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Aims: The pharmacokinetics of doravirine has been studied in clinical trials but not in real‐world settings. Our study aims to characterize and identify factors influencing doravirine (a CYP3A4 substrate) pharmacokinetics in real‐world people with HIV (PWH). Methods: A total of 174 doravirine concentrations measured in 146 PWH followed up in the therapeutic drug monitoring (TDM) program at the University Hospital of Lausanne (Switzerland) between 2019 and 2023 were included in the analysis. Demographic data, clinical information and comedications were recorded during the routine SHCS visits (every 3–6 months). Population pharmacokinetic analysis and Monte Carlo simulations to investigate the clinical significance of the covariates retained in the final model were performed using NONMEM. Results: A one‐compartment model with first‐order absorption and linear elimination best described doravirine pharmacokinetics. Potent CYP3A4 inhibitors and, to a lesser extent age, were the only tested covariates to significantly impact doravirine clearance (CL). Potent CYP3A4 inhibitors reduced CL by 50%, and a 30% decrease in CL was observed in an 80‐year‐old compared with a 55‐year‐old PWH. The effect of potent CYP3A4 inhibitors was prominent, explaining 59% of between‐subject variability in CL. Model‐based simulations predicted 2.8‐fold and 1.6‐fold increases in median steady‐state trough and maximum doravirine concentrations, respectively, when a potent CYP3A4 inhibitor was co‐administered. Conclusions: Our findings show that potent CYP3A4 inhibitors and age influence doravirine pharmacokinetics. However, given the good tolerability of doravirine, dosing adjustment of doravirine is probably not mandatory in those situations. TDM remains useful essentially in specific clinical situations, such as hepatic impairment, suspected nonadherence or pregnancy. [ABSTRACT FROM AUTHOR]

The interpretation of long-acting cabotegravir and rilpivirine concentrations is complicated by the lack of consensus on the threshold to consider. Building on real-world therapeutic drug monitoring data and documented virologic failures, this article provides a reappraisal of the existing thresholds and guidance for the interpretation of cabotegravir and rilpivirine concentrations. [ABSTRACT FROM AUTHOR]

Aims: To assess the associations of exposure and modifications in exposure (i.e., discontinuation on admission, initiation during hospitalization) to eight common cardiovascular therapies with the risk of in-hospital death among inpatients with coronavirus disease 2019 (COVID-19). Methods: In this observational study including 838 hospitalized unvaccinated adult patients with confirmed COVID-19, the use of cardiovascular therapies was assessed using logistic regression models adjusted for potential confounders. Results: No cardiovascular therapy used before hospitalization was associated with an increased risk of in-hospital death. During hospitalization, the use of diuretics (aOR 2.59 [1.68–3.98]) was associated with an increase, and the use of agents acting on the renin-angiotensin system (aOR 0.39 [0.23–0.64]) and lipid-lowering agents (aOR 0.41 [0.24–0.68]) was associated with a reduction in the odds of in-hospital death. Exposure modifications associated with decreased survival were the discontinuation of an agent acting on the renin-angiotensin system (aOR 4.42 [2.08–9.37]), a β-blocker (aOR 5.44 [1.16–25.46]), a lipid-modifying agent (aOR 3.26 [1.42–7.50]) or an anticoagulant (aOR 5.85 [1.25–27.27]), as well as the initiation of a diuretic (aOR 5.19 [2.98–9.03]) or an antiarrhythmic (aOR 6.62 [2.07–21.15]). Exposure modification associated with improved survival was the initiation of an agent acting on the renin-angiotensin system (aOR 0.17 [0.03–0.82]). Conclusion: In hospitalized and unvaccinated patients with COVID-19, there was no detrimental association of the prehospital use of any regular cardiovascular medication with in-hospital death, and these therapies should be continued as recommended. [ABSTRACT FROM AUTHOR]

Levosimendan is a positive inotrope and vasodilator used in patients with acute and chronic decompensated heart failure. It is metabolized into OR-1855 (inactive metabolite), which is further acetylated into OR-1896 (active metabolite having a prolonged half-life, hence a sustained effect). Levosimendan represents a valuable alternative to traditional inotropes with broad clinical applications in critically ill patients with cardiogenic shock, advanced heart failure and post-cardiac surgery. However, while levosimendan demonstrates dose-dependent hemodynamic effects, its pharmacokinetics has not yet been investigated in adult critically ill patients, a vulnerable population characterized by complex and unstable conditions that may significantly alter drug disposition. Therefore, pharmacokinetics studies of levosimendan and metabolites in critically ill patients require a reliable and sensitive quantification method. We developed and validated a highly sensitive method using ultra-high-performance liquid-chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) for the quantification of levosimendan, OR-1855 and OR-1896 in human plasma. To achieve the required analytical sensitivity, plasma sample preparation included protein precipitation with acetonitrile, subsequent supernatant's evaporation to dryness under nitrogen, and reconstitution of the solid residues with a solution of H 2 O:MeOH 4:1, followed by a 40 µL-aliquot injection into the LC column. Chromatographic separation of the three analytes was achieved in a 6-minute run in gradient mode, using an Acquity UPLC BEH C18 1.7 µm, 2.1 × 150 mm column. The method was extensively validated according to international bioanalytical assay guidelines, on a clinically relevant concentration range of 0.1–100 ng/mL, for each analyte. Considering these very low concentrations, the assay showed excellent performances in terms of trueness (94.3–105.3 %), repeatability (1.9–7.2 %) and intermediate fidelity (2.3–9.7 %). Of note, during our ex vivo studies on whole blood samples stability, acetylation of the metabolite OR-1855 into the active OR-1896 metabolite was observed in the presence of red blood cells. The UHPLC method is being applied for a prospective observational pharmacokinetics study of levosimendan in patients undergoing extracorporeal membrane oxygenation support. The benefit of levosimendan therapeutic drug monitoring in intensive care patients remains to be assessed. • UHPLC-MS/MS method development and validation for levosimendan and its metabolites. • Quantification of levosimendan and metabolites OR-1855, OR-1896 in human plasma. • Highly sensitive assay covering the clinically relevant range of concentrations. • Suitable for studies on levosimendan pharmacokinetics in intensive care patients. • The role of levosimendan therapeutic drug monitoring remains to be defined. [ABSTRACT FROM AUTHOR]

• A HPLC-MS/MS method was developed and validated to quantify 6 Janus kinase inhibitors. • Janus kinase inhibitors were quantified in human plasma. • The multiplex assay was fast and highly sensitive. • TDM of Janus Kinase inhibitors is expected to optimize the dosage regimen. • TDM could provide insights for assessing the Janus Kinase inhibitors' risk–benefit trade-off. Janus kinase inhibitors (JAKi) are oral small molecules used in the treatment of a broad spectrum of autoimmune and myeloproliferative diseases. JAKi exhibit significant intra- and inter-individual pharmacokinetic variabilities, due to fluctuations in compliance with oral treatments and their metabolism essentially driven by cytochrome P450 enzymes. Intrinsically, JAKi have dose–response relationship and narrow therapeutic index: therapeutic drug monitoring (TDM) is expected to optimize and adapt their dosage regimen in order to resolve problems of efficacy and tolerance linked to dose and safety. A sensitive analytical method using multiplex high-performance liquid-chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) was developed and validated for the simultaneous quantification in plasma of the 6 major currently used JAKi, namely abrocitinib, baricitinib, fedratinib, ruxolitinib, tofacitinib, and upadacitinib. Plasma samples are subjected to protein precipitation with MeOH, using stable isotopically labelled internal standards. The separation of JAKi in supernatants diluted 1:1 with ultrapure H 2 O was performed using a C 18 column Xselect HSS T3 2.5 µm, 2.1x150 mm using a mobile phase composed of formic acid (FA) 0.2% and acetonitrile (+FA 0.1%) in gradient mode. The analytical run time for the multiplex assay was 7 min. JAKi drugs were monitored by electrospray ionization in the positive mode followed by triple-stage quadrupole MS/MS analysis. The method was validated according to SFSTP and ICH guidelines over the clinically relevant concentration ranges (0.5–200 ng/mL for abrocitinib, baricitinib and upadacitinib; 1–400 ng/mL for tofacitinib; 0.5–400 ng/mL for ruxolitinib, and 10–800 ng/mL for fedratinib). This multiplex HPLC-MS/MS assay achieved good performances in term of trueness (91.1-113.5%), repeatability (3.0-9.9%), and intermediate precision (4.5-11.3%). We developed and validated a highly sensitive method for the multiplex quantification of the JAKi abrocitinib, baricitinib, fedratinib, ruxolitinib, tofacitinib, and upadacitinib in human plasma. The method will be applied for prospective clinical pharmacokinetic studies to determine whether TDM programs for JAKi based on residual drug concentrations can be recommended using disease-specific therapeutic ranges. [ABSTRACT FROM AUTHOR]

Importance: Sudden cardiac death is a leading cause of mortality in psychiatric patients. Long QT (LQT) is common in this population and predisposes to Torsades-de-Pointes (TdP) and subsequent mortality. Objective: To estimate the cost-effectiveness of electrocardiographic screening to detect LQT in psychiatric inpatients. Design, Setting, and Participants: We built a decision analytic model based on a decision tree to evaluate the cost-effectiveness and utility of LQT screening from a health care perspective. LQT proportion parameters were derived from an in-hospital cross-sectional study. We performed experts' elicitation to estimate the risk of TdP, given extent of QT prolongation. A TdP reduction of 65% after LQT detection was based on positive drug dechallenge rate and through adequate treatment and electrolyte adjustments. The base-case model uncertainty was assessed with one-way and probabilistic sensitivity analyses. Finally, the TdP related mortality and TdP avoidance parameters were varied in a two-way sensitivity analysis to assess their effect on the Incremental Cost-Effectiveness Ratio (ICER). Main Outcomes and Measures: Costs, Quality Ajusted Life Year (QALY), ICER, and probability of cost effectiveness thresholds ($ 10 000, $25 000, and $50 000 per QALY). Results: In the base-case scenario, the numbers of patients needed to screen were 1128 and 2817 to avoid one TdP and one death, respectively. The ICER of systematic ECG screening was $8644 (95%CI, 3144-82 498) per QALY. The probability of cost-effectiveness was 96% at a willingness-to-pay of $50 000 for one QALY. In sensitivity analyses, results were sensitive to the case-fatality of TdP episodes and to the TdP reduction following the diagnosis of LQT. Conclusion and Relevance: In psychiatric hospitals, performing systematic ECG screening at admission help reduce the number of sudden cardiac deaths in a cost-effective fashion. [ABSTRACT FROM AUTHOR]