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Infliximab, a monoclonal antibody used for immune‐mediated diseases, shows high interpatient pharmacokinetic variability. Prolonged exposure increases the risk of adverse effects and costs, making dose personalization essential to balance safety, efficacy, and cost‐effectiveness. Population pharmacokinetic models support individualized dosing, but different models may predict varying drug exposure for the same patient. This study aims to identify compatible models for each patient and assess the impact of model selection on dosing. This retrospective study included adult Crohn's disease patients receiving infliximab. Published pharmacokinetic models were screened. Model‐patient compatibility was evaluated using Multivariate Exact Discrepancy through 100,000 Monte Carlo simulations. The Metropolis‐Hastings algorithm generated individual parameter distributions. For each model‐patient pair, the median and 90% confidence interval of the dose required to achieve a target exposure of 2079 mg*day/L were computed. Sixteen models were tested. No model was compatible with all patients. Dosing was calculated only for compatible pairs. The average median dose was 9.25 mg/kg, with an average imprecision of 6.63 mg/kg. The highest median dose reached 23.21 mg/kg, reflecting inter‐model differences, while the greatest imprecision (25.69 mg/kg) stemmed from patient variability. This concentration‐based method personalizes dosing via pharmacokinetic profiling. Patients can be classified into three groups: (1) those for whom all models provide similar recommendations, indicating high reliability across models; (2) those incompatible with all models, for whom the posology recommended by the manufacturer should be prioritized; and (3) those for whom some models are compatible but intensified therapeutic drug monitoring is required.

Background The widespread practice of delivering antimicrobials through drinking water to livestock leads to considerable variability in exposure levels among animals, raising concerns regarding disease outbreaks and the emergence of antimicrobial resistance. This variability is primarily driven by three pivotal factors: fluctuations in drug concentration within water pipes, variances in drinking behavior among animals, and differences in individual pharmacokinetic parameters. The objective of this study is to develop and evaluate a strategy that tailors medication delivery based on the drinking patterns of pigs, aiming to improve medication distribution without increasing the overall dose of medication. Results Our results demonstrate that several distribution strategies based on the animals’ drinking behavior can effectively increase their overall exposure. These strategies include increasing the exposure of the least exposed animals, raising the average exposure, maximizing the exposure of the majority of the well-exposed animals, or increasing exposure to ensure that a Pharmacokinetics/Pharmacodynamics (PK/PD) criterion reaches a threshold value for a large number of the animals. In summary, constructing an effective distribution strategy for drinking water requires optimizing a specific criterion. The various criteria and methods for optimizing then are detailed. Conclusions As examples, this article demonstrate that incorporating the drinking behavior into the delivery of amoxicillin results in an increase in the percentage of piglets reaching an AUC/MIC ratio greater than 25h. Specifically, with Pasteurella multocida , the percentage rises from 30 % to at least 60 % , while with Actinobacillus pleuropneumoniae , it increases from 20 % to more than 70 % .

Medical diagnostic processes often rely on comprehensive biological assessments, but current methods have drawbacks, such as insufficient consideration of variable dependence. Modern databases enable precise estimation of multidimensional variable distributions, prompting this study to enhance methodologies for biological variables. The focus is on establishing better reference regions and defining more accurate decision boundaries. Using an American database (1999-2017) with 19,231 healthy and 24,257 diseased individuals, the study examined plasma biochemical markers. The methodology involved constructing reference regions based on level sets of the healthy and diseased distributions and establishing decision boundaries. An example involved selecting diseased liver patients and considering 9 biological variables characterizing liver dysfunction. The proposed method is consistently more sensitive and specific than traditional approaches. Our results show that other biological functions, such as renal and cardiac functions, in a patient with liver dysfunction are also likely to be altered, even if the biochemical variables measuring these functions remain within the reference range. Therefore, it is preferable to consider a large panel of biological variables rather than just 9 to accurately characterize liver function. Despite potential limitations in identifying diseases, the proposed methodology provides valuable insights into physiological dysfunctions, enhancing early detection.

Nematode parasites enter their definitive host at the developmentally arrested infectious larval stage (iL3), and the ligand-dependent nuclear receptor DAF-12 contributes to trigger their development to adulthood. Here, we characterized DAF-12 from the filarial nematodes Brugia malayi and Dirofilaria immitis and compared them with DAF-12 from the non-filarial nematodes Haemonchus contortus and Caenorhabditis elegans . Interestingly, Dim and Bma DAF-12 exhibit high sequence identity and share a striking higher sensitivity than Hco and Cel DAF-12 to the natural ligands Δ4- and Δ7-dafachronic acids (DA). Moreover, sera from different mammalian species activated specifically Dim and Bma DAF-12 while the hormone-depleted sera failed to activate the filarial DAF-12. Accordingly, hormone-depleted serum delayed the commencement of development of D . immitis iL3 in vitro . Consistent with these observations, we show that spiking mouse charcoal stripped-serum with Δ4-DA at the concentration measured in normal mouse serum restores its capacity to activate Dim DAF-12. This indicates that DA present in mammalian serum participate in filarial DAF-12 activation. Finally, analysis of publicly available RNA sequencing data from B . malayi showed that, at the time of infection, putative gene homologs of the DA synthesis pathways are coincidently downregulated. Altogether, our data suggest that filarial DAF-12 have evolved to specifically sense and survive in a host environment, which provides favorable conditions to quickly resume larval development. This work sheds new light on the regulation of filarial nematodes development while entering their definitive mammalian host and may open the route to novel therapies to treat filarial infections.

Vancomycin is an antibiotic used for severe infections. To ensure microbiological efficacy, a ratio of AUC/MIC ≥400 is recommended. However, there is significant interindividual variability in its pharmacokinetic parameters, necessitating therapeutic drug monitoring to adjust dosing regimens and ensure efficacy while avoiding toxicity. Population pharmacokinetic (PopPK) models enable dose personalization, but the challenge lies in the choice of the model to use among the multitude of models in the literature. We compared 18 PopPK models created from populations with the same sociodemographic and clinicobiological characteristics. Simulations were performed for a 47 years old man, weighing 70 kg, with an albumin level of 35.5 g/L, a creatinine clearance of 100 mL/min, an eGFR of 106 mL/min/1.73 m 2 , and receiving an intravenous infusion of 1 g × 2/day of VCM over 1 h for 48 h. Simulations of time–concentration profiles revealed differences, leading us to determine the probability of achieving microbiological efficacy (AUC/MIC ≥ 400) with each model. Depending on some models, a dose of 1 g × 2/day is required to ensure microbiological efficacy in over 90% of the population, while with the same dose other models do not exceed 10% of the population. To ensure that 90% of the patients are correctly exposed, a dose of vancomycin ranging from 0.9 g × 2/day to 2.2 g × 2/day is necessary a priori depending on the chosen model. These differences raise an issue in choosing a model for performing therapeutic drug monitoring using a PopPK model with or without Bayesian approach. Thus, it is fundamental to evaluate the impact of these differences on both efficacy/toxicity.

Heart morphology as well as global and regional myocardial function can be assessed in awake orangutans with good to excellent repeatability and reproducibility. Conclusions This non-stressful method may be used for longitudinal cardiac follow-up in awake orangutans.

Surprisingly, misinterpretation of the influence of hypoalbuminemia on pharmacokinetics and the clinical effects of drugs seems to be a current problem, even though hypoalbuminemia has no impact on the pharmacologically active exposure. Exceptions to this fact are highly protein-bound anaesthetics with high elimination capacity (i.e., <5 drugs on the market). To assess the frequency of misinterpretation of the influence of hypoalbuminemia on pharmacokinetics and the clinical effects of drugs between 1975 and 2021, a PubMed literature review was conducted. Each paragraph on albumin binding was classified as correct, ambiguous or incorrect, creating two acceptable categories: (1) content without any errors, and (2) content containing some incorrect and/or ambiguous statements. The analyses of these articles showed that fewer than 11% of articles contained no interpretation errors. In order to contain this misinterpretation, several measures are proposed: (1) Make the message accessible to a wide audience by offering a simplified and didactic video representation of the lack of impact of albumin binding to drugs. (2) Precise terminology (unbound/free form/concentration) should be used for highly bound drugs. (3) Unbound/free forms should be systematically quantified for highly plasma protein bound drugs for clinical trials as well as for therapeutic drug monitoring.

he medical literature is replete with articles in which there is confusion between “free concentration” and “unbound fraction” (fu), which is the ratio of free to total plasma concentration. The lack of clarity in distinguishing between these two terms has led to biased computations, erroneous interpretations, and misleading recommendations. The problems are highlighted in this paper, taking the example of calculation of Probability of Target Attainment (PTA). This metric is used to propose pharmacokinetic/pharmacodynamic (PK/PD) breakpoints required for the interpretation of Antimicrobial Susceptibility Testing. Based on Monte Carlo simulations of the PK/PD index, area under the unbound concentration time curve/minimum inhibitory concentration (fAUC/MIC), computation of PTA from total plasma concentrations scaled by fu ineluctably leads to biased estimates. The bias is greater if the variability associated with fu is added, instead of removing it during this scaling. The explanation for the bias is that total plasma drug concentrations are intrinsically more variable than the corresponding free concentrations. This is due to the variability of antimicrobial binding for total, but not for free plasma concentrations. In consequence, the greater variability always leads to underestimation of the PK/PD cutoff (i.e., the critical MIC that is guaranteed for a given percentile of the population). A further consequence is an increase in calculated dosage required to attain the targeted quantile. This erroneous approach, of using free antimicrobial drug fraction, is not limited to the derivation of PK/PD cutoff, but may also have consequences for antimicrobials drug safety in clinical patients.

BackgroundExtracorporeal membrane oxygenation (ECMO) is increasingly used in intensive care units and can modify drug pharmacokinetics and lead to under-exposure associated with treatment failure. Ceftolozane/tazobactam is an antibiotic combination used for complicated infections in critically ill patients. Launched in 2015, sparse data are available on the influence of ECMO on the pharmacokinetics of ceftolozane/tazobactam. The aim of the present study was to determine the influence of ECMO on the pharmacokinetics of ceftolozane-tazobactam.MethodsAn ex vivo model (closed-loop ECMO circuits primed with human whole blood) was used to study adsorption during 8-h inter-dose intervals over a 24-h period (for all three ceftolozane/tazobactam injections) with eight samples per inter-dose interval. Two different dosages of ceftolozane/tazobactam injection were studied and a control (whole blood spiked with ceftolozane/tazobactam in a glass tube) was performed. An in vivo porcine model was developed with a 1-h infusion of ceftolozane–tazobactam and concentration monitoring for 11 h. Pigs undergoing ECMO were compared with a control group. Pharmacokinetic analysis of in vivo data (non-compartmental analysis and non-linear mixed effects modelling) was performed to determine the influence of ECMO.ResultsWith the ex vivo model, variations in concentration ranged from − 5.73 to 1.26% and from − 12.95 to − 2.89% respectively for ceftolozane (concentrations ranging from 20 to 180 mg/l) and tazobactam (concentrations ranging from 10 to 75 mg/l) after 8 h. In vivo pharmacokinetic exploration showed that ECMO induces a significant decrease of 37% for tazobactam clearance without significant modification in the pharmacokinetics of ceftolozane, probably due to a small cohort size.ConclusionsConsidering that the influence of ECMO on the pharmacokinetics of ceftolozane/tazobactam is not clinically significant, normal ceftolozane and tazobactam dosing in critically ill patients should be effective for patients undergoing ECMO.

A number of drugs are given in drinking water in piglet farming, although this way of administering drugs leads to significant and uncontrolled variability in exposures. Three main explanations for this variability have been described in the literature: (1) the drinking behavior of animals, (2) the drug concentration in water, and (3) the inter-individual variability in the pharmacokinetic (PK) parameters. This article assesses the relative importance of these three sources of exposure variability for doxycycline and amoxicillin using pharmacokinetic simulations and by observing watering behavior, and analyzes the consequences of this exposure variability. The water consumption behavior was by far the most important factor as it led to a variation in exposures of up to a factor of 7 between piglets. The second most influential factor was the drug concentration in the drinking water with variations ranging from −43.3% to +48.7% at the beginning and the end of the pipeline. Finally, the between-individual variation in PK parameters depends on the drug, but had a low impact on exposure variability. In the most variable case (doxycycline), the mean ratio between the 10% less exposed and the 10% most exposed piglets varied from 3.7 without PK parameters variability to 6 with PK variability. For both drugs, this study also showed that only a small percentage of the piglets (36%) could be considered as well exposed in case of infection by Actinobacillus pleuropneumoniae or Pasteurella multocida. There may be some existing technical ways to reduce this important variability. However, their cost and ease of implementation merit examination.