Background: Model-informed precision dosing (MIPD) combines population pharmacokinetic knowledge with therapeutic drug monitoring (TDM) to optimize dosage adjustment. It could improve target concentration attainment over empirical TDM, still widely practised for broad-spectrum antibiotics. Objectives: To evaluate the respective performance of TDM and MIPD in achieving target piperacillin exposure. Methods: Measurements from 80 courses of intermittent piperacillin infusions, each with two TDM samples, were retrospectively submitted to our MIPD software TUCUXI. We considered six dosage adjustment strategies: identical dosage for all (4000 mg q8h), actual initial dosage (chart-based), actual empirical adjustment following first TDM, a priori MIPD-based dosage, a posteriori MIPD-based adjustment after first TDM and MIPD including both TDM measurements. Dosing strategies were compared regarding daily dosage, trough levels distribution and PTA (with target trough 8–32 mg/L). Results: Median trough concentration fell within 8–32 mg/L for all strategies except a priori MIPD-based dosage (42 mg/L). Distributions of trough concentrations predicted with the six dosage adjustment strategies showed significant differences, with both a posteriori MIPD-based strategies best reducing their standard deviation (P < 0.001). PTA of 32%, 32%, 55%, 29%, 83% and 94% were estimated, respectively for the six strategies (P < 0.001). Poor performance of a priori MIPD-based dosage did not hinder a posteriori MIPD-based strategies from significantly improving target attainment. Conclusions: Whilst empirical TDM improves exposure standardization and target attainment compared with no TDM, MIPD can still bring further improvement. Prospective trials remain warranted to confirm MIPD benefits not only on target attainment but also on clinical endpoints.

Background Coronavirus disease 2019 (COVID-19) is now a global pandemic with Europe and the USA at its epicenter. Little is known about risk factors for progression to severe disease in Europe. This study aims to describe the epidemiology of COVID-19 patients in a Swiss university hospital. Methods This retrospective observational study included all adult patients hospitalized with a laboratory confirmed SARS-CoV-2 infection from March 1 to March 25, 2020. We extracted data from electronic health records. The primary outcome was the need to mechanical ventilation at day 14. We used multivariate logistic regression to identify risk factors for mechanical ventilation. Follow-up was of at least 14 days. Results 200 patients were included, of whom 37 (18.5%) needed mechanical ventilation at 14 days. The median time from symptoms onset to mechanical ventilation was 9.5 days (IQR 7.00, 12.75). Multivariable regression showed increased odds of mechanical ventilation in males (3.26, 1.21-9.8; p=0.025), in patients who presented with a qSOFA score ≥2 (6.02, 2.09-18.82; p=0.001), with bilateral infiltrate (5.75, 1.91-21.06; p=0.004) or with a CRP of 40 mg/l or greater (4.73, 1.51-18.58; p=0.013). Conclusions This study gives some insight in the epidemiology and clinical course of patients admitted in a European tertiary hospital with SARS-CoV-2 infection. Male sex, high qSOFA score, CRP of 40 mg/l or greater and a bilateral radiological infiltrate could help clinicians identify patients at high risk for mechanical ventilation.

Background: Extracorporeal membrane oxygenation (ECMO) can affect the disposition of drugs, notably by sequestering them in a circuit. This review aimed to provide a comprehensive summary of existing ex vivo studies investigating the impact of contemporary ECMO circuits on drug sequestration, and to examine the associations between the physicochemical properties of drugs, the features and settings of ECMO devices, and the extent of drug sequestration. Method: A comprehensive search was conducted to identify ex vivo studies that determined drug concentrations in ECMO circuits. Studies that did not allow for the proper assessment of drug loss by degradation were excluded. Drug characteristics and experimental conditions were recorded. Drug sequestration in the circuit was calculated as the difference between the drug loss measured in the ECMO circuit and the drug loss due to spontaneous degradation measured under control conditions. To identify predictors of drug sequestration, a stepwise multiple linear meta-regression was applied by testing the physicochemical properties of drugs and ECMO device features/settings. Results: A total of 40 studies were identified, of which 21 were included in the analysis, covering 41 drugs. The Maquet membrane oxygenator was the most used brand (73%). About half of the circuits were adult and half were pediatric. Our final regression model retained lipophilicity, and to a lesser extent ionization at a physiological pH, as significant predictors of drug sequestration (R² 0.44, relative standard error 23%). Protein binding had no additional effect. Anti-infectives were the most studied class of drugs (n = 28). Antibiotics were overall not significantly sequestered, while lipophilic drugs such as posaconazole, voriconazole, paracetamol, fentanyl, sufentanil, propofol, thiopental, dexmedetomidine and amiodarone were highly sequestered (≥50%). However, this sequestration occurred mainly within the first few hours of the experiments, possibly reflecting a saturation effect. Conclusions: Lipophilic drugs are significantly sequestered in ex vivo ECMO circuits, although this effect may be limited by early saturation.

Background and Objective Levosimendan is an inotrope and vasodilator agent commonly used in critical care, particularly to facilitate weaning from veno-arterial extracorporeal membrane oxygenation (VA-ECMO). However, critical illness and ECMO may affect levosimendan and its clinically relevant metabolites’ pharmacokinetics, potentially compromising circulating exposure and efficacy. There are limited data on levosimendan pharmacokinetics in critically ill patients, including those on VA-ECMO, thus emphasising the need for further research in this area. The aim of this study was to characterise the pharmacokinetic profile of levosimendan and its metabolites OR-1855 and OR-1896 in both critically ill adults and neonates/infants on VA-ECMO. Methods We conducted a bicentric, prospective, observational, pharmacokinetic study in critically ill adults and neonates/infants on VA-ECMO receiving levosimendan. Dosage history, sampling and clinical information were gathered. Samples were analysed by ultra-high-performance liquid chromatography coupled to tandem mass spectrometry using a validated highly sensitive method. A population pharmacokinetic model describing levosimendan and its metabolites OR-1855 (inactive) and OR-1896 (active, long-lasting) was developed using non-linear mixed-effects modelling (NONMEM). Model-based simulations were performed to compare exposures produced by various dosing scenarios. Results Twenty-one patients, 15 adults, three neonates and three infants, provided 155 blood samples. In adults, levosimendan was started at a rate of 0.05 µg/kg/min for 1–4 h, then increased to maintenance doses reaching 0.1 (n = 9), 0.15 (n = 3) or 0.2 (n = 3) µg/kg/min for a total infusion time of approximately 24 h. The neonates/infants received a continuous infusion of 0.1 µg/kg/min for 48 h. A two-compartment model best characterised levosimendan pharmacokinetics, with a transit compartment adequately describing the metabolites’ delayed synthesis. The transformation of OR-1855 into OR-1896 was 3.7-fold slower in neonates/infants than in adults. Model-based simulations using a standard 0.1-µg/kg/min regimen for 24 and 48 h in adults and neonates/infants, respectively, achieved lower levosimendan and metabolite concentrations in neonates/infants. Simulations using a 48-h infusion of 0.2 µg/kg/min in neonates/infants predict levosimendan concentrations comparable to those in adults receiving a 0.1-µg/kg/min maintenance dose. However, in this scenario, OR-1896 concentrations would remain considerably lower than in adults. Conclusions Our data indicate that levosimendan and its metabolites exhibit altered the pharmacokinetics in neonates/infants on VA-ECMO. Although some of these changes may be associated with ECMO, definitive conclusions on causality cannot be drawn, as age-dependent specific physiology and critically ill conditions may also contribute. These findings support the consideration of dose optimisation in this population. In adults, levosimendan pharmacokinetics seem unaffected, although metabolite concentrations appear slightly reduced compared with non-critically ill patients with heart failure. Graphical Abstract

Ruxolitinib pharmacokinetics (PK) has been characterized in clinical trials but remains poorly documented in real‐world practice. This project aimed to investigate ruxolitinib PK in routine clinical practice, identify factors driving its variability, and explore exposure–response relationships to assess the potential role of therapeutic drug monitoring. In total, 221 steady‐state ruxolitinib concentrations from 77 adult patients enrolled across several centers in Switzerland were analyzed. Demographic and clinical data were recorded at each visit. Population pharmacokinetic (popPK) analysis was performed with MonolixSuite® 2024R1 (Lixoft, France). Model‐based simulations were used to predict trough concentration ( C _min ) and the area under the concentration–time curve over 24 h (AUC ₂₄ ) for the recommended dosage regimens, as a function of covariates. An exploratory pharmacokinetic/pharmacodynamic analysis was conducted in the overall cohort. Ruxolitinib PK was characterized by a marked between‐subject variability in clearance (45%). Strong cytochrome (CYP) 3A4 or dual CYP2C9/CYP3A4 inhibitors reduced clearance by 39%. At 10 mg twice daily, model‐based simulations showed CYP inhibitors increased median C _min and AUC ₂₄ by 2.9‐ and 1.7‐fold, respectively. Still, no significant exposure–efficacy relationship was identified. However, higher ruxolitinib exposure tended to be associated with increased toxicity in the overall population ( C _min and AUC ₂₄ , P ≈0.02–0.03). In clinical practice, ruxolitinib exposure shows substantial variability and is strongly affected by strong CYP inhibitors that are frequently co‐administered. Whilst no clear exposure–efficacy relationship was observed, higher exposure was linked to increased toxicity risk, arguing for careful dose adjustment.