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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.

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.

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

Background Debate on the use of biosimilars focuses on the therapeutic efficacy and safety of switching between biosimilars and their reference products. Purpose To determine the clinical results and pharmacokinetic behaviour of switching from originator infliximab to biosimilar in patients with inflammatory bowel disease (IBD) over 2 years. Materials and methods Prospective, longitudinal study (April 2017–March 2019). Patients with ulcerative colitis (UC) or Crohn’s disease (CD) treated with originator infliximab (Remicade) and changed to biosimilar (CT-P13) were included. The following outcome variables were defined: Clinical Remission (CR)= Harvey Bradshaw index Infliximab serum concentrations were determined by ELISA and pharmacokinetic parameters (volume of distribution (Vd) and clearance (CL)) were estimated by Bayesian population pharmacokinetics analysis. Evaluation of variables was performed in four temporal sections: prior to the switch, immediately after, and again 8 months and 2 years after. ANOVA test was used to compare pharmacokinetic parameters means and the percentage of patients who reached the outcome variables in the different temporal sections was calculated. Results 42 patients (55% women) were included, with a median [range] age of 42 [18-70] years, 10 diagnosed of UC and 32 of CD. Prior to the switch, 93% of the patients presented CR and ER, and 95% BR. These results were identical immediately after switching. Eight months after the switch, 93% of the patients presented CR and 88% ER and BR. At the end of the two years’ follow-up, 97% presented CR and 92% ER and BR. Regarding pharmacokinetic behaviour, there were no significant differences between the average values of CL estimated in the different sections, which were: 0.393 L/d; 0.392 L/d; 0,395 L/d and 0,390 L/d (p=0.91), nor among the Vd, whose results were: 5.25 L; 5.25 L; 5.24 L and 5.28 L (p=0.93), respectively. Conclusion After switching from infliximab originator to biosimilar in a real cohort of IBD patients, no changes in clinical outcomes or pharmacokinetic behaviour were observed over 2 years, which supports the switch in clinical practice.

Tumour necrosis factor inhibitor therapy has drastically changed the management of chronic inflammatory diseases. Some important drawbacks that can cause loss of response during treatment with these drugs are related to their large individual variability, the disease burden and the formation of antidrug antibodies that increase its clearance. Therapeutic drug monitoring of these drugs is not yet recommended by all scientific societies, and if so, only in patients with inflammatory symptoms. Proactive therapeutic drug monitoring represents a new strategy with many potential clinical benefits, including the prevention of immunogenicity, a reduction in the need for rescue therapy and greater durability of tumour necrosis factor inhibitor treatment. The review is based on a systematic search of the literature for controlled trials, systematic reviews, experimental studies, guideline papers and cohort studies addressing the best practice in tumour necrosis factor inhibitor therapeutic drug monitoring. Although there is ample evidence supporting the use of therapeutic drug monitoring in clinical practice to achieve better outcomes, some challenges have been detected. Many studies are focused on finding solutions for the lack of standardization of analytical methods to measure tumour necrosis factor inhibitor and antidrug antibodies concentrations. Other challenges are development of effective cost-saving proactive algorithms to identify optimal drug concentrations and the research on the role of antidrug antibodies, especially in the management and prevention of loss of response. Therapeutic drug monitoring of tumour necrosis factor inhibitor offers a rational approach to the optimization of the treatment of chronic inflammatory disease. Although prospective controlled trials yield little conclusive evidence of its benefits, there is growing acceptance of its value in clinical practice.

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.

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.

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.

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.

OBJECTIVES: Inflammatory bowel disease (IBD) is more complex in children and they will have to live with the disease for much longer. For this reason, it is necessary to optimize treatment. The polymorphisms associated with the response to anti-tumor necrosis factor (TNF) drugs in adults with IBD have not been analyzed in children. The aim of the study was to identify genetic variants associated with the long-term response to anti-TNF drugs in children with IBD. METHODS: An observational, longitudinal, ambispective cohort's study was conducted. We recruited 209 anti-TNF-treated children diagnosed with IBD and genotyped 21 polymorphisms previously studied in adults with Crohn disease (CD) using real-time PCR. The association between single-nucleotide polymorphisms (SNPs) and time-to-failure was analyzed using the log-rank test. RESULTS: After multivariate analysis, 3 SNPs in IL10, IL17A and IL6 were significantly associated with response to anti-TNF treatment among patients diagnosed with CD (rs1800872-HR, 4.749 (95% confidence interval [CI] 1.156-19.517), P value < 0.05; rs2275913-HR, 0.320 [95% CI 0.111-0.920], P value < 0.05; and rs10499563-HR, 0.210 [95% CI 0.047-0.947], P value 0.05, respectively). None of these SNPs were associated with response to infliximab in adults diagnosed with CD. Among patients diagnosed with ulcerative colitis (UC), 1 SNP in LY96 was significantly associated with response to anti-TNF treatment (rs-11465996-HR, 10.220 [95% CI 1.849-56.504] P value < 0.05). CONCLUSIONS: Genotyping of these DNA variants before starting treatment may help to identify children who are long-term responders to anti-TNF drugs, and thus tailor treatment of pediatric IBD.

BACKGROUND: Etanercept is an approved monoclonal antibody for the treatment of rheumatic disease (RD). Individual clinical response to etanercept can be influenced by their pharmacokinetics (PK) and immunogenicity, so therapeutic drug monitoring (TDM) can guide these biologic treatments. PURPOSE: Develop a population pharmacokinetic (popPK) model of etanercept in patients with RD and explore the clinical relevance of covariates which affect significantly the PK of this drug. MATERIAL AND METHODS: A prospective study of patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PS) treated with etanercept and TDM from October 2015 until December 2016 was conducted. Serum etanercept trough levels (SETLs) and anti-drug antibodies (ADA) in steady state were measured by Elisa (Promonitor(®)). The popPK analysis was performed using a non-linear mixed effects modelling approach (NONMEM 7.2). Clinical information was collected from the patients’ medical records and evaluated as a prognostic factor of the PK: sex, age, weight and inflammatory markers (serum albumin (ALB), protein C-reactive (PCR) and erythrocyte sedimentation rate (ESR)). RESULTS: Thirty-two Caucasian patients (63.3% females) were included with a median age of 53 years (range: 18–75) diagnosed with RA (n=15), AS (n=9) and PS (n=8). A total of 42 SETLs were quantified with a mean of 1.29 mcg/mL (±1.1 mcg/mL). No ADA was found in any patient. One open-compartment model with first order absorption and elimination was selected to describe the PK of Etanercept.(1) The PK estimates (V=5.46 L, CL=0.046 L/h) were similar to previous information, except for a reduced CL in the Chinese population.(1,2) ALB and PCR were identified for the first time as prognostic factors of CL according to the equation: CL=0.05x(ALB/4.24)(-1. 99)x(PCR/0.50)(0.13) (ALB in g/dL, PCR in mg/dL).(1,2,3) Pharmacokinetic-adjusted doses aimed to reach SETLs in therapeutics range (1.5–4 mcg/mL) were: 50 mg/4 days if ALB 2 mg/dL, 50 mg/7 days (4 g/dL≤ALB

Background Serum cystatin C (CysC) is a marker that could be useful in haematologic adult patients with protein malnutrition (hypoalbuminaemia) secondary to oral mucositis and gut graft-vs-host-disease, because it detects acute renal failure (ARF) earlier than serum creatinine, the standard marker, and is not affected by sex, age or muscle mass. Purpose To describe the usefulness of CysC as a predictor of glomerular filtration rate (GFR) in a haematologic patient with low serum creatinine concentration (CrC) and protein malnutrition, where the value of creatinine clearance (CrCl) to evaluate ARF is limited. Material and methods A 62-year-old patient with acute myeloid leukaemia was admitted for donor haematopoietic progenitor allogeneic transplant not related with myeloablative conditioning. Tacrolimus and methotrexate were administrated as graft-vs-host-disease prophylaxis. Patient weight, albumin, CrC and CysC, and tacrolimus dosage were obtained from medical records. Tacrolimus levels were measured in the autoanalyser Architect i1000 (Abbott). CrCl and CysC clearance (CysCl) were estimated by the Cockcroft–Gault and Larsson formulas respectively. The influence of ARF in the clearance of tacrolimus and dose requirements was assessed by the level/dose ratio. Results At the start of treatment, tacrolimus was initiated at a dose of 1.3 mg (0.02 mg/kg) IV daily, since renal function was normal (CrCl=89.22 mL/min). No interactions with tacrolimus or other nephrotoxic drugs were found. After determining tacrolimus trough levels (TTL), the individual dose to reach therapeutic range was adjusted to 0.6 mg/day IV (level/dose: 12.5 mg/mL*mg). On +10 day post-transplant, radiologic diagnosis suggested invasive fungal infection, and treatment with amphotericin B liposomal was started. An increase in TTL was detected and a dose adjustment was necessary (level/dose: 29.10 mg/mL*mg). CrCL was 75.27 mL/min, not reflecting severe ARF. Other evidence suggestive of renal failure such as hyperphosphataemia and dermal toxicity secondary to amphotericin were observed. A CysCl control of 34.58 mL/min confirmed a worsening of kidney function and explained the increase in level/dose for tacrolimus. Conclusion Given that CrCl presents major limitations in adult haematologic patients with protein malnutrition, CysCl could be a useful marker for ARF to guide dose adjustments of drugs with renal elimination. Pharmacokinetic studies evaluating the relationship between CysCl and drug clearance would be desirable. No conflict of interest