Multidimensional reference regions is a new tool to optimize the personalized care of patients.

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.

Ceftobiprole in Critically Ill Patients: Proposal for New Dosage Regimens.

Background: Ceftobiprole is a broad-spectrum cephalosporin. It is currently approved for the treatment of community- and hospital-acquired pneumonia. However, the recommended dosage regimen of ceftobiprole may not be sufficient to achieve the optimal pharmacokinetic/pharmacodynamic criterion in critically ill patients.

Vancomycin population pharmacokinetic models: Uncovering pharmacodynamic divergence amid clinicobiological resemblance.

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.

Delivery strategies to improve piglets exposure to oral antimicrobials.

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.

Multivariate Exact Discrepancy: A New Tool for PK/PD Model Evaluation.

Background: Pharmacokinetic models are evaluated using three types of metrics: those based on estimating the typical pharmacokinetic parameters, those based on predicting individual pharmacokinetic parameters and those that compare data and model distributions. In the third groups of metrics, the best-known methods are Visual Predictive Check (VPC) and Normalised Prediction Distribution Error (NPDE). Despite their usefulness, these methods have some limitations, especially for the analysis of dependent concentrations, i.

Evaluation of a smartphone-based colorimetric method for urinalysis dipstick readings in cats.

Objectives: The aim of the study was to compare the diagnostic performances of a smartphone-based colorimetric method (SBCM) for urinalysis with a semi-automated point-of-care (POC) analyser using standardised solutions and cat urine.

Methods: Artificial solutions (negative and positive quality controls, and purposely designed artificial urine) and natural urine from 216 cats were used. Two urine reagent strips were simultaneously dipped in each sample.

Exploration of the relationship between cumulative exposure to tobramycin and ototoxicity in patients with cystic fibrosis.

Background: Aminoglycosides (AGs), such as tobramycin, are essential antibiotics in the management of pulmonary infections in patients with cystic fibrosis (CF). They induce ototoxicity without the relationship being clearly described in the literature. Our aim is to propose a mathematical and statistical model describing the relationship between the estimated cumulative exposure (Area Under the Curve, AUC) to tobramycin and ototoxicity with audiogram interpretation in young patients with CF.

Biased computation of probability of target attainment for antimicrobial drugs.

The medical literature is replete with articles in which there is confusion between "free concentration" and "unbound fraction" (f ), 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).

Hypoalbuminemia and Pharmacokinetics: When the Misunderstanding of a Fundamental Concept Leads to Repeated Errors over Decades.

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.

"De-Shrinking" EBEs: The Solution for Bayesian Therapeutic Drug Monitoring.

Background: Therapeutic drug monitoring (TDM) aims at individualising a dosage regimen and is increasingly being performed by estimating individual pharmacokinetic parameters via empirical Bayes estimates (EBEs). However, EBEs suffer from shrinkage that makes them biased. This bias is a weakness for TDM and probably a barrier to the acceptance of drug dosage adjustments by prescribers.

CardiOvascular examination in awake Orangutans (Pongo pygmaeus pygmaeus): Low-stress Echocardiography including Speckle Tracking imaging (the COOLEST method).

Introduction: Cardiovascular diseases have been identified as a major cause of mortality and morbidity in Borneo orangutans (Pongo pygmaeus pygmaeus). Transthoracic echocardiography is usually performed under anesthesia in great apes, which may be stressful and increase risks of peri-anesthetic complications in case of cardiac alteration. The aim of the present pilot study was hence to develop a quick and non-stressful echocardiographic method (i.

The Rare, the Best: Spread of Antimalarial-Resistant Plasmodium falciparum Parasites by Mosquito Vectors.

The emergence of resistance to antimalarials has prompted the steady switch to novel therapies for decades. Withdrawal of antimalarials, such as chloroquine in sub-Saharan Africa in the late 1990s, led to rapid declines in the prevalence of resistance markers after a few years, raising the possibility of reintroducing them for malaria treatment. Here, we provide evidence that the mosquito vector plays a crucial role in maintaining parasite genetic diversity.

What Matters in Piglets' Exposure to Antibiotics Administered through Drinking Water?

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.

Population Pharmacokinetic Model of Iohexol in Dogs to Estimate Glomerular Filtration Rate and Optimize Sampling Time.

Monitoring iohexol plasma clearance is considered a useful, reliable, and sensitive tool to establish glomerular filtration rate (GFR) and early stages of kidney disease in both humans and veterinary medicine. The assessment of GFR based on iohexol plasma clearance needs repeated blood sampling over hours, which is not easily attainable in a clinical setting. The study aimed to build a population pharmacokinetic (Pop PK) model to estimate iohexol plasma clearance in a population of dogs and based on this model, to indicate the best sampling times that enable a precise clearance estimation using a low number of samples.

Machine-learning algorithm as a prognostic tool in non-obstructive acute-on-chronic kidney disease in the cat.

Objectives: The aim of this study was to develop an algorithm capable of predicting short- and medium-term survival in cases of intrinsic acute-on-chronic kidney disease (ACKD) in cats.

Methods: The medical record database was searched to identify cats hospitalised for acute clinical signs and azotaemia of at least 48 h duration and diagnosed to have underlying chronic kidney disease based on ultrasonographic renal abnormalities or previously documented azotaemia. Cases with postrenal azotaemia, exposure to nephrotoxicants, feline infectious peritonitis or neoplasia were excluded.

Neglecting Plasma Protein Binding in COVID-19 Patients Leads to a Wrong Interpretation of Lopinavir Overexposure.

Boffito et al. recalled the critical importance to correctly interpret protein binding. Changes of lopinavir pharmacokinetics in coronavirus disease 2019 (COVID-19) are a perfect illustration.

Comparing ultrafiltration and equilibrium dialysis to measure unbound plasma dolutegravir concentrations based on a design of experiment approach.

Dolutegravir therapeutic drug monitoring (TDM) could be improved by measuring the unbound dolutegravir plasma concentration (Cu), particularly in patients experiencing virological failure or toxicity despite achieving appropriate DTG total plasma concentrations. Equilibrium dialysis (ED) is the gold standard to measure Cu, but ED is time consuming, precluding its use in clinical practice. In contrast, ultrafiltration is applicable to TDM, but is sensitive to numerous analytical conditions.

Influence of extracorporeal membrane oxygenation on the pharmacokinetics of ceftolozane/tazobactam: an ex vivo and in vivo study.

Background: Extracorporeal 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.

Hydroxychloroquine in Coronavirus Disease 2019 Patients: What Still Needs to Be Known About the Kinetics.

Different dosage regimens of hydroxychloroquine are used to manage coronavirus disease 2019 (COVID-19) patients, without information on the pharmacokinetics in this population. Blood samples (n = 101) were collected from 57 COVID-19 patients for 7 days, and concentrations were compared with simulated kinetic profiles. Hydroxychloroquine exposure is low and cannot be predicted by other populations.

Why Were More Than 200 Subjects Required to Demonstrate the Bioequivalence of a New Formulation of Levothyroxine with an Old One?

At the request of French Regulatory Authorities, a new formulation of Levothyrox was licensed in France in 2017, with the objective of avoiding the stability deficiencies of an existing licensed formulation. Before launching the new formulation, an average bioequivalence (ABE) trial was conducted, having enrolled 204 subjects and selected for interpretation a narrow a priori bioequivalence range of 0.90-1.