% to 80.4% (P < .0001) and the median infliximab trough concentrations increased from 3.21 (0.99-5.45) to 5.13 mg/L (3.57-6.53) (P < .0001). In the intensified group, the remission rate increased from 35.3% to 61.8% (P = .001) and the percentage of patients in clinical remission or with mild symptoms increased from 76.5% to 94.1%. In the de-intensification cohort, no patients experienced an increase in the Harvey-Bradshaw index or partial Mayo scores, and all patients maintained an infliximab trough concentration of >5 mg/L. CONCLUSION: In our cohort of inflammatory bowel disease patients, Bayes-based optimized dosing improved the short-term efficacy of infliximab treatment.

HLA-B*57: 01 genotyping in the prevention of hypersensitivity to abacavir: 5 years of experience.

INTRODUCTION: Most of the cost-effectiveness analyses are based on estimations to make decisions on the future implementation of a test. However, the model should be verified with real data to prove that previous estimations have been successfully fulfilled. OBJECTIVE: To study the economic impact of the systematic HLA-B*57:01 genotyping in preventing hypersensitivity reactions (HSRs) in the patient population of a tertiary-care hospital treated with abacavir (ABC) using retrospective data of 5 years of experience. METHODS: A retrospective study was carried out with two cohorts including 780 and 473 patients before and after the implementation of the systematic HLA-B*57:01 genotyping before ABC treatment. Cost-effectiveness analysis was carried out by the parameter 'cost per HSR avoided'. The clinical utility of the test was verified by evaluating the differences in HSR incidence between both cohorts. Finally, a sensitivity analysis including all variables was carried out. RESULTS: In the population studied, systematic genotyping represents an additional cost of &OV0556;306 per HSR avoided. In the sensitivity analysis, pharmacological therapy cost is the major influencing factor found in the estimation of the 'cost per HSR avoided'. In terms of clinical utility, the incidence ratio was 0.040 (95% confidence interval 0.0009-0.2399) and statistically significant differences were found between both groups (P=1.40×10). CONCLUSION: Retrospective data from 5 years of experience have confirmed the cost-effectiveness of the systematic genotyping in candidate patients for ABC therapy, and have shown that cost-effectiveness is a dynamic parameter closely linked to allele prevalence and pharmacological therapy costs.

PEG-Interferon-α ribavirin-induced HCV viral clearance: a pharmacogenetic multicenter Spanish study.

OBJECTIVE: Dual PEGylated interferon-α (PEG-IFN) and ribavirin therapy has been the main hepatitis C virus (HCV) treatment of the last decade. Current direct-acting antiviral agents have improved the outcome of therapy but also have increased the cost and management complexity of treatment. The current study analyzes host genetics, viral and clinical predictors of sustained viral response (SVR) to dual PEG-IFN and ribavirin therapy in a representative Spanish population. METHODS: Observational prospective multicentre pharmacogenetic cohort study conducted in 12 different hospitals of 12 different Spanish regions. A total of 98 patients with SVR and 106 with non-SVR in response to PEG-IFN and ribavirin therapy were included. 33 single nucleotide polymorphisms located in 24 different genes related with inflammatory, immune and virus response were selected. Clinical and viral data were also analyzed as candidate of SVR predictors. RESULTS: IL-28B (rs12979860, rs7248668, rs8105790, rs8099917) and TNFRSF1B (rs1061622) genotypes, as well as TNFRSF1B/IL-10/TNFα (-308) non-TTG and TNFRSF1B/IL- 10/IL-4 non-TTC haplotypes together with lower age, lower basal HCV RNA load, higher basal serum LDL cholesterol values, VHC genotypes 2 and 3 and basal low grade fibrosis 0-2 were associated with a SVR in the univariate analysis. Independent predictors of SVR in the multivariate analysis were IL-28B rs12979860 CC, TNFRSF1B/IL-10/IL-4 non-TTC along with low baseline HCV RNA load and HCV genotypes 2 and 3. CONCLUSIONS: IL-28B rs12979860 CC, TNFRSF1B/ IL-10/ IL-4 non-TTC haplotype, low baseline HCV RNA load and HCV genotypes 2 and 3 may help to predict successful outcome to PEG-IFN/ribavirin therapy in Spanish population.

Objetivo: El interferon-pegilado (IFN-PEG) junto a ribavirina ha sido el principal tratamiento de la infeccion por el virus de la hepatitis C (VHC) de la ultima decada. Los agentes antivirales de accion directa actuales han mejorado los resultados de la terapia, pero tambien han aumentado el costo y la gestion de la complejidad del tratamiento. El presente estudio analiza factores geneticos de los pacientes, asi como predictores virales y clinicos de respuesta sostenida viral (RSV) al tratamiento con IFN-PEG y ribavirina en poblacion Espanola. Métodos: Estudio farmacogenetico, multicentrico, prospectivo, observacional de cohortes realizado en 12 hospitales diferentes de 12 comunidades autonomas diferentes. Se incluyeron un total de 98 pacientes con RVS y 106 sin SVR al tratamiento con IFNPEG y ribavirina. Se seleccionaron 33 polimorfismos de nucleotido unico ubicados en 24 genes diferentes relacionados con la respuesta inflamatoria, inmunologica y viral. Los datos clinicos y virales tambien se analizaron como candidatos predictores de RVS. Resultados: Los genotipos IL-28B (rs12979860, rs7248668, rs8105790, rs8099917) y TNFRSF1B (rs1061622), asi como los haplotipos TNFRSF1B / IL-10 / TNF(-308) no-TTG y TNFRSF1B / IL-10 / IL-4 no-TTC junto con la menor edad, menor carga de ARN-VHC basal, valores elevados de colesterol LDL en suero basal, genotipos VHC2 y 3 y bajo grado de fibrosis basal (0-2) se asociaron con una RVS en el analisis univariante. Los predictores independientes de RVS en el analisis multivariante fueron el genotipo IL-28B rs12979860 CC, el haplotipo TNFRSF1B / IL-10 / IL-4 no-TTC junto con los bajos niveles basales de VHCARN y los genotipos virales VHC2 y 3. Conclusiones: El genotipo IL-28B rs12979860 CC, el haplotipo TNFRSF1B / IL-10 / IL-4 haplotipos no-TTC, la carga viral basal baja y los genotipos del VHC2 y 3 pueden ayudar a predecir una buena respuesta a la terapia con IFN-PEG y ribavirina en poblacion espanola.

[Retrospective analysis of omalizumab in patients with severe allergic asthma]. / Estudio observacional retrospectivo de la utilización de omalizumab en el tratamiento del asma grave persistente.

OBJECTIVE: To assess the efficacy and safety profile of omalizumab treatment. The conditions under which omalizumab was prescribed agreed with those in Xolair® drug information: age > 12 years old, severe uncontrolled asthma, FEV1 < 80%, IgE 30-700 UI/ml and positive test results for perennial allergens. METHODS: Asthmatic patients treated with omalizumab between January 2010 and July 2011 were evaluated retrospectively. Age, sex, weight, IgE level, concomitant asthma medications, change in FEV1, emergency department visits, hospitalizations, asthma exacerbations and corticosteroids bursts were recorded before and after omalizumab initiation. A 1.5- year period was chosen. RESULTS: A total of 22 patients were included. The mean weight of subjects was 73 Kg (range, 51-102). Mean IgE was 203 UI/ml (range, 30-992) and mean FEV1 60% (range, 30-93%) at baseline. Adverse events were observed in 4 patients. There were no significant changes in FEV1 values after omalizumab treatment but omalizumab was associated with a reduction in concomitant asthma medications use in 14 patients and improvements in global asthma control in 12. CONCLUSION: In these patients add-on therapy with omalizumab reduced asthma exacerbations and emergency visits or hospitalizations. Only 55% of patients significantly improved global asthma control and no significant changes in FEV1 were observed.

Objetivo: Evaluar la eficacia y seguridad del omalizumab. Las condiciones para la administración de dicho fármaco fueron las indicadas en ficha técnica: edad superior a 12 años, asma alérgica grave persistente, mal control de síntomas, FEV1<80%, IgE total entre 30 y 700 UI/mL y pruebas cutáneas y/o IgE específica positiva al alérgeno persistente. Método: Estudio retrospectivo observacional de pacientes que hubieran sido tratados con omalizumab en la indicación de asma grave durante el período enero 2010 a julio de 2011. Se registraron la edad, sexo, peso, IgE y reactividad in vitro a los alergenos perennes, FEV1, tratamiento de base, exacerbaciones asmáticas y necesidad de corticosteroides sistémicos o ingresos en urgencias, presencia de síntomas durante el día o que originen despertares durante la noche al inicio del tratamiento, a las 16 semanas, 32 semanas y a los 1,5 años tras al inicio del tratamiento. Se recogieron los efectos secundarios y los cambios en el tratamiento de base. Resultados: 22 pacientes con un peso medio de 73 kg (51-102). La concentración basal de IgE antes del inicio de omalizumab fue de 203 UI/ml (30-992). 21 pacientes presentaban una función pulmonar reducida, con un FEV1 al inicio del 60% (30-93%). El FEV1 a las 16 semanas fue del 60% (39-71%) y a las 32 semanas del 68% (29-102%). La dosis media de omalizumab administrada cada 30 días fue de 368 mg (150- 900 mg). Se observaron reacciones adversas en 4 pacientes, uno de los cuales requirió la retirada del tratamiento. Al final del periodo de seguimiento 14 pacientes habían disminuido el tratamiento control y doce presentaron mejoría global. Conclusión: Omalizumab se ha utilizado en pacientes con asma grave alérgica no respondedores a terapia convencional observándose una disminución en el número de exacerbaciones y visitas a urgencias e ingresos. Sólo un 55% experimentan una mejoría global según criterios clínicos y no se observaron cambios estadísticamente significativos en la FEV1.

Use of methoxy polyethylene glycol-epoetin beta in stage 3, 4 or 5 non-dialysis chronic kidney disease.

BACKGROUND: Methoxy polyethylene glycol-epoetin beta (PEG-EPO) is indicated for the treatment of anaemia due to chronic kidney disease. Its long half-life allows it to be administered once per month in maintenance therapy. OBJECTIVE: To evaluate the use, effectiveness and cost of PEG-EPO in a group of pre-dialysis chronic renal failure patients. METHOD: Retrospective observational study in pre-dialysis patients who began treatment with PEG-EPO between May 2008 and February 2009. The following data were gathered: age, sex, haemoglobin levels (Hb) and erythropoiesis-stimulating agent (ESA) dose and frequency. The follow-up period was 12 months. RESULTS: We included 198 patients. Mean Hb upon starting PEG-EPO in patients who had received no prior treatment was 10.8g/l, and 11.6g/l at 90 days (P<.0001). In patients previously treated with ESA, mean Hb before starting PEG-EPO treatment was 11.2g/l, and 11.4g/l at 12 months (P=.846). Hb values were higher than 12g/l (P<.0001) after 12 months of treatment in 25% of patients; of these, 45% had values above 13g/l. We observed doses 39% lower than those indicated on the drug leaflet, resulting in a reduction in the originally expected theoretical costs. CONCLUSIONS: The doses of PEG-EPO administered to patients with a prior history of ESA treatment were lower than those indicated by the drug leaflet, and Hb remained stable after 12 months of treatment. A large portion of the patients had levels above the 13g/l threshold.

[Pharmacokinetics of alpha1-antitrypsin replacement therapy in severe congenital emphysema]. / Farmacocinética de la alfa-1-antitripsina utilizada en el tratamiento sustitutivo del enfisema congénito grave.

OBJECTIVE: Alpha1-antitrypsin (AAT) deficiency is a codominant autosomal genetic disorder that predisposes a patient to chronic obstructive pulmonary disease and emphysema. Specific treatment is systemic, consisting of intravenous infusion of AAT. The protocol currently recommended by the Spanish Registry is infusion of 180 mg/kg every 21 days. The objective of this study was to assess the pharmacokinetic behavior of AAT and estimate the level of protection, defined as the percentage of time that the AAT plasma concentration was above the assumed protective threshold of 50 mg/dL with the usual protocol and with other alternative ones. MATERIAL AND METHODS: Plasma concentrations at 4 times were analyzed for 9 patients to profile the pharmacokinetics of AAT. The data were fitted to a single compartment open model with the WinNonlin software package. The duration of protection was estimated by simulating the evolution of AAT plasma activity over time according to the model constructed based on data recorded in the study. RESULTS: Five men and 4 women (mean weight, 69 kg; range, 59-84 kg) were given a mean AAT dose of 12.06 g (range, 11-15 g). The mean (SD) volume infused was 516.67 (88.17) mL. The half-life of AAT was 8.7 days and the volume of distribution was 127.6 mL/kg. The currently recommended treatment protocol (180 mg/kg every 21 days) gave a level of protection of 67% (considering 60 mg/dL to be protective threshold) or 76% (for a threshold of 50 mg/dL). Protection values for the alternative protocol of 120 mg/kg every 14 days were 82% and 100%, respectively. For the alternative protocol of 60 mg/kg every 7 days, protection was 100% for both thresholds. CONCLUSIONS: Profiling the pharmacokinetic behavior of AAT has enabled the coverage time to be assessed for several treatment protocols. The regimen of 120 mg/kg every 14 days had the most appropriate profile.