RESUMO
The treatment of inflammatory bowel disease has undergone a significant transformation following the introduction of biologic drugs. Thanks to these drugs, treatment goals have evolved from clinical response and remission to more ambitious objectives, such as endoscopic or radiologic remission. However, even though biologics are highly effective, a significant percentage of patients will not achieve an initial response or may lose it over time. We know that there is a direct relationship between the trough concentrations of the biologic and its therapeutic efficacy, with more demanding therapeutic goals requiring higher drug levels, and inadequate exposure being common. Therapeutic drug monitoring of biologic medications, along with pharmacokinetic models, provides us with the possibility of offering a personalized approach to treatment for patients with IBD. Over the past few years, relevant information has accumulated regarding its utility during or after induction, as well as in the maintenance of biologic treatment, in reactive or proactive strategies, and prior to withdrawal or treatment de-escalation. The aim of this document is to establish recommendations regarding the utility of therapeutic drug monitoring of biologics in patients with inflammatory bowel disease, in different clinical practice scenarios, and to identify areas where its utility is evident, promising, or controversial.
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Produtos Biológicos , Colite Ulcerativa , Doença de Crohn , Monitoramento de Medicamentos , Humanos , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Produtos Biológicos/farmacocinética , Doenças Inflamatórias Intestinais/tratamento farmacológicoRESUMO
Few genetic polymorphisms predict early response to anti-TNF drugs in inflammatory bowel disease (IBD), and even fewer have been identified in the pediatric population. However, it would be of considerable clinical interest to identify and validate genetic biomarkers of long-term response. Therefore, the aim of the study was to analyze the usefulness of biomarkers of response to anti-TNFs in pediatric IBD (pIBD) as long-term biomarkers and to find differences by type of IBD and type of anti-TNF drug. The study population comprised 340 children diagnosed with IBD who were treated with infliximab or adalimumab. Genotyping of 9 selected SNPs for their association with early response and/or immunogenicity to anti-TNFs was performed using real-time PCR. Variants C rs10508884 (CXCL12), A rs2241880 (ATG16L1), and T rs6100556 (PHACTR3) (p value 0.049; p value 0.03; p value 0.031) were associated with worse long-term response to anti-TNFs in pIBD. DNA variants specific to disease type and anti-TNF type were identified in the pediatric population. Genotyping of these genetic variants before initiation of anti-TNFs would enable, if validated in a prospective cohort, the identification of pediatric patients who are long-term responders to this therapy.
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Doenças Inflamatórias Intestinais , Inibidores do Fator de Necrose Tumoral , Humanos , Criança , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfa/genética , Estudos Prospectivos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/genética , Polimorfismo de Nucleotídeo Único , BiomarcadoresRESUMO
AIMS: Identifying DNA variants associated with trough serum anti-tumour necrosis factor (TNF) levels could predict response to treatment in inflammatory bowel disease (IBD). To date, no specific studies have been performed in children. The aim of this study was to identify genetic variants associated with trough serum anti-TNF levels and whether these variants are differential markers for infliximab and adalimumab. METHODS: We included 154 children (age < 18 years) from 17 hospitals who had been diagnosed with IBD and actively treated with infliximab or adalimumab. Twenty-one polymorphisms were genotyped using real-time PCR. Trough serum anti-TNF levels were measured using enzyme-linked immunosorbent assay (ELISA). The association between DNA polymorphisms and the therapeutic range or the absolute values of anti-TNF drugs was analysed by Fisher exact test, student's t-test and logistic regression. RESULTS: The variants rs5030728 (TLR4) and rs11465996 (LY96) were associated with subtherapeutic infliximab levels. rs1816702 (TLR2) was associated with supratherapeutic levels and rs3397 (TNFRSF1B) with subtherapeutic levels of adalimumab (P < .05). In addition, rs1816702 (TLR2) and rs2569190 (CD14) were associated with absolute values of trough serum adalimumab, and rs2569190 (CD14) was associated with absolute values of trough serum adalimumab and infliximab (P < .05). CONCLUSION: Genotyping of these DNA variants before starting treatment may help to select the best anti-TNF drug in paediatric patients. The SNP rs1816702 is the most promising marker for tailoring the anti-TNF regimen in children with IBD. For the first time, DNA variants are associated with trough serum anti-TNF levels.
Assuntos
Doenças Inflamatórias Intestinais , Inibidores do Fator de Necrose Tumoral , Adalimumab , Adolescente , Criança , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/genética , Infliximab , Farmacogenética , Inibidores do Fator de Necrose Tumoral/farmacocinéticaRESUMO
AIMS: Therapeutic drug monitoring (TDM) of trough serum infliximab concentrations has been mainly used in case of loss of response in patients with inflammatory bowel disease (IBD). The aim of this study was to evaluate the effectiveness and safety of a multidisciplinary early proactive TDM (mep-TDM) programme for dose adjustment. METHODS: A 3-year prospective study was conducted based on a sample of 81 patients who started treatment and were subsequently subjected to mep-TDM with the first control at week 14. Data of a historical control group of 72 patients treated with infliximab and managed with empirical dosing were included. Effectiveness variables were treatment failure, IBD-related surgery and IBD-related hospitalization. Safety variables were serious infusion reactions (SIRs) and adverse reactions. Cox regression was used for survival analysis. RESULTS: In the mep-TDM study group, compared to the control group, there was a significant reduction in the risk of treatment failure (hazard ratio [HR]: 0.51; 95% confidence interval [CI]: 0.27-0.92; P = .037), IBD-related surgery (HR: 0.14; 95% CI: 0.03-0.65; P = .012) and hospitalization (HR: 0.38; 95% CI: 0.17-0.87; P = .022). SIRs were lower in the mep-TDM group (2.5% vs 10.4%; P < .050); the incidence of adverse reactions was similar (3.7% vs 3.9%; p > .999). CONCLUSION: This study found that compared to empirical dosing, mep-TDM is associated with improved efficacy and safety of infliximab therapy, reduced IBD-related hospitalization and surgery and incidence of SIRs, and increasing long-term durability of treatment effects.
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Monitoramento de Medicamentos , Doenças Inflamatórias Intestinais , Fármacos Gastrointestinais/efeitos adversos , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/efeitos adversos , Estudos ProspectivosRESUMO
BACKGROUND: Accidental falls have a significant economic and human impact. The use of certain drugs is one of the modifiable risk factors associated with these events. OBJECTIVE: The aim of this study was to determine the prevalence of use and to explore changes in treatment with fall-related drugs in patients over 65 years of age admitted as a result of a fall-related fracture. METHODS: Observational and prospective study performed in a tertiary level hospital. A list of fall risk-increasing drugs (FRIDs) was drawn up. The main study variables were number and type of FRIDs prescribed at admission and 1 month after the fracture and number, type, treating physician and place where changes in FRIDs were implemented. RESULTS: In total, 252 patients were included. At admission, 91.3% were receiving at least one FRID, mean daily use was 3.1 FRIDs and the most frequently prescribed FRIDs were diuretics (18%), renin-angiotensin system-acting agents (15.8%) and antidepressants (15%). One month later, mean daily use was 3.4 FRIDs (p=0.099) and a significant increase was detected in the use of hypnotics (p=0.003) and antidepressants (p=0.042). A total of 327 changes in treatment were recorded (1.3 changes/patient). Of the changes, 52.6% were new prescriptions, 72.2% occurred at discharge and 56.6% were ordered by a geriatrician. CONCLUSIONS: The use of FRIDs among patients with a fall-related fracture is very high. This use rises 1 month after the fracture, significantly in the case of hypnotics and antidepressants.
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Acidentes por Quedas , Fraturas Ósseas , Idoso Fragilizado/estatística & dados numéricos , Hospitalização/estatística & dados numéricos , Polimedicação , Acidentes por Quedas/economia , Acidentes por Quedas/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Antagonistas de Receptores de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/uso terapêutico , Antidepressivos/efeitos adversos , Antidepressivos/uso terapêutico , Diuréticos/efeitos adversos , Diuréticos/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/etiologia , Hospitalização/economia , Humanos , Hipnóticos e Sedativos/efeitos adversos , Hipnóticos e Sedativos/uso terapêutico , Masculino , Prevalência , Estudos Prospectivos , Fatores de Risco , Espanha/epidemiologiaRESUMO
We evaluated the safety and viral rebound, after analytical treatment interruption (ATI), of vedolizumab and ART in recent HIV-1 infection. We used this model to analyze the impact of α4ß7 on the HIV-1 reservoir size. Participants started ART with monthly Vedolizumab infusions and ATI was performed at week 24. Biopsies were obtained from ileum and caecum at baseline and week 24. Vedolizumab levels, HIV-1 reservoir, flow cytometry and cell-sorting and antibody competition experiments were assayed. Vedolizumab was safe and well-tolerated. No participant achieved undetectable viremia off ART 24 weeks after ATI. Only a modest effect on the time to achieve >1000 HIV-RNA copies/mL and the proportion of participants off ART was observed, being higher compared to historical controls. Just before ATI, α4ß7 expression was associated with HIV-1 DNA and RNA in peripheral blood and with PD1 and TIGIT levels. Importantly, a complete blocking of α4ß7 was observed on peripheral CD4+ T-cells but not in gut (ileum and caecum), where α4ß7 blockade and vedolizumab levels were inversely associated with HIV-1 DNA. Our findings support α4ß7 as an important determinant in HIV-1 reservoir size, suggesting the complete α4ß7 blockade in tissue as a promising tool for HIV-cure combination strategies.
RESUMO
OBJECTIVE: Switching patients from the originator infliximab to a biosimilar is a measure to expand access to treatments and counteract its negative impact on healthcare budgets. However, industry-independent long-term studies on the effect of switching in real life to support the lack of switch-related problems in inflammatory bowel disease (IBD) patients are sparse, as are studies addressing infliximab pharmacokinetic behaviour. The objectives were to investigate the effectiveness and the pharmacokinetics of CT-P13 after switching from originator infliximab in a real-world population of IBD patients with a follow-up of 2 years. METHOD: Prospective, single-centre, observational 2 year study conducted in IBD adult patients with stable disease treated with the originator infliximab who were switched to CT-P13. Four time points were defined for follow-up: prior to the switch, 4-8 weeks after the switch, 8 months later, and 2 years later. Outcome measures were the proportion of patients with clinical, endoscopic and biochemical remission, and changes in biochemical inflammation markers (albumin, C-reactive protein, faecal calprotectin) and infliximab clearance. RESULTS: 42 IBD patients were switched, of which 36 (85.7%) remained on CT-P13 throughout the 2 year study period. Only two patients discontinued CT-P13 due to loss of response. The proportion of patients who displayed clinical, endoscopic and biochemical remission were unchanged during the follow-up (p<0.05) and no statistically significant changes were observed in the biochemical markers of disease activity. The median (IQR) clearance estimated for the infliximab originator before the change was 0.364 (0.321-0.415) L/day, and for the CT-P13 biosimilar it was 0.361 (0.323-0.415) L/day 4-8 weeks after the change, and 0.370 (0.334-0.419) L/day 2 years after (p=0.395). CONCLUSION: Switching from originator infliximab to biosimilar CT-P13 did not affect the long-term clinical outcomes or the pharmacokinetic behaviour. This information provides the clinician more evidence for the success of switching and supports non-medical switching in adult IBD patients.
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Medicamentos Biossimilares , Doenças Inflamatórias Intestinais , Adulto , Anticorpos Monoclonais , Medicamentos Biossimilares/efeitos adversos , Substituição de Medicamentos , Fármacos Gastrointestinais , Humanos , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/uso terapêutico , Estudos ProspectivosRESUMO
BACKGROUND: Posaconazole is an antifungal agent extensively used as a prophylaxis for invasive fungal infections (IFIs) in allogeneic stem cell transplant (SCT) recipients. Low posaconazole concentrations have been associated with reduced clinical response. The aim of this study was to develop a population pharmacokinetic (popPK) model of a posaconazole tablet formulation in allogeneic SCT adult recipients for supporting model-informed precision dosing (MIPD). MATERIALS AND METHOD: Prospective observational study performed in adult allogeneic SCT recipients receiving posaconazole as prophylaxis for IFIs and followed up by a therapeutic drug monitoring (TDM) program. Posaconazole plasma concentrations were quantified using an ultra-high-performance liquid chromatography (UPLC) with UV detector. A popPK model was developed using NONMEM v.7.4.0. Deterministic and stochastic simulations were carried out with the final model to evaluate the differences across physiological variables with impact on drug exposure. RESULTS: A one-compartment model with sequential absorption (zero and first order) and first order elimination described adequately 55 posaconazole concentrations from 36 patients. Higher doses of posaconazole were found to be required by males and patients with lower values of total serum proteins. A nomogram to estimate the posaconazole daily dose based on pharmacokinetic/pharmacodynamic (PKPD) criterion for males and females for different values of total proteins was developed. CONCLUSIONS: Gender and total serum proteins have been identified as covariates influencing posaconazole CL/F in adult allogeneic SCT recipients receiving the delay-released tablet formulation. Additional studies are required to better characterize the absorption of posaconazole and implications on dosage recommendations together with potential safety concerns.
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Transplante de Células-Tronco Hematopoéticas , Triazóis , Antifúngicos/uso terapêutico , Feminino , Humanos , Masculino , ComprimidosRESUMO
BACKGROUND: Therapeutic drug monitoring (TDM) of voriconazole is recommended for personalizing doses. The objective of this study was to compare the enzyme immunoassay developed by ARKTM Diagnostics Inc. for the quantification of voriconazole adapted to the Architect C4000 autoanalyzer (Abbott®) with ultra-performance liquid chromatography using ultraviolet detector (UPLC-UV) method. MATERIALS AND METHODS: Linearity, precision and accuracy of both methods were validated according to the Food and Drug Administration (FDA) and European Medicines Agency guidelines. The limit of quantification (LOQ) of the UPLC-UV method was determined experimentally. Both methods were applied to the analysis of 62 samples from patients. Correlation was evaluated by Passing-Bablok analysis and the concordance by the Bland-Altman method. Dosage recommendations were generated; the discordances according to the technique were evaluated. RESULTS: All validation parameters determined for UPLC-UV met the criteria set out and LOQ of 0.1 µg/mL was established. However, when the enzyme immunoassay was used to determine concentrations ≤1 µg/ml, CVs were >20%. A linear correlation between both methods was found. However, an overestimation of immunoassay (systematic error of 0.39 µg/mL) was detected. In 11.3% of the samples, the differences in concentrations when they were determined by different techniques would imply a different therapeutic regime. These samples had concentrations close to 1 µg/mL. CONCLUSION: Although both techniques can be used for TDM of voriconazole, when a value close to the lower limit of the therapeutic range is determined by the ARKTM immunoassay, it would be better to verify the result by a non-automated technique to avoid possible underdosing.
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Monitoramento de Medicamentos , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Humanos , Imunoensaio , VoriconazolRESUMO
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.
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Colite Ulcerativa , Adulto , Anticorpos Monoclonais Humanizados , Colite Ulcerativa/tratamento farmacológico , Humanos , Estudos ProspectivosRESUMO
Inflammatory bowel disease (IBD) is commonly treated with adalimumab. The main objective of the study was to develop a population pharmacokinetic model of adalimumab in IBD patients evaluating the potential biomarkers of disease activity and other factors and its implications in adalimumab dosing. A prospective observational study was performed in adult patients diagnosed with Crohn's disease and ulcerative colitis treated with adalimumab and following a proactive therapeutic drug monitoring of serum concentrations. Adalimumab serum concentrations (ASC) were quantified mainly prior the administration using an enzyme-linked immunosorbent assay (ELISA). A population pharmacokinetic model was developed based on 303 ASC data of 104 IBD patients using non-linear mixed effect modelling approach. Sixty-five ASC from 20 additional patients were randomly selected as an external validation group. A one-compartment model with first order absorption and elimination best describe the ASC time course. Body mass index (BMI), faecal calprotectin (FCP), unexplained decline in ASC and the specific administration pen device exhibited significant influence on apparent clearance (p-value < 0.001). FCP was the inflammatory activity biomarker showing the most relevant impact on adalimumab exposure, higher than C-reactive protein and albumin, and may be useful for adalimumab dosing adjustment. The population-based pharmacokinetic model developed adequately characterized adalimumab exposure in IBD patients. The unexplained decline in ASC, FCP, BMI and the specific administration pen device were identified as meaningful variables significantly influencing adalimumab pharmacokinetics.