[Pharmacogenetics of aminoglycoside ototoxicity: State of knowledge and practices - Recommendations of the Francophone Network of Pharmacogenetics (RNPGx)]. / Pharmacogénétique de l'ototoxicité des aminosides : état des connaissances et des pratiques ­ recommandations du Réseau francophone de pharmacogénétique (RNPGx).

The administration of aminoglycosides can induce nephrotoxicity or ototoxicity, which can be monitored through pharmacological therapeutic drug monitoring. However, there are cases of genetic predisposition to ototoxicity related to the MT-RNR1 gene, which may occur from the first administrations. Pharmacogenetic analysis recommendations have recently been proposed by the Clinical Pharmacogenetics Implementation Consortium (CPIC). The Francophone Pharmacogenetics Network (RNPGx) provides a bibliographic synthesis of this genetic predisposition, as well as professional recommendations. The MT-RNR1 gene codes for mitochondrial 12S rRNA, which constitutes the small subunit of the mitochondrial ribosome. Three variants can be identified: the variants m.1555A>G and m.1494C>T of the MT-RNR1 gene have a 'high' level of evidence regarding the risk of ototoxicity. The variant m.1095T>C has a 'moderate' level of evidence. The search for these variants can be performed in the laboratory if the administration of aminoglycosides can be delayed after obtaining the result. However, if the treatment is urgent, there is currently no rapid test available in France (a 'point-of-care' test is authorized in Great Britain). RNPGx considers: (1) the search for the m.1555A>G, m.1494C>T variants as 'highly recommended' and the m.1095T>C variant as 'moderately recommended' before the administration of an aminoglycoside (if compatible with the medical context). It should be noted that the level of heteroplasmy detected does not modify the recommendation; (2) pharmacogenetic analysis is currently not feasible in situations of short-term aminoglycoside administration, in the absence of an available analytical solution (rapid test to be evaluated in France); (3) the retrospective analysis in case of aminoglycoside-induced ototoxicity is 'recommended'; (4) analysis of relatives is 'recommended'. Through this summary, RNPGx proposes an updated review of the MT-RNR1-aminoglycoside gene-drug pair to serve as a basis for adapting practices regarding pharmacogenetic analysis related to aminoglycoside treatment.

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.e., evaluated in the same patient. OBJECTIVE: In this work, we propose an evaluation method that accounts for the dependency between concentrations. METHODS: Thanks to the study of the distribution of simulated vectors of concentrations, the method provides one probability per individual that its observations (i.e., concentrations) come from the studied model. The higher the probability, the better the model fits the individual. By examining the distribution of these probabilities for a set of individuals, we can evaluate the model as a whole. RESULTS: We demonstrate the effectiveness of our method through two examples. Our approach successfully detects misspecification in the structural model and identifies outlier kinetics in a set of kinetics. CONCLUSION: We propose a straightforward method for evaluating models during their development and selecting a model to perform therapeutic drug monitoring. Based on our preliminary results, the method is very promising but needs to be validated on a larger scale.

Evaluation of the Performance of the Novodiag® Stool Parasites Assay for the Detection of Intestinal Protozoa and Microsporidia.

OBJECTIVES: We aimed to assess the performance of the Novodiag® Stool Parasites (NSP) assay in the diagnosis of the most common intestinal protozoan and microsporidia infections. METHODS: A panel of 167 selected stool samples was retrospectively analysed with the NSP assay and compared to routine microscopy and qPCR methods for the detection of pathogenic protozoa and microsporidia. RESULTS: Whereas specificity was high for all protozoa and microsporidia, NSP sensitivity was strongly dependent on the comparative method used as reference. When compared to microscopic methods, NSP sensitivity was high (96.7 to 100%) for Blastocystis hominis, Entamoeba histolytica and Cyclospora cayetanensis but was lower for Giardia intestinalis (85.2%) and ≤50% for Cystoisospora belli and Dientamoeba fragilis. In comparison to conventional qPCR, the NSP assay demonstrated lower sensitivity characteristics dependent on parasite loads, reaching 60 to 70% for G. intestinalis, D. fragilis, Cryptosporidium spp. and E. histolytica. Sensitivity was 100% for Enterocytozoon bieneusi, but none of the five samples containing Encephalitozoon spp. were detected. CONCLUSIONS: The overall performance of the NSP assay in the diagnosis of gastrointestinal protozoa and microsporidia seems to be better than or equivalent to that observed with microscopic methods but inferior to that obtainable with classical targeted qPCR.

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., <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.

Evaluation of 4 quantification methods for monitoring 16 antibiotics and 1 beta-lactamase inhibitor in human serum by high-performance liquid chromatography with tandem mass spectrometry detection.

Antibiotic (ATB) prescription in an intensive care unit (ICU) requires continuous monitoring of serum dosages due to the patient's pathophysiological condition. Dosing adjustment is necessary to achieve effective targeted concentrations. Since ICUs routinely use a large number of ATBs, global monitoring needs to be developed. In the present study, we developed a global analytical method for extracting, separating and quantifying the most widely used ATBs in ICUs: amoxicillin, piperacillin, cefazolin, cefepime, cefotaxime, ceftazidime, ceftolozane, ceftriaxone, ertapenem, meropenem, ciprofloxacin, moxifloxacin, levofloxacin, daptomycin, dalbavancin, linezolid and a beta-lactamase inhibitor: tazobactam. To guarantee the robustness of the quantification, we differentiated the 16 ATBs and the beta lactamase inhibitor into 4 pools (ATB1 to ATB4), taking into account prescription frequency in the ICU, the physicochemical properties and the calibration ranges of the ATBs selected. The whole ATB was then separated with two LC columns in reversed phase: Kinetex Polar-C18 100 Å and Polar-RP-80 synergy, in less than 6.5 min. Detection was carried out by electrospray in positive ion mode, by tandem mass spectrometry (LC-MS/MS. The four quantification methods were validated according to the European guidelines on bioanalytical method validation (EMEA guide), after determining the extraction yields, matrix effects, recovery, precision, accuracy, within-run precision and between-run precision. For all analyses, bias is < 15% and is comparable to the literature and LOQs vary from 0.05 mg.L-1 for ciprofloxacin to 1.00 mg.L-1 for ceftriaxone and dalbavancin. The stability time of cefepime and piperacillin is 3 hrs and for the other ATBs 6 hrs in serum at room temperature. For long-term stability, freezing at - 80 °C guarantees 3 months of stability for ceftriaxone and dalbavancin and more than 6 months for the other ATBs.

"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. OBJECTIVE: The aim of this article is to propose a methodology that allows a correction of EBE shrinkage and an improvement in their precision. METHODS: As EBEs are defined, they can be seen as a special case of ridge estimators depending on a parameter usually denoted λ. After a bias correction depending on λ, we chose λ so that the individual pharmacokinetic estimations have minimal imprecision. Our estimate is by construction always better than EBE with respect to bias (i.e. shrinkage) and precision. RESULTS: We illustrate the performance of this approach with two different drugs: iohexol and isavuconazole. Depending on the patient's actual pharmacokinetic parameter values, the improvement given by our approach ranged from 0 to 100%. CONCLUSION: This innovative methodology is promising since, to the best of our knowledge, no other individual shrinkage correction has been proposed.

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. A Pop PK model was developed based on 5 iohexol plasma samples taken from 5 to 180 minutes (min) after an intravenous iohexol nominal dose of 64.7 mg/kg from 49 client-owned dogs of different breeds, sexes, ages, body weights, and clinical conditions (healthy or presenting chronic kidney disease CKD). The design of the best sampling times could contain either 1 or 2 or 3 sampling times. These were discretized with a step of 30 min between 30 and 180 min. A two-compartment Pop PK model best fitted the data; creatinine and kidney status were the covariates included in the model to explain a part of clearance variability. When 1 sample was available, 90 or 120 min were the best sampling times to assess clearance for healthy dogs with a low creatinine value. Whereas for dogs with CKD and medium creatinine value, the best sampling time was 150 or 180 min, for CKD dogs with a high creatinine value, it was 180 min. If 2 or 3 samples were available, several sampling times were possible. The method to define the best sampling times could be used with other Pop PK models as long as it is representative of the patient population and once the model is built, the use of individualized sampling times for each patient allows to precisely estimate the GFR.