Therapeutic drug monitoring in inflammatory bowel diseases. Position statement of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis. / Monitorización terapéutica de los fármacos biológicos en la enfermedad inflamatoria intestinal. Documento de Posicionamiento del Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU).

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.

Polymorphisms indicating risk of inflammatory bowel disease or antigenicity to anti-TNF drugs as biomarkers of response in children.

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.

Population pharmacokinetics of a posaconazole tablet formulation in transplant adult allogeneic stem cell recipients.

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.

Pharmacogenetics of trough serum anti-TNF levels in paediatric inflammatory bowel disease.

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.

Biomarkers of disease activity and other factors as predictors of adalimumab pharmacokinetics in inflammatory bowel disease.

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.

A 3-year prospective study of a multidisciplinary early proactive therapeutic drug monitoring programme of infliximab treatments in inflammatory bowel disease.

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.

Study of fall risk-increasing drugs in elderly patients before and after a bone fracture.

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.