Development of a strategy to secure chemotherapy : application to adaptive dosing of 5-Fluoro-Uracile

Utilisé depuis plus de 60 ans, le 5-fluorouracile (5-FU) est un médicament qui reste un des piliers du traitement de nombreuses tumeurs solides (cancer digestif, de la sphère oropharyngée, du sein). Administré par voie intraveineuse, cette molécule va immédiatement subir un métabolisme hépatique intensif, si bien que seul 10% de la dose administrée est active. Ce métabolisme est issu de l'action d'une enzyme, la dihydropyrimidine déshydrogénase (DPD), pour laquelle il existe une importante variation d'activité entre les individus. On estime à 15 à 35 % le risque de toxicité sévère induite par le 5-FU. Les principaux effets indésirables rencontrés sont surtout d'ordre gastro-digestif, et hématologique. La survenue de décès intervient dans 1 à 3 % des cas. Souvent, un déficit en DPD est dépisté post-cure. L’objectif principal de notre travail était donc de réduire l'incidence des toxicités sous 5-FU en relation avec le déficit en DPD, à travers une étude de pharmacovigilance qui témoigne de l'importance du problème ; une contribution à l’implantation du typage systématique prospectif par un test fonctionnel de la DPD avec réduction empirique des doses en fonction du ratio UH2/U ; le suivi de la performance du phénotypage dans deux indications emblématiques: les cancers colorectal et ORL ; la participation au développement bioanalytique de méthodes de dosage du 5-FU, afin de permettre le bon déroulement de l'étude clinique reposant sur du suivi thérapeutique pharmacologique et de la pharmacocinétique en rich data ; la participation à un programme de recherche clinique visant à développer, cette fois, un modèle PK/PD/PGx dévolu à une adaptation plus fine des doses de FU.5-Fluoro-Uracil (5-FU) ranks among the most widely prescribed anticancer agents world- wide. Fluoropyrimidines are a mainstay in the treatment of numerous solid tumors, mostly used in combination with other cytotoxics, targeted therapies or biologics. Because most of the administered 5-FU dose will undergo extensive catabolism driven by dihydropyrimidine dehydrogenase (DPD), a liver enzyme that converts 5-FU into inactive metabolite, drug dosing is particularly high in some settings such as digestive or head-and-neck cancers. Variations in fluoropyrimidine disposition are a major cause for the erratic pharmacokinetics profile observed in cancer patients. Because of the elevated doses administered, DPD-deficient patients are likely to experience life-threatening toxicities and those are now a rising issue regarding pre-emptive strategies to be undertaken to improve safety. The main objective of this work was to reduce 5-FU induced toxicities related to DPD-deficiency syndrome with a Pharmacovigilance survey describing the phenomenon, the implementation of a simple functional testing strategy phenotyping DPD-deficiency with empiric cut in dosing according to UH2/U ratio, the evaluation of this method in colorectal and head and neck cancer, the analytical development of immunoanalysis and chromatographic method in Marseille and the European Hospital Georges Pompidou, and the participation of a clinical research program for the development of a PK/PD/PGx model for a better individualization of the doses

Correction du valgus dynamique par le core stability dans la prévention des blessures du ligament croise antérieur chez la femme

Introduction: ACL injuries are frequently encountered in sports and affect more women than men in this environment. They are the result of a complex multifactorial mechanism; avoidable risk factors have been identified. In recent years, prevention protocols have focused on the biomechanics of the lower limbs, in particular at the moment of dynamic valgus. It would seem that the strengthening of the muscles of the trunk forming the core, would favor the reduction of this harmful moment for the ACL.Objective: This literature review brings together five recent scientific studies to investigate the effects of core muscle strengthening on improving lower limb biomechanics.Method: The five clinical trials have come from investigative work in various databases including Pubmed, PEDro, and Google Scholar, were consulted until January 2023.Result: The main judgment criterion studied is the kinematics of the knee and its influence on the ACL before and after intervention in two comparable groups, one experimental and the other controlled. The analysis is based on a population of 108 female athletes. The results are heterogeneous, although an improvement in the risk factors inherent in the biomechanics of the knees is statistically and clinically observed.Discussion: Biases are identified allowing the results presented to be weighted. Biases are identified concerning the population, the intervention, the judgment criteria. To minimize bias, further study in a larger population should be considered.Introduction : les blessures du LCA sont fréquemment rencontré dans le milieu sportif et touchent plus les femmes que les hommes dans ce milieu. Elles sont la résultante de mécanisme multifactoriel complexe, des facteurs de risques évitables ont été identifié. Ces dernières années des protocoles de prévention s’intéressent à la biomécanique des membres inférieurs, en particulier au moment de valgus dynamique. Il semblerait que le renforcement des muscles du tronc formant le « core », favoriserait la diminution de ce moment néfaste pour le LCA.Objectif : cette revue de littérature réunis cinq études scientifiques récentes afin d’étudier les effets du renforcement des muscles de base sur l’amélioration de la biomécanique des membres inférieurs.Méthode : les 5 essais cliniques proviennent d’un travail d’investigation dans différentes bases de données dont Pubmed, PEDro, et Google Scholar, consultées jusqu’en janvier 2023. Résultat : le critère de jugement principal étudiés est la cinématique du genou et son influence sur le LCA avant et après intervention au sein de deux groupes comparables, l’un expérimental et l’autre contrôle. L’analyse repose sur une population de 108 femmes sportives. Les résultats sont hétérogènes, bien qu’une amélioration des facteurs de risque inhérents à la biomécanique des genoux est statistiquement et cliniquement constaté.Discussion : des biais sont identifiés permettant de pondérer les résultats présentés. Des biais sont identifiés concernant la population, l’intervention, les critères de jugements. Afin de minimiser les biais une étude supplémentaire dans une population plus large devrait être envisagée

Le suivi thérapeutique pharmacologique de la ciclosporine dans les greffes de cellules souches hématopoïétiques en pédiatrie

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF

Dosing Regimen for Cefotaxime Should Be Adapted to the Stage of Renal Dysfunction in Critically Ill Adult Patients—A Retrospective Study

Cefotaxime administration is recommended in doses of 3–12 g/day in adults with a Glomerular Filtration Rate (GFR) > 5 mL/min. This study aimed to assess the impact of renal function and obesity on cefotaxime concentrations in intensive care unit (ICU) patients. A retrospective cohort study was conducted on consecutive ICU patients receiving continuous cefotaxime infusion between 2020 and 2022 [IRBN992021/CHUSTE]. Doses were not constant; consequently, a concentration-to-dose ratio (C/D) was considered. Statistical analysis was performed to assess the relationship between cefotaxime concentrations, renal function, and obesity. A total of 70 patients, median age 61 years, were included, with no significant difference in cefotaxime concentrations between obese and non-obese patients. However, concentrations varied significantly by GFR, with underdosing prevalent in patients with normal to increased renal function and overdosing in those with severely impaired renal function. Adjustment of cefotaxime dosing according to GFR was associated with improved target attainment. Cefotaxime dosing in critically ill patients should consider renal function, with higher initial doses required in patients with normal to increased GFR and lower doses in those with severely impaired renal function. Therapeutic drug monitoring may aid in optimising dosing regimens. Prospective studies are warranted to validate these findings and inform clinical practice

How can we best monitor 5-FU administration to maximize benefit to risk ratio?

International audience5-Fluorouracil (5-FU) is currently used as a chemotherapy in several cancers such as head-and-neck (H&N) and colorectal cancers. 5-FU dosing is traditionally based on body surface area (BSA), but this strategy is usually associated with severe toxicities. 5-FU is mainly catabolized by dihydropyrimidine dehydrogenase (DPD), and 5-FU dosage adaptation according to DPD status at the first cycle of treatment is now recommended. To further optimize 5-FU-based chemotherapy, a body of evidences justifies therapeutic drug monitoring (TDM). Areas covered: 5-FU pharmacokinetics, relationships between pharmacokinetics and efficacy or toxicity of 5-FU, proofs of interest of 5-FU TDM and its practical considerations are discussed. Expert opinion: BSA-adjusted 5-FU administration is associated with a large inter-individual variability, and according to this strategy, many patients experience under- or overexposure. Moreover, relationships between 5-FU area under the curve (AUC) and its toxicity or efficacy have been demonstrated, at least in patients with colorectal or H&N cancers. 5-FU therapeutic index has been validated and algorithms of 5-FU dosage adaptation according to its AUC are now available. Advances in pre-analytical and analytical steps of 5-FU TDM make its use feasible in clinical practice. Thus, there are consistent evidences to recommend 5-FU TDM in patients with advanced colorectal or H&N cancers

An ultra performance liquid chromatography-tandem mass spectrometry method for the therapeutic drug monitoring of isavuconazole and seven other antifungal compounds in plasma samples

International audienceA new analytical method was developed for the routine Therapeutic Drug Monitoring of 8 antifungals compounds in 50 μL of plasma: isavuconazole (ISZ), voriconazole (VRZ), posaconazole (PSZ), fluconazole (FCZ), caspofungin (CSF), flucytosine (5FC), itraconazole (ITZ) and its metabolite OH-itraconazole (OH-ITZ). After adding 50 μL of the internal standard, which consisted in a mixture of the deuterated isotopes of the quantified compounds, the sample treatment consisted in a simple protein precipitation with 400 μL of acetonitrile. Five microliters of the supernatant were directly injected into the chromatographic system. The chromatographic separation was performed with a Waters C18-BEH column and a mobile phase consisting in a mixture of water and acetonitrile, both containing 0.1% of formic acid. The total run time was 3 min and the detection of the analytes was performed by electrospray ionization in a positive mode using selected reaction monitoring. Intra and inter-day precision and inaccuracy were < 15% over the calibration ranges that were determined according to their clinical relevance: 0.20–20.0 mg/L for ISZ, VRZ, PSZ, ITZ, and OH-ITZ; 0.50–50.0 mg/L for FCZ and CSF; 2.00–200 mg/L for 5FC. This simple and fast method was found suitable for routine therapeutic drug monitoring

An ultra performance liquid chromatography-tandem mass spectrometry method for the therapeutic drug monitoring of isavuconazole and seven other antifungal compounds in plasma samples

International audienceA new analytical method was developed for the routine Therapeutic Drug Monitoring of 8 antifungals compounds in 50 μL of plasma: isavuconazole (ISZ), voriconazole (VRZ), posaconazole (PSZ), fluconazole (FCZ), caspofungin (CSF), flucytosine (5FC), itraconazole (ITZ) and its metabolite OH-itraconazole (OH-ITZ). After adding 50 μL of the internal standard, which consisted in a mixture of the deuterated isotopes of the quantified compounds, the sample treatment consisted in a simple protein precipitation with 400 μL of acetonitrile. Five microliters of the supernatant were directly injected into the chromatographic system. The chromatographic separation was performed with a Waters C18-BEH column and a mobile phase consisting in a mixture of water and acetonitrile, both containing 0.1% of formic acid. The total run time was 3 min and the detection of the analytes was performed by electrospray ionization in a positive mode using selected reaction monitoring. Intra and inter-day precision and inaccuracy were < 15% over the calibration ranges that were determined according to their clinical relevance: 0.20–20.0 mg/L for ISZ, VRZ, PSZ, ITZ, and OH-ITZ; 0.50–50.0 mg/L for FCZ and CSF; 2.00–200 mg/L for 5FC. This simple and fast method was found suitable for routine therapeutic drug monitoring

The bacterial effector DspA/E is toxic in Arabidopsis thaliana and is required for multiplication and survival of fire blight pathogen

The type III effector DspA/E is an essential pathogenicity factor of the phytopathogenic bacterium Erwinia amylovora. We showed that DspA/E was required for transient bacterial growth in nonhost Arabidopsis thaliana leaves, as an E.amylovora dspA/E mutant was unable to grow. We expressed DspA/E in A.thaliana transgenic plants under the control of an oestradiol-inducible promoter, and found that DspA/E expressed inplanta restored the growth of a dspA/E mutant. DspA/E expression in these transgenic plants led to the modulation by at least two-fold of the expression of 384 genes, mostly induced (324 genes). Both induced and repressed genes contained high proportions of defence genes. DspA/E expression ultimately resulted in plant cell death without requiring a functional salicylic acid signalling pathway. Analysis of A.thaliana transgenic seedlings expressing a green fluorescent protein (GFP):DspA/E fusion indicated that the fusion protein could only be detected in a few cells per seedling, suggesting the degradation or absence of accumulation of DspA/E in plant cells. Consistently, we found that DspA/E repressed plant protein synthesis when injected by E.amylovora or when expressed in transgenic plants. Thus, we conclude that DspA/E is toxic to A.thaliana: it promotes modifications, among which the repression of protein synthesis could be determinant in the facilitation of necrosis and bacterial growth

Influence of Renal Function and Age on the Pharmacokinetics of Levofloxacin in Patients with Bone and Joint Infections

Despite its efficacy and toxicity being exposure-related, levofloxacin pharmacokinetics in patients with bone and joint infections has been poorly described to date, so the possible need for a dose adjustment is unknown in this population. A prospective population pharmacokinetic study was conducted in 59 patients to answer this question. The final model consisted of a one-compartment model with first-order absorption and elimination. Mean parameter estimates (% interindividual variability) were 0.895 h&minus;1 for the absorption rate constant (Ka), 6.10 L/h (40%) for the apparent clearance (CL/F), 90.6 L (25%) for the apparent distribution volume (V/F). Age and glomerular filtration rate (GFR), estimated by the modification of diet in renal disease formula, were related to CL/F by power models, and CL/F was found to increase for increasing GFR and decreasing age. For a similar GFR, the simulated area under the curve (AUC) was 55% higher in 70 years-old patients compared to 30 year-old patients. Based on this model, a 750 mg dose should provide an optimal exposure (AUC/ minimum inhibitory concentration (MIC) &ge;100), with the possible exception of patients older than 60 years and with GFR &lt;70 mL/min/m&sup2; who may necessitate a dose reduction, and patients with infections caused by bacteria with MIC close to 1 mg/L who may need an increase in the dose

Suivi thérapeutique pharmacologique du 5-fluorouracile : mise au point et recommandations du groupe STP-PT de la SFPT et du GPCO-Unicancer

International audienceDespite being 60-years old now, 5-FU remains the backbone of numerous regimen to treat a variety of solid tumors such as breast, head-and-neck and digestive cancers either in neo-adjuvant, adjuvant or metastatic settings. Standard 5-FU usually claims 15-40% of severe toxicities and up to 1% of toxic-death. Numerous studies show a stiff relationship between 5-FU exposure and toxicity or efficacy. In addition, 5-FU pharmacokinetics is highly variable between patients. Indeed, 80% of the 5-FU dose is catabolized in the liver by dihydropyrimidine dehydrogenase (DPD) into inactive compounds. It is now well established that DPD deficiency could lead to severe toxicities and, thus, require dose reduction in deficient patients. However, despite dosage adaptation based on DPD status, some patients may still experience under- or over-exposure, leading to inefficacy or major toxicity. The "Suivi thérapeutique pharmacologique et personnalisation des traitements" (STP-PT) group of the "Société française de pharmacologie et de thérapeutique" (SFPT) and the "Groupe de pharmacologie clinique oncologique" (GPCO)-Unicancer, based on the latest and most up-to-date literature data, recommend the implementation of 5-FU Therapeutic Drug Monitoring in order to ensure an adequate 5-FU exposure