To investigate the population pharmacokinetics of teicoplanin in patients treated by the subcutaneous (sc) and/or intravenous (iv) route. Non-linear mixed-effects modelling described teicoplanin concentrations from 98 patients with infection caused by Gram-positive cocci. Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA) of various dosage regimens. Teicoplanin concentrations were best described by a two-compartment model with clearance predicted by estimated glomerular filtration rate. Estimated absorption rate constant (between-subject variability) was 0.039 h⁻¹ (77%), clearance was 0.305 L/h (28%), central volume was 10.3 L (49%), inter-compartmental clearance was 4.42 L/h (66%) and peripheral volume was 97.4 L (51%). The sc route was associated with lower initial C_min and AUC (day 3: loading phase) compared with the iv route. This difference appeared to vanish after 14 days, with comparable simulated PTAs based on the C_min and AUC for all tested dosages (400, 600, 800 and 1000 mg every 12 h). However, a loading dose regimen with five administrations of either 400 or 600 mg was not sufficient to achieve the target C_min (≥15 mg/L) for both routes. Also, PTAs for higher MIC (≥1.0 mg/L) were poor with all regimens for both routes. This is the first study examining the pharmacokinetic/pharmacodynamic implications of using the sc route for teicoplanin. Subcutaneous administration is associated with lower C_min and AUC values after the loading phase compared with iv administration. Therefore, iv administration should be preferred in the first few days of therapy. This study also shows that loading doses of teicoplanin higher than currently recommended should be used to improve PTA.

Isavuconazole is a triazole antifungal agent recently recommended as first-line therapy for invasive pulmonary aspergillosis. With the COVID-19 pandemic, cases of COVID-19-associated pulmonary aspergillosis (CAPA) have been described with a prevalence ranging from 5 to 30%. We developed and validated a population pharmacokinetic (PKpop) model of isavuconazole plasma concentrations in intensive care unit patients with CAPA. Nonlinear mixed-effect modeling Monolix software were used for PK analysis of 65 plasma trough concentrations from 18 patients. PK parameters were best estimated with a one-compartment model. The mean of ISA plasma concentrations was 1.87 [1.29–2.25] mg/L despite prolonged loading dose (72 h for one-third) and a mean maintenance dose of 300 mg per day. Pharmacokinetics (PK) modeling showed that renal replacement therapy (RRT) was significantly associated with under exposure, explaining a part of clearance variability. The Monte Carlo simulations suggested that the recommended dosing regimen did not achieve the trough target of 2 mg/L in a timely manner (72 h). This is the first isavuconazole PKpop model developed for CAPA critical care patients underlying the need of therapeutic drug monitoring, especially for patients under RRT.

Despite the well-demonstrated efficacy of infliximab in inflammatory diseases, treatment failure remains frequent. Dose adjustment using Bayesian methods has shown in silico its interest in achieving target plasma concentrations. However, most of the published models have not been fully validated in accordance with the recommendations. This study aimed to submit these models to an external evaluation and verify their predictive capabilities. Eight models were selected for external evaluation, carried out on an independent database (409 concentrations from 157 patients). Each model was evaluated based on the following parameters: goodness-of-fit (comparison of predictions to observations), residual error model (population weighted residuals (PWRES), individual weighted residuals (IWRES), and normalized prediction distribution errors (NPDE)), and predictive performances (prediction-corrected visual predictive checks (pcVPC) and Bayesian simulations). The performances observed during this external evaluation varied greatly from one model to another. The eight evaluated models showed a significant bias in population predictions (from −7.19 to 7.38 mg/L). Individual predictions showed acceptable bias and precision for six of the eight models (mean error of −0.74 to −0.29 mg/L and mean percent error of −16.6 to −0.4%). Analysis of NPDE and pcVPC confirmed these results and revealed a problem with the inclusion of several covariates (weight, concomitant immunomodulatory treatment, presence of anti-drug antibodies). This external evaluation showed satisfactory results for some models, notably models A and B, and highlighted several prospects for improving the pharmacokinetic models of infliximab for clinical-biological application.

Background: Vascular endothelial injury during ischemia generates apoptotic cell death and precedes apoptosis of underlying tissues. We aimed at studying the role of extracellular adenosine triphosphate (ATP) on endothelial cells protection against hypoxia injury. Methods: In a hypoxic model on endothelial cells, we quantified the extracellular concentration of ATP and adenosine. The expression of mRNA (ectonucleotidases, adenosine, and P2 receptors) was measured. Apoptosis was evaluated by the expression of cleaved caspase 3. The involvement of P2 and adenosine receptors and signaling pathways was investigated using selective inhibitors. Results: Hypoxic stress induced a significant increase in extracellular ATP and adenosine. After a 2-h hypoxic injury, an increase of cleaved caspase 3 was observed. ATP anti-apoptotic effect was prevented by suramin, pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS), and CGS15943, as well as by selective A2A, A2B, and A3 receptor antagonists. P2 receptor-mediated anti-apoptotic effect of ATP involved phosphoinositide 3-kinase (PI3K), extracellular signal-regulated kinases (ERK1/2), mitoK_ATP, and nitric oxide synthase (NOS) pathways whereas adenosine receptor-mediated anti-apoptotic effect involved ERK1/2, protein kinase A (PKA), and NOS. Conclusions: These results suggest a complementary role of P2 and adenosine receptors in ATP-induced protective effects against hypoxia injury of endothelial. This could be considered therapeutic targets to limit the development of ischemic injury of organs such as heart, brain, and kidney.

Potential under- or overdose of antibiotics may occur in intensive care units due to high variability in plasma concentrations. The risk is either treatment failure or toxicity. Thus, therapeutic drug monitoring of antibiotics may guide dosing adjustment, maximising antibacterial efficacy and minimising toxicity. The aim of this study was to develop and validate a method for the analysis of 15 antibiotics including beta-lactams, linezolid, fluoroquinolones, daptomycin, and clindamycin to have a complete panel in the management of infections. We proposed to develop a fast, sensitive, and quantitative method for the analysis of 15 antibiotics using ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometer (UPLC-MS/MS) technology. this method required only 100 µL of plasma and consisted of a rapid liquid–liquid deproteinisation using methanol. Calibration curves ranged from 0.078 to 500 mg/L depending on the molecules, and were defined according to a therapeutic range. Inter- and intra-assay precisions values were less than 15%. This work described the development and the full validation of a precise, sensitive and accurate assay using UPLC-MS/MS technology. After validation, this new assay was successfully applied to routine therapeutic drug monitoring.