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The European Cooperation in Science and Technology (COST) action ENOTTA (The European Network on Optimising Treatment with Therapeutic Antibodies in chronic inflammatory diseases) was launched in 2022. To pave the way for harmonization of analytical methods for quantitation of serum levels of therapeutic antibodies in research and clinical settings, ENOTTA recently performed an online survey mapping laboratories in the field. The survey, which contained 30 questions surrounding therapeutic drug monitoring of relevant drugs and anti-drug antibodies, was distributed via the ENOTTA and European Federation of Clinical Chemistry and Laboratory networks. Among 63 respondents across Europe, 45 reported analytical activity, with a range of utilized methods. Future engagement of as many sites as possible will enable comparison of methodologies and facilitate progress in the field.

Background Higher serum concentrations of vedolizumab have been associated with improved outcomes in inflammatory bowel disease. It is unclear how vedolizumab exposure is linked to endoscopic remission in Crohn disease (CD). We aimed to develop a pharmacokinetic-pharmacodynamic model linking vedolizumab exposure to endoscopic remission in CD. Methods Data were obtained from the first 110 patients participating in a phase 4 prospective multicenter trial (LOVE-CD; ClinicalTrials.gov identifier: NCT02646683), where vedolizumab was dosed at 300 mg every 8 weeks and serum concentrations and antibodies to vedolizumab were measured before each infusion. Concentration-time profiles were described by a 2-compartment model with parallel linear and nonlinear elimination. A first-order discrete-time Markov model was used to describe the relationship between pharmacokinetic exposure metrics and the probability of endoscopic remission (Simple Endoscopic Score for CD < 4). Results Linear clearance was 0.215 L/d, and the volume of distribution of the central compartment was 4.92 L. Linear clearance was higher and vedolizumab exposure was lower in patients with lower serum albumin concentrations, in the presence of antibodies to vedolizumab, and in patients with previous exposure to other biologic therapy. A week 22 vedolizumab concentration of 20.0 mg/L was predicted to yield a 35% probability of achieving endoscopic remission at week 26. Model-based simulations suggested that endoscopic remission rates of 46.5% or 40.0% could be reached with every-4-weeks dosing in patients who were naive or previously exposed to biologic therapy, respectively. Conclusions Model-informed dosing of vedolizumab in CD provides a foundation for future research aiming to maximize endoscopic remission rates., Correction in: INFLAMMATORY BOWEL DISEASES Volume 28, Issue 5, Page 817-817, DOI 10.1093/ibd/izab270

Aims: In the UNITI endoscopy sub-study, only 17.4% of patients with Crohn's disease (CD) on ustekinumab achieved endoscopic response and 10.9% of patients achieved endoscopic remission at week (w)44. We aimed to evaluate the impact of alternative ustekinumab dosage regimens on endoscopic outcomes based on population pharmacokinetic-pharmacodynamic (popPK-PD) modelling and simulation analysis. Methods: Real-world data were obtained from 83 patients with moderate-to-severe CD (95% biological-refractory) enrolled in a prospective cohort study receiving intravenous ustekinumab (similar to 6 mg/kg) followed by every eight-week (q8w) subcutaneous maintenance therapy (90 mg). Three sequential models were developed: a two-compartment popPK model linking ustekinumab dose to ustekinumab exposure, an indirect response popPK-PD model describing the effect of ustekinumab exposure on fecal calprotectin (fCal), and a logistic regression outcome model linking fCal to endoscopic outcomes. Results: Ustekinumab clearance increased with decreasing serum albumin and increasing bodyweight. fCal decreased with increasing ustekinumab exposure. The probability of endoscopic response at w24 increased from 10.0% to 17.9% with fCal at w8 decreasing from 1800 mu g/g to 694 mu g/g (EC50). The probability of endoscopic remission at w24 increased from 2.1% to 10.0% with fCal at w8 decreasing from 1800 mu g/g to 214 mu g/g (EC50). Simulation-based comparison of q8w and q4w maintenance dosing regimens predicted 16.7% and 22.2% endoscopic response rates, respectively. Endoscopic remission rates were estimated to be 4.2% on q8w dosing and 6.7% on q4w dosing. Conclusions: The developed models can guide clinical trial design and support model-informed dose optimization (stratified or individualized dosing) to improve endoscopic outcomes.

Objectives: PTA of protein-unbound ceftriaxone may be compromised in critically ill patients with community-acquired pneumonia (CAP) with augmented renal clearance (ARC). We aimed to determine an optimized ceftriaxone dosage regimen based on the probability of developing ARC on the next day (P-ARC,P-d+1; www.arcpredictor.com). Patients and methods: Thirty-three patients enrolled in a prospective cohort study were admitted to the ICU with severe CAP and treated with ceftriaxone 2 g once daily. Patients contributed 259 total ceftriaxone concentrations, collected during 1 or 2 days (+/- 7 samples/day). Unbound fractions of ceftriaxone were determined in all peak and trough samples (n= 76). Population pharmacokinetic modelling and simulation were performed using NONMEM7.4. Target attainment was defined as an unbound ceftriaxone concentration >4 mg/L throughout the dosing interval. Results: A two-compartment population pharmacokinetic model described the data well. The maximal protein-bound ceftriaxone concentration decreased with lower serum albumin. Ceftriaxone clearance increased with body weight and P-ARC,P-d+1 determined on the previous day. A high P-ARC,P-d+1 was identified as a clinically relevant predictor for underexposure on the next day (area under the receiver operating characteristics curve 0.77). Body weight had a weak predictive value and was therefore considered clinically irrelevant. Serum albumin had no predictive value. An optimal P-ARC,P-d+1 threshold of 5.7% was identified (sensitivity 73%, specificity 69%). Stratified once- or twice-daily 2 g dosing when below or above the 5.7% P-ARC,P-d+1 cut-off, respectively, was predicted to result in 81% PTA compared with 47% PTA under population-level once-daily 2 g dosing. Conclusions: Critically ill patients with CAP with a high P-ARC,P-d+1 may benefit from twice-daily 2 g ceftriaxone dosing for achieving adequate exposure on the next day.

Matthias Gijsen,1,2 Omar Elkayal,1 Pieter Annaert,1,3 Ruth Van Daele,1,2 Philippe Meersseman,4 Yves Debaveye,4 Joost Wauters,4 Erwin Dreesen,1 Isabel Spriet1,2 1Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium; 2Pharmacy Department, University Hospitals Leuven, Leuven, Belgium; 3BioNotus, Niel, Belgium; 4Department of Cellular and Molecular Medicine, KU Leuven, Leuven, BelgiumCorrespondence: Matthias GijsenPharmacy Department, University Hospitals Leuven, Herestraat 49, Leuven, 3000, BelgiumTel +32 16 340087Fax +32 16 343080Email mathias.gijsen@uzleuven.bePurpose: Critically ill patients with preserved or increased renal function have been shown to be at risk of underexposure to meropenem. Although many meropenem population pharmacokinetic (PK) models have been published, there is no large prospective population PK study with rich sampling focusing on patients most at risk of suboptimal pharmacokinetic/pharmacodynamic (PK/PD) target attainment. Therefore, the aim of the present study was to evaluate PK/PD target attainment and to perform a thorough covariate screening using population PK modelling of meropenem in septic patients with preserved or increased renal function.Patients and Methods: A single-centre prospective observational PK study was performed in the intensive care unit (ICU) of the University Hospitals Leuven. Patients with severe sepsis or septic shock and treated with meropenem in the ICU were screened for inclusion. Patients were excluded if they received renal replacement therapy or had an estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology collaboration equation < 70 mL/min/1.73m2 on the day of PK sampling. Successful PK/PD target attainment was defined as an unbound meropenem trough concentration above 2 mg/L or 8 mg/L. Population PK modelling was performed with NONMEM7.4.Results: In total, 58 patients were included, contributing 345 plasma samples over 70 dosing interv

We aimed to evaluate the predictive performance and predicted doses of a single-model approach or several multi-model approaches compared with the standard therapeutic drug monitoring (TDM)-based vancomycin dosing. We performed a hospital-wide monocentric retrospective study in adult patients treated with either intermittent or continuous vancomycin infusions. Each patient provided two randomly selected pairs of two consecutive vancomycin concentrations. A web-based precision dosing software, TDMx, was used to evaluate the model-based approaches. In total, 154 patients contributed 308 pairs. With standard TDM-based dosing, only 48.1% (148/308) of all of the second concentrations were within the therapeutic range. Across the model-based approaches we investigated, the mean relative bias and relative root mean square error varied from −5.36% to 3.18% and from 24.8% to 28.1%, respectively. The model averaging approach according to the squared prediction errors showed an acceptable bias and was the most precise. According to this approach, the median (interquartile range) differences between the model-predicted and prescribed doses, expressed as mg every 12 h, were 113 [−69; 427] mg, −70 [−208; 120], mg and 40 [−84; 197] mg in the case of subtherapeutic, supratherapeutic, and therapeutic exposure at the second concentration, respectively. These dose differences, along with poor target attainment, suggest a large window of opportunity for the model-based TDM compared with the standard TDM-based vancomycin dosing. Implementation studies of model-based TDM in routine care are warranted.