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BACKGROUND AND OBJECTIVE: Efficacy of infliximab in children with inflammatory bowel disease can be enhanced when serum concentrations are measured and further dosing is adjusted to achieve and maintain a target concentration. Use of a population pharmacokinetic model may help to predict an individual's infliximab dose requirement. The aim of this study was to evaluate the predictive performance of available infliximab population pharmacokinetic models in an independent cohort of Dutch children with inflammatory bowel disease. METHODS: In this retrospective study, we used data of 70 children with inflammatory bowel disease (443 infliximab concentrations) to evaluate eight models that focused on infliximab pharmacokinetic models in individuals with inflammatory bowel disease, preferably aged ≤ 18 years. Predictive performance was evaluated with prior predictions (based solely on patient-specific covariates) and posterior predictions (based on covariates and infliximab trough concentrations). Model accuracy and precision were calculated with relative bias and relative root mean square error and we determined the classification accuracy at the trough concentration target of ≥ 5 mg/L. RESULTS: The population pharmacokinetic model by Fasanmade was identified to be most appropriate for the total dataset (relative bias before/after therapeutic drug monitoring: -20.7%/11.2% and relative root mean square error before/after therapeutic drug monitoring: 84.1%/51.6%), although differences between models were small and several were deemed suitable for clinical use. For the Fasanmade model, sensitivity and specificity for maximum posterior predictions for the next infliximab trough concentration to be ≥ 5 mg/L were respectively 83.5% and 80% with an area under the receiver operating characteristic curve of 0.870. CONCLUSIONS: In our paediatric cohort, various models provided acceptable predictive performance, with the Fasanmade model deemed most suitable for clinical use. Model-informed precision dosing can therefore be expected to help to maintain infliximab trough concentrations in the target range.
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Monitoreo de Drogas , Fármacos Gastrointestinales , Enfermedades Inflamatorias del Intestino , Infliximab , Modelos Biológicos , Humanos , Infliximab/farmacocinética , Infliximab/administración & dosificación , Infliximab/sangre , Infliximab/uso terapéutico , Niño , Adolescente , Femenino , Masculino , Estudios Retrospectivos , Países Bajos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/sangre , Fármacos Gastrointestinales/farmacocinética , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/sangre , Fármacos Gastrointestinales/uso terapéutico , Monitoreo de Drogas/métodos , Estudios de Cohortes , PreescolarRESUMEN
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that encompasses two major conditions: Crohn's disease (CD) and ulcerative colitis (UC). Historically, IBD has been primarily reported in western countries, but over the past decades, its prevalence is rapidly increasing, especially in lower and middle-income countries (LMICs) such as India and China and also in Sub-Saharan Africa. The prevalence of IBD in LMICs has been the subject of growing concern due to the impact of access to public healthcare and the burden it places on healthcare resources. The classical thiopurines face significant challenges due to cessation of therapy in approximately half of patients within one year due to side effects or ineffectiveness. In this article, we highlight innovating thiopurine treatment for IBD patients in downregulating side effects and improving efficacy.
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Colitis Ulcerosa , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Purinas , Compuestos de Sulfhidrilo , Humanos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Colitis Ulcerosa/tratamiento farmacológico , Mercaptopurina , Azatioprina/uso terapéutico , Inmunosupresores/efectos adversosRESUMEN
Background: Exposure-response studies have shown that higher infliximab concentrations are associated with better outcomes in inflammatory bowel disease. There is little agreement about the optimal time to measure infliximab levels in children. Objectives: We aimed to evaluate whether trough levels at week 6 or week 14 predict sustained remission. The secondary aim was to define target trough levels at weeks 6 and 14. Design: We used routinely collected electronic healthcare data of 70 anti-tumour necrosis factor naïve children with inflammatory bowel disease treated with a standard infliximab induction- and variable maintenance scheme. Methods: Trough levels and blood and faecal markers for disease activity were measured before every infliximab administration. Sustained remission was defined as the absence of symptoms and low inflammatory markers between weeks 26 and 52 after the start of infliximab therapy. Optimal infliximab levels at weeks 6 and 14 were determined using the receiver operating characteristic curve. Results: The median infliximab level at week 6 was not significantly higher in children who achieved sustained remission compared to those who did not (16.9 mg/L versus 12.0 mg/L; p = 0.058) but the median infliximab level at week 14 was significantly higher in those with sustained remission (7.7 mg/L versus 3.8 mg/L; p = 0.006). The area under the receiver operating characteristics curves at weeks 6 and 14 to predict sustained remission was 0.67 (95% CI 0.51-0.83) and 0.75 (95% CI 0.60-0.90), respectively. Target trough levels at weeks 6 and 14 were ⩾13.2 and ⩾6.9 mg/L, respectively. Conclusion: An infliximab measurement at week 14 with a target through level ⩾6.9 mg/L best predicted sustained remission.
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Therapeutic drug monitoring (TDM) of tumor necrosis factor-α (TNFα)-inhibitors adalimumab and infliximab is important to establish optimal drug dose and maximize treatment efficacy. Currently, TDM is primarily performed with ELISA techniques in clinical laboratories, resulting in a long sample-to-result workflow. Point-of-care (POC) detection of these therapeutic antibodies could significantly decrease turnaround times and allow for user-friendly home-testing. Here, we adapted the recently developed bioluminescent dRAPPID (dimeric Ratiometric Plug-and-Play Immunodiagnostics) sensor platform to allow POC TDM of infliximab and adalimumab. We applied the two best performing dRAPPID sensors, with limit-of-detections of 1 pM and 17 pM, to measure the infliximab and adalimumab levels in 49 and 40 patient serum samples, respectively. The analytical performance of dRAPPID was benchmarked with commercial ELISAs and yielded Pearson's correlation coefficients of 0.93 and 0.94 for infliximab and adalimumab, respectively. Furthermore, a dedicated bioluminescence reader was fabricated and used as a readout device for the TDM dRAPPID sensors. Subsequently, infliximab and adalimumab patient serum samples were measured with the TDM dRAPPID sensors and bioluminescence reader, yielding Pearson's correlation coefficients of 0.97 and 0.86 for infliximab and adalimumab, respectively, and small proportional differences with ELISA (slope was 0.97 ± 0.09 and 0.96 ± 0.20, respectively). The adalimumab and infliximab dRAPPID sensors, in combination with the dedicated bioluminescence reader, allow for ease-of-use TDM with a fast turnaround time and show potential for POC TDM outside of clinical laboratories.
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Tioguanine is metabolised by fewer enzymatic steps compared to azathioprine and mercaptopurine, without generating 6-methylmercaptopurine ribonucleotides. However, thiopurine S-methyl transferase (TPMT) plays a role in early toxicity in all thiopurines. We aimed to describe the hazards and opportunities of tioguanine use in inflammatory bowel disease (IBD) patients with aberrant TPMT metabolism and propose preventative measures to safely prescribe tioguanine in these patients. In this retrospective cohort study, all determined TPMT genotypes (2016-2021) were evaluated for aberrant metabolism (i.e., intermediate and poor TPMT metabolisers). Subsequently, all IBD patients on tioguanine with aberrant TPMT genotypes were evaluated for tioguanine dosages, adverse drug events, lab abnormalities, treatment duration and effectiveness. TPMT genotypes were determined in 485 patients, of whom, 50 (10.3%) and 4 patients (0.8%) were intermediate and poor metabolisers, respectively. Of these patients, 12 intermediate and 4 poor TPMT metabolisers had been prescribed tioguanine in varying doses. In one poor TPMT metaboliser, tioguanine 10 mg/day induced delayed pancytopenia. In general, reduced tioguanine dosages of 5 mg/day for intermediate TPMT metabolisers, and 10 mg two-weekly for poor TPMT metabolisers, resulted in a safe, long-term treatment strategy. Diminished or absent TPMT enzyme activity was related with a pharmacokinetic shift of tioguanine metabolism which is associated with relatively late-occurring myelotoxicity in patients on standard tioguanine dose. However, in strongly reduced dose regimens with strict therapeutic drug and safety monitoring, tioguanine treatment remained a safe and effective option in IBD patients with dysfunctional TPMT.
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BACKGROUND: Currently thioguanine is solely used as treatment for inflammatory bowel disease after azathioprine and/or mercaptopurine failure. This study aimed to determine the safety, effectiveness, and 12-month drug survival of thioguanine in thiopurine-naïve patients with inflammatory bowel disease. METHODS: A retrospective cohort study was performed in thiopurine-naïve patients with inflammatory bowel disease treated with thioguanine as first thiopurine derivate. Clinical effectiveness was defined as the continuation of thioguanine without the (re)initiation of concurrent biological therapy, systemic corticosteroids, or a surgical intervention. All adverse events were categorized by the Common Terminology Criteria for Adverse Events. RESULTS: A total of 114 patients (male 39%, Crohn's disease 53%) were included with a median treatment duration of 25 months and a median thioguanine dosage of 20 mg/d. Clinical effectiveness at 12 months was observed in 53% of patients, and 78% of these responding patients remained responsive until the end of follow-up. During the entire follow-up period, 26 patients were primary nonresponders, 8 had a secondary loss of response, and 11 patients were unable to cease therapy with systemic corticosteroids within 6 months and were therefore classified as nonresponders. After 12 months, thioguanine was still used by 86% of patients. Fifty (44%) patients developed adverse events (grade 1 or 2) and 9 (8%) patients ceased therapy due to the occurrence of adverse events. An infection was documented in 3 patients, none of them requiring hospitalization and pancytopenia occurred in 2 other patients. No signs of nodular regenerative hyperplasia or portal hypertension were observed. CONCLUSIONS: At 12 months, first-line thioguanine therapy was clinically effective in 53% of thiopurine-naïve inflammatory bowel disease patients with an acceptable safety profile.
After 12 months, first-line thioguanine therapy was still used by 86% of thiopurine-naïve patients with inflammatory bowel disease and clinically effective in 53%. The safety profile was acceptable and only 8% of patients ceased therapy due to adverse events.
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BACKGROUND AND OBJECTIVE: Underdosing of adalimumab can result in non-response and poor disease control in patients with rheumatic disease or inflammatory bowel disease. In this pilot study we aimed to predict adalimumab concentrations with population pharmacokinetic model-based Bayesian forecasting early in therapy. METHODS: Adalimumab pharmacokinetic models were identified with a literature search. A fit-for-purpose evaluation of the model was performed for rheumatologic and inflammatory bowel disease (IBD) patients with adalimumab peak (first dose) and trough samples (first and seventh dose) obtained by a volumetric absorptive microsampling technique. Steady state adalimumab concentrations were predicted after the first adalimumab administration. Predictive performance was calculated with mean prediction error (MPE) and normalised root mean square error (RMSE). RESULTS: Thirty-six patients (22 rheumatologic and 14 IBD) were analysed in our study. After stratification for absence of anti-adalimumab antibodies, the calculated MPE was -2.6% and normalised RMSE 24.0%. Concordance between predicted and measured adalimumab serum concentrations falling within or outside the therapeutic window was 75%. Three patients (8.3%) developed detectable concentrations of anti-adalimumab antibodies. CONCLUSION: This prospective study demonstrates that adalimumab concentrations at steady state can be predicted from early samples during the induction phase. CLINICAL TRIAL REGISTRATION: The trial was registered in the Netherlands Trial Register with trial registry number NTR 7692 ( www.trialregister.nl ).
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Artritis Reumatoide , Enfermedades Inflamatorias del Intestino , Humanos , Adalimumab/uso terapéutico , Inhibidores del Factor de Necrosis Tumoral , Proyectos Piloto , Estudios Prospectivos , Teorema de Bayes , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológicoRESUMEN
Background: Inflammatory bowel disease (IBD) is a chronic relapsing-remitting disease. An adverse immune reaction toward the intestinal microbiota is involved in the pathophysiology and microbial perturbations are associated with IBD in general and with flares specifically. Although medical drugs are the cornerstone of current treatment, responses vary widely between patients and drugs. The intestinal microbiota can metabolize medical drugs, which may influence IBD drug (non-)response and side effects. Conversely, several drugs can impact the intestinal microbiota and thereby host effects. This review provides a comprehensive overview of current evidence on bidirectional interactions between the microbiota and relevant IBD drugs (pharmacomicrobiomics). Methods: Electronic literature searches were conducted in PubMed, Web of Science and Cochrane databases to identify relevant publications. Studies reporting on microbiota composition and/or drug metabolism were included. Results: The intestinal microbiota can both enzymatically activate IBD pro-drugs (e.g., in case of thiopurines), but also inactivate certain drugs (e.g., mesalazine by acetylation via N-acetyltransferase 1 and infliximab via IgG-degrading enzymes). Aminosalicylates, corticosteroids, thiopurines, calcineurin inhibitors, anti-tumor necrosis factor biologicals and tofacitinib were all reported to alter the intestinal microbiota composition, including changes in microbial diversity and/or relative abundances of various microbial taxa. Conclusion: Various lines of evidence have shown the ability of the intestinal microbiota to interfere with IBD drugs and vice versa. These interactions can influence treatment response, but well-designed clinical studies and combined in vivo and ex vivo models are needed to achieve consistent findings and evaluate clinical relevance.
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There are limited data on therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients treated with vedolizumab (VDZ). Although an exposure-response relation has been demonstrated in the post-induction phase, this relationship is more uncertain in the maintenance phase of treatment. The aim of our study was to determine whether there is an association between VDZ trough concentration and clinical and biochemical remission in the maintenance phase. A prospective, observational multicenter study has been performed on patients with IBD on VDZ in the maintenance treatment (≥14 weeks). Patient demographics, biomarkers, and VDZ serum trough concentrations were collected. Clinical disease activity was scored by the Harvey Bradshaw Index (HBI) for Crohn's disease (CD) and the Simple Clinical Colitis Activity Index (SCCAI) for ulcerative colitis (UC). Clinical remission was determined as HBI < 5 and SCCAI < 3. Biochemical remission was defined as fecal calprotectin <250 mg/kg and serum CRP <5 mg/L. A total of 159 patients (59 CD, 100 UC) were included. In none of the patient groups, a statistically significant correlation between trough VDZ concentration and clinical remission was observed. Patients in biochemical remission had higher VDZ trough concentrations (p = 0.019). In this population, higher trough VDZ concentrations were associated with biochemical remission but not with clinical remission.
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BACKGROUND: In inflammatory bowel disease (IBD), conventional thiopurine users cease treatment in 60% of cases within 5 years, mostly because of adverse events or nonresponse. In this study, the authors aimed to investigate the role of 6-thioguanine nucleotide (TGN) measurements, geno/phenotyping of thiopurine S-methyltransferase (TPMT), and their mutual relationship with TG therapy in IBD. METHODS: An international retrospective, multicenter cohort study was performed at 4 centers in the Netherlands (Máxima Medical Centre) and the United Kingdom (Guy's and St. Thomas' Hospital, Queen Elizabeth Hospital, and East Surrey Hospital). RESULTS: Overall, 526 6-TGN measurements were performed in 316 patients with IBD. The median daily dosage of TG was 20 mg/d (range 10-40 mg/d), and the median duration of TG use was 21.1 months (SD, 28.0). In total, 129 patients (40.8%) had a known TPMT status. In the variant-type and wild-type TPMT genotype metabolism groups, median 6-TGN values were 1126 [interquartile range (IQR) 948-1562] and 467.5 pmol/8 × 10E8 red blood cells (RBCs) (IQR 334-593). A significant difference was observed between the 2 groups (P = 0.0001, t test). For TPMT phenotypes, in the slow, fast, and normal metabolism groups, the median 6-TGN values were 772.0 (IQR 459-1724), 296.0 (IQR 200-705), and 774.5 pmol/8 × 10E8 RBCs (IQR 500.5-981.5), with a significant difference observed between groups (P < 0.001, analysis of variance). CONCLUSIONS: Our findings indicated that TPMT measurements at TG initiation can be useful but are not necessary for daily practice. TPMT genotypes and phenotypes are both associated with significant differences in 6-TGN levels between metabolic groups. However, the advantage of TG remains that RBC 6-TGN measurements are not crucial to monitor treatments in patients with IBD because these measurements did not correlate with laboratory result abnormalities. This presents as a major advantage in countries where patients cannot access these diagnostic tests.
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Inmunosupresores , Enfermedades Inflamatorias del Intestino , Metiltransferasas , Tioguanina , Adulto , Azatioprina , Femenino , Genotipo , Nucleótidos de Guanina , Humanos , Inmunosupresores/farmacocinética , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/genética , Masculino , Mercaptopurina , Metiltransferasas/genética , Persona de Mediana Edad , Fenotipo , Estudios Retrospectivos , Tioguanina/farmacocinética , TionucleótidosRESUMEN
OBJECTIVE: To establish the storage conditions of oxytocin in a health facility in a low-income country with a tropical climate, as suboptimal storage may lead to ineffectiveness of drugs essential to prevent and treat postpartum hemorrhage. METHODS: At Mulago National Referral Hospital (28 000-33 000 deliveries/year) in Kampala, Uganda, temperature logging Safe-Rx cards were placed in boxes of oxytocin and in every known storage location. The route of the boxes through the hospital was tracked for 54 days, and storage conditions were observed. RESULTS: Oxytocin was stored within the recommended temperature range (2°C-8°C) 24% of the time. The average temperature measured within the oxytocin boxes was 18.2°C, with a minimum of -2.3°C and maximum of 30.4°C. Six out of twelve known storage places had a refrigerator, but not one location stored medication at the recommended temperature constantly. The average temperature in the storage places ranged from 9.5°C to 27.6°C, with a minimum temperature of 2.3°C and maximum of 30.9°C. CONCLUSION: Oxytocin is not stored in the recommended temperature range for the majority of time. The presence of refrigerators does not ensure adherence to advised temperature storage conditions.
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Almacenaje de Medicamentos , Oxitocina/química , Clima Tropical , Femenino , Humanos , Hemorragia Posparto/prevención & control , Pobreza , Embarazo , Refrigeración , Temperatura , UgandaRESUMEN
BACKGROUND AND AIMS: Decreased thiopurine S-methyltransferase [TPMT] enzyme activity increases the risk of haematological adverse drug reactions [ADRs] in patients treated with thiopurines. Clinical studies have shown that in patients with inflammatory bowel disease [IBD], pharmacogenetic TPMT-guided thiopurine treatment reduces this risk of ADRs. The aim of this study was to investigate whether this intervention impacts on healthcare costs and/or quality of life. METHODS: An a priori defined cost-effectiveness analysis was conducted in the Thiopurine response Optimization by Pharmacogenetic testing in Inflammatory bowel disease Clinics [TOPIC] trial, a randomized controlled trial performed in 30 Dutch hospitals. Patients diagnosed with IBD [age ≥18 years] were randomly assigned to the intervention [i.e. pre-treatment genotyping] or control group. Total costs in terms of volumes of care, and effects in quality-adjusted life years [QALYs], based on EuroQol-5D3L utility scores, were measured for 20 weeks. Mean incremental cost savings and QALYs with confidence intervals were calculated using non-parametric bootstrapping with 1000 replications. RESULTS: The intervention group consisted of 381 patients and the control group 347 patients. The mean incremental cost savings were 52 per patient [95% percentiles -682, 569]. Mean incremental QALYs were 0.001 [95% percentiles -0.009, 0.010]. Sensitivity analysis showed that the results were robust for potential change in costs of screening, costs of biologicals and costs associated with productivity loss. CONCLUSIONS: Genotype-guided thiopurine treatment in IBD patients reduced the risk of ADRs among patients carrying a TPMT variant, without increasing overall healthcare costs and resulting in comparable quality of life, as compared to standard treatment.
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Azatioprina/administración & dosificación , Azatioprina/economía , Inmunosupresores/administración & dosificación , Inmunosupresores/economía , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/genética , Mercaptopurina/administración & dosificación , Mercaptopurina/economía , Adulto , Edad de Inicio , Análisis Costo-Beneficio , Femenino , Genotipo , Humanos , Masculino , Metiltransferasas , Países Bajos , Calidad de VidaRESUMEN
While the biographical dimensions of chronic illness have been well researched, the concrete dimensions of patients' work have not been as thoroughly investigated as yet. With the growing concern for self-management, such research would be timely. This study aims to better understand patients' invisible work by highlighting the causes of unintentional non-adherence as well as strategies for adherence. For this purpose, it defines medical treatment adherence as the repetition of the pattern of tasks through which a patient succeeds, in a technical sense, in taking the right medication at the right time, in the right amount, for the right duration. Applying a failure modes and effects analysis approach to 48 semi-structured interviews with Dutch patients, it shows the negative impact of schedule changes, pressure, positioning changes, lack of backup pills and lack of verification tools. Symmetrically, it highlights the role of anchoring, sequencing, positioning, cueing, correcting and verifying. This result points to the need for an analytical approach of patients' work and treatment adherence that would build on the role of routines in organisations and in the workplace.
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Enfermedad Crónica , Intención , Estilo de Vida , Cumplimiento de la Medicación , Adulto , Femenino , Humanos , Entrevistas como Asunto , Masculino , Persona de Mediana Edad , Países BajosRESUMEN
According to recent clinical consensus, pharmacotherapy of inflammatory bowel disease (IBD) is, or should be, personalized medicine. IBD treatment is complex, with highly different treatment classes and relatively few data on treatment strategy. Although thorough evidence-based international IBD guidelines currently exist, appropriate drug and dose choice remains challenging as many disease (disease type, location of disease, disease activity and course, extraintestinal manifestations, complications) and patient characteristics [(pharmaco-)genetic predisposition, response to previous medications, side-effect profile, necessary onset of response, convenience, concurrent therapy, adherence to (maintenance) therapy] are involved. Detailed pharmacological knowledge of the IBD drug arsenal is essential for choosing the right drug, in the right dose, in the right administration form, at the right time, for each individual patient. In this in-depth review, clinical pharmacodynamic and pharmacokinetic considerations are provided for tailoring treatment with the most common IBD drugs. Development (with consequent prospective validation) of easy-to-use treatment algorithms based on these considerations and new pharmacological data may facilitate optimal and effective IBD treatment, preferably corroborated by effectiveness and safety registries.
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Antiinflamatorios/farmacología , Antiinflamatorios/farmacocinética , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Corticoesteroides/efectos adversos , Corticoesteroides/farmacocinética , Corticoesteroides/farmacología , Antiinflamatorios/efectos adversos , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/farmacología , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/farmacología , Monitoreo de Drogas , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/farmacocinética , Inmunosupresores/farmacología , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/inmunología , Medicina de PrecisiónRESUMEN
BACKGROUND: Patients' beliefs about medicine may either reflect the necessity for treatment or concerns regarding the treatment. We explored the extent to which these beliefs have an effect on thiopurine metabolite levels and premature discontinuation in patients with inflammatory bowel disease (IBD). PATIENTS AND METHODS: Patients enrolled in the 'Thiopurine response Optimization by Pharmacogenetic testing in Inflammatory Bowel Disease Clinics' (TOPIC) trial were asked to complete the Beliefs about Medicine Questionnaire (BMQ) 4 weeks after thiopurine initiation. The BMQ measures perceptions about treatment necessity and concerns. On the basis of the necessity and concern scores, patients can be categorized as accepting, ambivalent, indifferent, or skeptical. The thiopurine discontinuation rates for these belief subgroups were compared by Kaplan-Meier curves. Furthermore, clinical response and metabolite levels were compared between the belief subgroups. RESULTS: A total of 767 patients with IBD started thiopurine treatment, of whom 576 (75%) completed the BMQ. Patients could be classified as accepting (34%), indifferent (17%), ambivalent (34%), or skeptical (15%). Compared with patients in the accepting group (discontinuation rate 22%), patients with an indifferent (35%; P=0.02), ambivalent (37%; P<0.01), or skeptical belief (54%; P<0.01) had higher thiopurine discontinuation rates. No differences were observed in the steady-state thiopurine metabolite levels between the different belief subgroups. CONCLUSION: Patients with a low perceived treatment necessity or high concerns toward IBD treatment were more likely to discontinue thiopurine treatment prematurely. Extra attention toward these patients might prevent premature discontinuation.
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Conocimientos, Actitudes y Práctica en Salud , Inmunosupresores/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Cumplimiento de la Medicación/psicología , Mercaptopurina/análogos & derivados , Mercaptopurina/uso terapéutico , Adulto , Femenino , Nucleótidos de Guanina/sangre , Humanos , Inmunosupresores/metabolismo , Masculino , Mercaptopurina/metabolismo , Persona de Mediana Edad , Encuestas y Cuestionarios , Tioinosina/análogos & derivados , Tioinosina/sangre , Tionucleótidos/sangre , Resultado del Tratamiento , Adulto JovenRESUMEN
Medication adherence is a major issue for patients with a chronic illness, who sometimes rationally choose temporary nonadherence. This study aims at better understanding intentional nonadherence and especially why it seems to fluctuate over time. It is based on 48 semi-structured interviews conducted in a hospital in the Netherlands with patients who had been prescribed a medication for a chronic disease for at least 1 year, and who had either type 2 diabetes, hypertension, Parkinson's disease, inflammatory bowel disease, or chronic myeloid leukemia. The analysis uses a simplified version of the failure modes and effects analysis (FMEA) method. Intentional nonadherence appeared to be the result of the respondents' desire (a) to exert control over the treatment and its effects on their body, and (b) to control the hold of the treatment on their daily life. This result provides a rationale for the fluctuation of intentional nonadherence behavior.
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Enfermedad Crónica/tratamiento farmacológico , Enfermedad Crónica/psicología , Control Interno-Externo , Cumplimiento de la Medicación/psicología , Adulto , Anciano , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/psicología , Femenino , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/psicología , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/psicología , Entrevistas como Asunto , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/psicología , Masculino , Persona de Mediana Edad , Países Bajos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/psicologíaRESUMEN
BACKGROUND: There are substantial global differences in the preference for mercaptopurine (MP) or its prodrug azathioprine (AZA) as first-choice thiopurine to treat inflammatory bowel diseases. Studies comparing both agents are scarce. Our aim was to compare AZA and MP in thiopurine-naive patients with inflammatory bowel disease for the frequency of side effects and efficacy. METHODS: Post hoc analysis of the "Thiopurine response Optimization by Pharmacogenetic testing in Inflammatory bowel disease Clinics" (TOPIC) trial, in which thiopurine-naive patients with inflammatory bowel disease with an indication for a thiopurine were randomized for a genotype-based dose versus standard of care. For this study, Cox proportional hazard ratios (HRs) were calculated to compare AZA and MP for discontinuation rates within 5 months, incidence of hepatotoxicity, leukopenia, and gastrointestinal side effects. Treatment efficacy was compared by logistic regression. RESULTS: Patient characteristics were similar for patients treated with AZA (n = 494, 64.4%) and MP (n = 273, 35.6%), yet patients with MP were relatively higher dosed compared with those on AZA. Discontinuation rates within 5 months were not different, 39.3% (AZA) and 38.1% (MP), HR 0.92 (95% confidence interval, 0.72-1.17; P = 0.50); however, patients on MP were more often subjected to dose reductions (30% versus 14%, P < 0.01). Higher rates of hepatotoxicity, HR 1.93 (95% confidence interval, 1.35-2.76; P < 0.01) and leukopenia, HR 2.55 (95% confidence interval, 1.51-4.30; P < 0.01) were observed with MP, which annulled in a secondary analysis with adjustment for the higher dose and metabolite levels. CONCLUSIONS: Patients treated with MP were relatively higher dosed, which resulted in more dose-dependent side effects and a higher rate of dose reductions.
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Azatioprina/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Leucopenia/epidemiología , Mercaptopurina/efectos adversos , Adulto , Azatioprina/administración & dosificación , Femenino , Humanos , Leucopenia/inducido químicamente , Modelos Logísticos , Masculino , Mercaptopurina/administración & dosificación , Persona de Mediana Edad , Países Bajos , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: This study was designed to evaluate whether standardizing total parenteral nutrition (TPN) is at least non-inferior to TPN with individualized composition in premature infants with a gestational age (GA) < 32 weeks. METHODS: In this retrospective cohort study, all preterm born in or transferred to Maxima Medical Center (MMC) within 24 hours after birth with a GA < 32 weeks were included. The individualized group (2011) was compared to the partially standardized group (2012) and completely standardized group (2014) consequently. The primary endpoint was difference in growth. Secondary endpoints included differences in electrolyte concentrations. RESULTS: A total of 299 preterm were included in this study. When comparing weight gain, the infants in the (partially) standardized group demonstrated significantly (P < 0.05) less weight loss during the first days of life and grew faster subsequently in the following days than the individualized TPN regimen. Furthermore, significant differences in abnormal serum sodium, chloride, calcium, creatinine, magnesium and triglycerides values were demonstrated. CONCLUSION: TPN with a (partially) standardized composition revealed to be at least non-inferior to TPN with an individualized composition.