Drug Level Monitoring Research Articles

Prevalence of Brucella melitensis and Brucella abortus Fluoroquinolones Resistant Isolates: A Systematic Review and Meta-Analysis.

Background: Brucellosis impact both animals and humans worldwide. However, using antibiotics for brucellosis remains controversial despite decades of research. Relapse can complicate treatment in this area. Since the mid-1980s, microbiologists, and physicians have studied fluoroquinolones' use for treating human brucellosis. The principal advantages of fluoroquinolones are their intracellular antimicrobial activity, low nephrotoxicity, good pharmacokinetics, and the lack of drug-level monitoring. Fluoroquinolones inhibit disease recurrence. In vitro and clinical data were used to study the prevalence of Brucella melitensis and Brucella abortus fluoroquinolone-resistant isolates. Methods: The PubMed, Scopus, Embase, and Web of Science databases were carefully searched until August 6, 2022, for relevant papers. The number of resistant isolates and sample size were used to estimate the proportion of resistant isolates, fitting a model with random effects, and DerSimonian-Laird estimated heterogeneity. Furthermore, meta-regression and subgroup analyses were used to assess the moderators to identify the sources of heterogeneity. Meta-analysis was performed using R software. Results: Forty-seven studies evaluated fluoroquinolone resistance in Brucella spp. Isolates. Fluoroquinolones have shown high in vitro efficacy against Brucella spp. The resistance rates to ofloxacin, sparfloxacin, fleroxacin, pefloxacin, and lomefloxacin were 2%, 1.6%, and 4.6%, respectively. Conclusion: Clinical in vitro tests demonstrated that fluoroquinolones can eradicate Brucella spp. Owing to first-line medication resistance, recurrence, and toxicity, it is essential to standardize the Brucella antimicrobial susceptibility test method for a more precise screening of resistance status. Fluoroquinolones are less resistant to fluoroquinolone-based treatments in modern clinical practice as alternatives to standard therapy for patients with brucellosis relapse after treatment with another regimen and in patients who have developed toxicity from older agents.

Venlafaxine’s therapeutic reference range in the treatment of depression revised: a systematic review and meta-analysis

IntroductionThe selective serotonin and norepinephrine reuptake inhibitor venlafaxine is among the most prescribed antidepressant drugs worldwide and, according to guidelines, its dose titration should be guided by drug-level monitoring of its active moiety (AM) which consists of venlafaxine (VEN) plus active metabolite O-desmethylvenlafaxine (ODV). This indication of therapeutic drug monitoring (TDM), however, assumes a clear concentration/effect relationship for a drug, which for VEN has not been systematically explored yet.ObjectivesWe performed a systematic review and meta-analysis to investigate the relationship between blood levels, efficacy, and adverse reactions in order to suggest an optimal target concentration range for VEN oral formulations for the treatment of depression.MethodsFour databases (MEDLINE (PubMed), PsycINFO, Web of Science Core Collection, and Cochrane Library) were systematically searched in March 2022 for relevant articles according to a previously published protocol. Reviewers independently screened references and performed data extraction and critical appraisal.ResultsHigh-quality randomized controlled trials investigating concentration/efficacy relationships and studies using a placebo lead-in phase were not found. Sixty-eight articles, consisting mostly of naturalistic TDM studies or small noncontrolled studies, met the eligibility criteria. Of them, five cohort studies reported a positive correlation between blood levels and antidepressant effects after VEN treatment. Our meta-analyses showed (i) higher AM and (ii) higher ODV concentrations in patients responding to VEN treatment when compared to non-responders (n = 360, k = 5). AM concentration-dependent occurrence of tremor was reported in one study. We found a linear relationship between daily dose and AM concentration within guideline recommended doses (75–225 mg/day). The population-based concentration ranges (25–75% interquartile) among 11 studies (n = 3200) using flexible dosing were (i) 225–450 ng/ml for the AM and (ii) 144–302 ng/ml for ODV. One PET study reported an occupancy of 80% serotonin transporters for ODV serum levels above 85 ng/ml. Based on our findings, we propose a therapeutic reference range for AM of 140–600 ng/ml.ConclusionVEN TDM within a range of 140 to 600 ng/ml (AM) will increase the probability of response in nonresponders. A titration within the proposed reference range is recommended in case of non-response at lower drug concentrations as a consequence of VEN’s dual mechanism of action via combined serotonin and norepinephrine reuptake inhibition. Drug titration towards higher concentrations will, however, increase the risk for ADRs, in particular with supratherapeutic drug concentrations.

Aptasensors: employing molecular probes for precise medical diagnostics and drug monitoring.

Accurate detection and monitoring of therapeutic drug levels are vital for effective patient care and treatment management. Aptamers, composed of single-stranded DNA or RNA molecules, are integral components of biosensors designed for both qualitative and quantitative detection of biological samples. Aptasensors play crucial roles in target identification, validation, detection of drug-target interactions and screening potential of drug candidates. This review focuses on the pivotal role of aptasensors in early disease detection, particularly in identifying biomarkers associated with various diseases such as cancer, infectious diseases and cardiovascular disorders. Aptasensors have demonstrated exceptional potential in enhancing disease diagnostics and monitoring therapeutic drug levels. Aptamer-based biosensors represent a transformative technology in the field of healthcare, enabling precise diagnostics, drug monitoring and disease detection.

Voclosporin: Unique Chemistry, Pharmacology and Toxicity Profile, and Possible Options for Implementation into the Management of Lupus Nephritis.

Calcineurin inhibitors (CNI) can suppress allo- and autoimmunity by suppressing T cell function but also have anti-proteinuric effects by stabilizing the cellular components of the kidney's filtration barrier. Therefore, CNI are used in autoimmune kidney diseases with proteinuria. However, the traditional CNI, cyclosporine A and tacrolimus, have a narrow therapeutic range, need monitoring of drug levels, and their use is associated with nephrotoxicity and metabolic alterations. Voclosporin (VOC), a novel CNI, no longer requires drug level monitoring and seems to lack these adverse effects, although hypertension and drug-drug interactions still occur. VOC demonstrated efficacy superior to standard-of-care in controlling active lupus nephritis in the phase 2 AURA-LV and the phase 3 AURORA-1 trials and was approved for the treatment of active lupus nephritis. However, how to implement VOC into the current and changing treatment landscape of lupus nephritis is still debated. Here, we review the unique chemistry, pharmacology, and toxicity profile of VOC, summarize the efficacy and safety data from the AURA-LV and AURORA-1 trials, and discuss the following four possible options to implement VOC into the management of lupus nephritis, namely regarding B cell-targeting therapy with belimumab (BEL). These include: 1. patient stratification to either VOC or BEL, 2. VOC/BEL combination therapy, 3. VOC-BEL sequential therapy, or 4. alternative options for the rapid antiproteinuric effect of VOC.

Optimal management of cardiac surgery patients using direct oral anticoagulants: recommendations for clinical practice.

Literature is scarce on the management of patients using direct oral anticoagulants (DOACs) undergoing elective, urgent and emergency surgery. Therefore, we summarize the current evidence and provide literature-based recommendations for the management of patients on DOACs in the perioperative phase. A general literature review was conducted on the pharmacology of DOACs and for recommendations on the management of cardiac surgical patients on DOACs. Additionally, we performed a systematic review for studies on the use of direct DOAC reversal agents in the emergency cardiac surgical setting. When surgery is elective, the DOAC cessation strategy is relatively straightforward and should be adapted to the renal function. The same approach applies to urgent cases, but additional DOAC activity drug level monitoring tests may be useful. In emergency cases, idarucizumab can be safely administered to patients on dabigatran in any of the perioperative phases. However, andexanet alfa, which is not registered for perioperative use, should not be administered in the preoperative phase to reverse the effect of factor Xa inhibitors, as it may induce temporary heparin resistance. Finally, the administration of (activated) prothrombin complex concentrate may be considered in all patients on DOACs, and such concentrates are generally readily available. DOACs offer several advantages over vitamin K antagonists, but care must be taken in patients undergoing cardiac surgery. Although elective and urgent cases can be managed relatively straightforwardly, the management of emergency cases requires particular attention.

Co prescription of anti-acid therapy reduces the bioavailability of mycophenolate mofetil in systemic sclerosis patients: A crossover trial

ObjectiveMycophenolate mofetil (MMF) is an effective treatment option for interstitial lung disease (ILD) in systemic sclerosis (SSc). Many patients require co-administration of proton pump inhibitors (PPI) or H2 receptor blockers (HRB) because of various gastrointestinal (GI) manifestations in SSc. Co-treatment with PPI or HRB have shown to reduce serum drug levels in post-transplant patients. We wanted to see if there is a similar phenomenon for Mycophenolate in SSc. MethodsTwenty SSc patients, who were on a stable dose of MMF (1.5-3 g) underwent a sequential cross over study with MMF alone in the first month, followed by co-treatment with Ranitidine and then Esomeprazole in the second and third month respectively. Estimation of 12-hour area under curve (AUC) of Mycophenolic Acid (MPA) levels and total GI score were calculated at the end of each month and compared between the treatment arms. [Trial registration: CTRI/2020/06/025,939] ResultsCo-administration of esomeprazole was associated with 32.7% (mean difference = 22.28 μg h ml–1) reduction in mean AUC MPA, whereas ranitidine caused a reduction of 21.97% (mean difference = 14.93 μg h ml–1) in MPA AUC when compared to MMF without anti-acid therapies. The addition of ranitidine or esomeprazole resulted in significant reduction in the total GI score. ConclusionCo-administration of PPI or HRB can significantly reduce the bioavailability of MMF in patients with SSc. To avoid therapeutic failure of MMF drug level monitoring is essential when these agents are co-prescribed with MMF.

Invasive fungal infection following venetoclax and posaconazole co-administration.

The co-administration of venetoclax, a BCL-2 inhibitor, with a mould-active azole, such a posaconazole, has potential to both prevent invasive fungal infection (IFI) and reduce the required treatment dose, and cost, of venetoclax. Posaconazole drug-level monitoring is critical to ensuring adequate mould prophylaxis. A retrospective audit of 99 patients at a tertiary cancer centre, with myeloid malignancies co-prescribed venetoclax and posaconazole between January 2018 and April 2022, was undertaken to evaluate the adequacy of posaconazole prescribing and the rate of breakthrough IFI. Seventy-six patients (77%) had at least one posaconazole level measured in the study period, with 37% requiring a dose adjustment based on steady-state trough levels. Breakthrough IFI occurred in 4% of patients, typically within 1 month of commencing anti-mould prophylaxis. Close monitoring of posaconazole levels in venetoclax-treated patients, particularly in the early, outpatient setting, is critical.

Intra-operative drug level monitoring of pre-operative antibiotic for surgical prophylaxis inthe patients of elective spinal surgery.

Single dose prophylaxis is good enough for general surgery with low risk patients. However, the evidence for the effectiveness of single dose anti-microbial prophylaxis (AMP) is not conclusive in high risk patients andspinal surgeries requiring instrumentation or the use of implants in particular. No studies have explored the various concentration of ceftriaxone in plasma and tissue as well during an ongoing spinal surgery. Therefore, the objective of study was to correlate the serum and tissue concentrations of ceftriaxone with the SSI and identify patients with increased risk of SSI. It was an open label prospective study in 50 consecutive patients who underwent elective spine surgery under prophylactic cover of ceftriaxone. Serum and tissue concentration were estimated by high pressure liquid chromatography during the ongoing surgery. Subjects were observed for any post-operative complications including SSI. Serum (p=0.002) and tissue (p=0.012) concentrations of ceftriaxone at the closure of spinal surgery were associated with SSI. Duration of the surgery (p=0.04) and use of implants (p=0.02) were also important surgery related risk factors. Serum and tissue concentrations of ceftriaxone atthe closure and duration of surgery and instrumentation or use of implants in the spinal surgery are good predictors of SSI.

Development of innovative methodology for determination of 6-thioguanine in whole blood erythrocytes by HPLC–PDA-based technique for medical diagnostics purposes

6-Thioguanine is an immunosuppressive drug, an analogue of guanine, applied to treat acute leukemia and inflammatory bowel disease. Excessive use of 6-thioguanine during clinical treatment may cause side effects. Moreover, providing a dose too low will be ineffective. Therefore, there is a critical need for a rapid, selective and routine approach to quantifying 6-thioguanine in body fluids to support a clinical application. A fully validated HPLC method has been developed to determine 6-thioguanine in whole blood samples using 5-bromouracil as an internal standard. 6-Thioguanine nucleotides were released from erythrocytes by perchloric acid, and then hydrolysed at 100 °C to the parent thiopurine, 6-thioguanine. The following validation parameters of the method were determined: specificity/selectivity, linearity range (479–17,118 ng/mL, R > 0.992), limits of detection (150 ng/mL) and quantification (479 ng/mL), accuracy (− 5.6 < Bias < 14.7), repeatability (CV 1.30–3.24%), intermediate precision (CV 4.19–5.78%), extraction recovery (79.1–103.6%) and carryover. Furthermore, the stability of the drug in whole blood samples under various storage conditions was investigated. The suggested method is suitable for determining 6-thioguanine in whole blood erythrocyte samples for drug level monitoring, thus correct dosing.

An Amperometric Biosensor Based on a Bilayer of Electrodeposited Graphene Oxide and Co-Crosslinked Tyrosinase for L-Dopa Detection in Untreated Human Plasma.

L-Dopa, a bioactive compound naturally occurring in some Leguminosae plants, is the most effective symptomatic drug treatment for Parkinson's disease. During disease progression, fluctuations in L-DOPA plasma levels occur, causing motor complications. Sensing devices capable of rapidly monitoring drug levels would allow adjusting L-Dopa dosing, improving therapeutic outcomes. A novel amperometric biosensor for L-Dopa detection is described, based on tyrosinase co-crosslinked onto a graphene oxide layer produced through electrodeposition. Careful optimization of the enzyme immobilization procedure permitted to improve the long-term stability while substantially shortening and simplifying the biosensor fabrication. The effectiveness of the immobilization protocol combined with the enhanced performances of electrodeposited graphene oxide allowed to achieve high sensitivity, wide linear range, and a detection limit of 0.84 μM, suitable for L-Dopa detection within its therapeutic window. Interference from endogenous compounds, tested at concentrations levels typically found in drug-treated patients, was not significant. Ascorbic acid exhibited a tyrosinase inhibitory behavior and was therefore rejected from the enzymatic layer by casting an outer Nafion membrane. The proposed device was applied for L-Dopa detection in human plasma, showing good recoveries.

Which trial do we need? Doxycycline vs. doxycycline-hydroxychloroquine and treatment duration protocol for Q fever endovascular infections

Chronic Q fever includes mainly endocarditis and other endovascular infections and more rarely osteoarticular infections. Treatment for the various manifestations of chronic Q fever has been standardized in the last 20 years to doxycycline and hydroxychloroquine given for a minimum of 18 to 24 months. 1 Anderson A. Bijlmer H. Fournier P.E. et al. Diagnosis and management of Q fever--United States, 2013: recommendations from CDC and the Q Fever Working Group. MMWR Recomm Rep. 2013; 62: 1-30 PubMed Google Scholar ,2 Raoult D 2019. DIAGNOSTIC ET TRAITEMENT FIEVRE Q. https://www.mediterranee-infection.com/wp-content/uploads/2019/08/Protocoles-FQ-franc%CC%A7ais-23-AOUT-2019-Anatomy-Bacteriology-OKDR.pdf. Google Scholar Recommendations on duration of treatment beyond the minimal period are based mostly on levels of Q fever IgG phase 1 titers. Monitoring of drug levels is recommended by some experts.

Switch from a ritonavir to a cobicistat containing antiretroviral regimen and impact on tacrolimus levels in a kidney transplant recipient

BackgroundSolid-organ transplantation due to end-stage organ disease is increasingly performed in people living with HIV. Despite improved transplant outcomes, management of these patients remains challenging due to higher risk for allograft rejection, infection and drug–drug interactions (DDIs). Complex regimens for multi-drug resistant HIV-viruses may cause DDIs particularly if the regimen contains drugs such as ritonavir or cobicistat.Case presentationHere we report on a case of an HIV-infected renal transplant recipient on long-term immunosuppressive therapy with mycophenolate mofetil and tacrolimus dosed at 0.5 mg every 11 days due to the co-administration of a darunavir/ritonavir containing antiretroviral regimen. In the presented case the pharmacokinetic booster was switched from ritonavir to cobicistat for treatment simplification. A close monitoring of tacrolimus drug levels was performed in order to prevent possible sub- or supratherapeutic tacrolimus trough levels. A progressive decrease in tacrolimus concentrations was observed after switch requiring shortening of tacrolimus dosing interval. This observation was unexpected considering that cobicistat is devoid of inducing properties.ConclusionsThis case highlights the fact that the pharmacokinetic boosters ritonavir and cobicistat are not fully interchangeable. Therapeutic drug monitoring of tacrolimus is warranted to maintain levels within the therapeutic range.

In vivo solid phase microextraction for therapeutic monitoring and pharmacometabolomic fingerprinting of lung during in vivo lung perfusion of FOLFOX

In vivo lung perfusion (IVLP) is a novel isolated lung technique developed to enable the local, in situ administration of high-dose chemotherapy to treat metastatic lung cancer. Combination therapy using folinic acid (FOL), 5-fluorouracil (F), and oxaliplatin (OX) (FOLFOX) is routinely employed to treat several types of solid tumours in various tissues. However, F is characterized by large interpatient variability with respect to plasma concentration, which necessitates close monitoring during treatments using of this compound. Since plasma drug concentrations often do not reflect tissue drug concentrations, it is essential to utilize sample-preparation methods specifically suited to monitoring drug levels in target organs. In this work, in vivo solid-phase microextraction (in vivo SPME) is proposed as an effective tool for quantitative therapeutic drug monitoring of FOLFOX in porcine lungs during pre-clinical IVLP and intravenous (IV) trials. The concomitant extraction of other endogenous and exogenous small molecules from the lung and their detection via liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) enabled an assessment of FOLFOX's impact on the metabolomic profile of the lung and revealed the metabolic pathways associated with the route of administration (IVLP vs. IV) and the therapy itself. This study also shows that the immediate instrumental analysis of metabolomic samples is ideal, as long-term storage at −80 °C results in changes in the metabolite content in the sample extracts.

Determination of 5-azacitidine in human plasma by LC-MS/MS: application to pharmacokinetics pilot study in MDS/AML patients.

Azacitidine (Vidaza®, AZA) is a mainstay for treating acute myeloid leukemia (AML) in patients unfit for standard induction and other myelodysplastic syndromes (MDS). However, only half of the patients usually respond to this drug and almost all patients will eventually relapse. Predictive markers for response to AZA are yet to be identified. AZA is metabolized in the liver by a single enzyme, cytidine deaminase (CDA). CDA is a ubiquitous enzyme coded by a highly polymorphic gene, with subsequent great variability in resulting activities in the liver. The quantitative determination of AZA in plasma is challenging due the required sensitivity and because of the instability in the biological matrix upon sampling, possibly resulting in erratic values. We have developed and validated following EMA standards a simple, rapid, and cost-effective liquid chromatography-tandem mass spectrometry method for the determination of azacitidine in human plasma. After a simple and rapid precipitation step, analytes were successfully separated and quantitated over a 5-500ng/mL range. The performance and reliability of this method were tested as part of an investigational study in MDS/AML patients treated with standard azacitidine (75mg/m2 for 7days a week every 28days). Overall, this new method meets the requirements of current bioanalytical guidelines and could be used to monitor drug levels in MDS/AML patients.

Pengembangan dan Validasi Metode Bioanalisis Trimetoprim dalam Sampel Plasma dan Urin Manusia Simulasi Menggunakan KCKT-PDA

To monitor trimethoprim levels (TMP) in humans, a validated, simple, and cost-efficient analytical method is needed to be applied regularly. However, most of the methods used to establish TMP levels in urine and plasma use complex instrumentation. Therefore, in this study, a simpler High-Performance Liquid Chromatography-based (HPLC) method was developed. The separation was carried out using a GIST® C18 column (150 × 4.6 mm, 5 μm) at a temperature of 35°C which was fed by a mobile phase in the form of an acetic acid solution pH 2.5: acetonitrile (87:13, v / v) at a speed of 1.4 ml/min. Detection was performed with Photodiode Array Detector (PDA) at wavelengths of 254 nm and 243 nm to quantify TMP in urine and plasma samples respectively. The preparation of urine and plasma sequentially was carried out by the liquid-liquid extraction (ECC) method using ethyl acetate and the protein precipitation using acetonitrile. This method proved to be selective, linear (R=0.997), accurate with %error ≤ 10.29% at LLOQ level and above LLOQ value %error ≤ 10.45%, precision with %RSD ≤ 11.79% at LLOQ level and %RSD ≤ 10.82% above LLOQ. In addition, this method is quite sensitive for pharmacokinetic studies in the urine and monitoring of TMP levels in the blood with LLOQ 5 mg/L in both urine and plasma. The stability of trimethoprim in solution, urine, and plasma was conducted to ensure storage time. The developed method is proven to be valid and can be applied in pharmacokinetic studies and monitoring of trimethoprim drug levels in urine and plasma.

Perspectives of Therapeutic Drug Monitoring of Biological Agents in Non-Infectious Uveitis Treatment: A Review

Biological drugs, especially those targeting anti-tumour necrosis factor α (TNFα) molecule, have revolutionized the treatment of patients with non-infectious uveitis (NIU), a sight-threatening condition characterized by ocular inflammation that can lead to severe vision threatening and blindness. Adalimumab (ADA) and infliximab (IFX), the most widely used anti-TNFα drugs, have led to greater clinical benefits, but a significant fraction of patients with NIU do not respond to these drugs. The therapeutic outcome is closely related to systemic drug levels, which are influenced by several factors such as immunogenicity, concomitant treatment with immunomodulators, and genetic factors. Therapeutic drug monitoring (TDM) of drug and anti-drug antibody (ADAbs) levels is emerging as a resource to optimise biologic therapy by personalising treatment to bring and maintain drug concentration within the therapeutic range, especially in those patients where a clinical response is less than expected. Furthermore, some studies have described different genetic polymorphisms that may act as predictors of response to treatment with anti-TNFα agents in immune-mediated diseases and could be useful in personalising biologic treatment selection. This review is a compilation of the published evidence in NIU and in other immune-mediated diseases that support the usefulness of TDM and pharmacogenetics as a tool to guide clinicians' treatment decisions leading to better clinical outcomes. In addition, findings from preclinical and clinical studies, assessing the safety and efficacy of intravitreal administration of anti-TNFα agents in NIU are discussed.

Isolation of Antidepressants and Their Metabolites from Saliva Using Supported Liquid Extraction (SLE).

The determination of antidepressant drugs and their metabolites in the body, mainly in the blood, allows for the monitoring of drug levels and their metabolism, helps identify drug interactions, and reduces the likelihood of increased side effects. Due to numerous inconveniences associated with collecting blood in patients, therapeutic drug monitoring (TDM) based on saliva sampling could significantly improve patient comfort. Therefore, the aim of this study was to develop a method for the simultaneous determination of selected antidepressants (amitriptyline, mianserin, duloxetine, mirtazapine, sertraline, citalopram, and venlafaxine) and their metabolites (N-desmethylmirtazapine, norsertraline, N-desmethylcitalopram, O-desmethylvenlafaxine) in human saliva using supported liquid extraction (SLE). Chlordiazepoxide was used as an internal standard. UHPLC coupled with DAD detection was used for the determinations. The proposed method was validated by determining its linearity for saliva concentrations in the range 10-1000 ng/mL. For all the analyzed compounds, a linear relationship between the analytical signal and analyte concentration was obtained (R2 > 0.99), with the intra- and inter-day precisions expressed as a coefficient of variation (% CV) below 15% in all tested cases. The study showed the usefulness of the proposed method for the isolation of antidepressant drugs and their metabolites in saliva patients' samples.

To Measure or Not to Measure: Direct Oral Anticoagulant Laboratory Assay Monitoring in Clinical Practice.

The need for therapeutic drug monitoring of direct oral anticoagulants (DOACs) remains an area of clinical equipoise. Although routine monitoring may be unnecessary given predictable pharmacokinetics in most patients, there may be altered pharmacokinetics in those with end organ dysfunction, such as those with renal impairment, or with concomitant interacting medications, at extremes of body weight or age, or in those with thromboembolic events in atypical locations. We aimed to assess real-world practices in situations in which DOAC drug-level monitoring was used at a large academic medical center. A retrospective review of the records of patients who had a DOAC drug-specific activity level checked from 2016 to 2019 was included. A total of 119 patients had 144 DOAC measurements (apixaban (n = 62) and rivaroxaban (n = 57)). Drug-specific calibrated DOAC levels were within an expected therapeutic range for 110 levels(76%), with 21 levels (15%) above the expected range and 13 levels (9%) below the expected range. The DOAC levels were checked in the setting of an urgent or emergent procedure in 28 patients (24%), followed by renal failure in 17 patients (14%), a bleeding event in 11 patients (9%), concern for recurrent thromboembolism in 10 patients (8%), thrombophilia in 9 patients (8%), a history of recurrent thromboembolism in 6 patients (5%), extremes of body weight in 7 patients (5%), and unknown reasons in 7 patients (5%). Clinical decision making was infrequently affected by the DOAC monitoring. Therapeutic drug monitoring with DOACs may help predict bleeding events in elderly patients, those with impaired renal function, and in the event of an emergent or urgent procedure. Future studies are needed to target the select patient-specific scenarios where monitoring DOAC levels may impact clinical outcomes.

P654 Controversies in the management of anti-TNF therapy in Crohn’s disease patients. A Delphi consensus

Abstract Background Over the last years significant advances have arisen in CD. New therapies with different mechanisms of action have been approved for the management of Crohn’s disease (CD). However, there is limited evidence on optimal positioning of agents as first-or second-line therapies due to the lack of head-to-head robust comparative data. Our aim was to establish feasible and practical recommendations for the management of patients with moderate to severe CD with the use of anti-tumour necrosis factor (TNF) drugs, with special focus on controversial areas. Methods A group of 9 expert gastroenterologists identified current relevant clinical controversies in the management of CD with anti-TNF therapies. A comprehensive literature review was performed to analyze them and a survey was launched to examine current clinical practice. This was a structured survey organized in 2 main sections that included several questions: 1) Sociodemographic and practice related questions; 2) Opinion and attitude in daily practice related to: the use of anti-TNFs, vedolizumab or ustekinumab in naïve and refractory patients, the role of HLA-DQA105, or monitoring of drug levels. An invitation to participate was emailed to a representative number of 244 IBD treating physicians all over the country. The results of the literature review and survey were discussed in a nominal group meeting, and a set of statements were proposed for a Delphi process. The participants of the survey were also invited to the Delphi. Agreement was defined if at least 70% of the participants voted ≥7 (from 1, totally disagree to 10, totally agree). For each statement, the level of evidence and grade of recommendation was established based on the Oxford Evidence Based Medicine categorization. Results A total of 14 statements were generated (table 1 depicts the statements and the results of the Delphi). All but two achieved required level of agreement. The statements cover the following areas: 1) use of first-line non-anti-TNF biologic therapy; 2) role of HLA-DQA1*05 in daily practice; 3) attitudes in primary nonresponse and loss of response to anti-TNF therapy due to immunogenicity; 4) ustekinumab or vedolizumab if a change of mechanism of action is considered; 5) anti-TNF drug levels monitoring during induction; 6) combined therapy with an immunomodulator and anti-TNF monotherapy. Conclusion This document sought to pull together the experts’ attitudes when dealing with different clinical scenarios of patients with CD on anti-TNF.

P437 Early therapeutic drug monitoring of Adalimumab, but not HLADQ*A1 determination, predicts inflammatory bowel disease outcome

Abstract Background Anti-TNF drugs are effective treatments for the management of Inflammatory Bowel Disease (IBD), yet treatment failure is common. Monitoring drug levels and their antibodies (ATIs) can be useful to optimize the management of patients. In addition, the HLA-DQA1*05 gene has been recently related as a possible marker of immunogenicity and loss of response to anti-TNF therapy.The aim of this study was to evaluate the clinical impact of determining adalimumab (ADA) levels and anti-adalimumab ATIs in patients with IBD, and the influence of the HLA-DQA1*05 allele on the response and maintenance of adalimumab treatment in this population. Methods This observational, multicentric and prospective study enrolled patients who started treatment with ADA from October 2020 to October 2022. Demographic data and IBD characteristics were recorded. Clinical Activity Index (Harvey Index and Parcial Mayo Score) and C reactive protein(CRP), faecal calprotectin (FC), endoscopy or radiological activity, Global Physician Assesment (GPA) and PRO (by IBDQ-9) were prospectively collected at baseline and at the same time that ADA levels: week 4, 10, 30 and 12 months. HLA-DQA1*05 was genotyped at baseline. Pearson coefficient was used to assess the correlation between ADA levels and activity disease at different points Results We included 131 (age 42±17 years, 56% female) IBD patients (78% Crohn`s Disease, 21% Ulcerative Colitis and 1% Indeterminate colitis) who started treatment with ADA (80% were naïve to anti-TNF and 57% started ADA combined with immunomodulator treatment). At baseline, 81% had an active disease (Global Physician Assesment=1), 49% had CRP &amp;gt;5 mg/L and 77% had FC &amp;gt; 150 mg/kg. PRO at baseline was 63±9.1. HLA was determined in 99 patients, of whom 42 (42%) were HLA-DQA1*05 positives. We found a positive correlation between PRO score and Hb levels and albumin, meanwhile a negative correlation with FC and CRP at week 0. No correlation with ADA levels or ATIs was established. Patients HLA-DQA1*05 positive had not more adverse reaction or ATIs during the observational period. Patients with ADA serum concentration &amp;gt;7µg/mL at week 4 had CRP &amp;lt;5mg/dL at week 4 (p=0.04) and at week 10 (p=0.01). Patients with ADA serum concentration &amp;gt;7µg/mL at week 10 had more stable disease (PGA =0) and CRP &amp;lt;5mg/L, FC &amp;lt;150 mg/kg at week 10 (p&amp;lt;0.05), CRP &amp;lt;5mg/L at week 30 (p&amp;lt;0.05) and FC &amp;lt;150 mg/kg at 12 months. Conclusion Early Drug level monitoring of Adalimumab (after induction) may improve the management of IBD patients. Our study shows that ADA levels &amp;gt;7 µg/mL is associated with a better clinical response in short and long-term, independent of HLADQA1*05.