Pharmacology of EAPB0203, a novel imidazo[1,2-a]quinoxaline derivative with anti-tumoral activity on melanoma

International audienceIn spite of the development of new anticancer drugs by the pharmaceutical industry, melanoma and T lymphomas are diseases for which medical advances remain limited. Thus, there was an urgent need of new therapeutics with an original mechanism of action. Since several years, our group develops quinox-alinic compounds. In this paper, the first preclinical results concerning one lead compound, EAPB0203, are presented. This compound exhibits in vitro cytotoxic activity on A375 and M4Be human melanoma cell lines superior to that of imiquimod and fotemustine. A liquid chromatography-mass spectrometry method was first validated to simultaneously quantify EAPB0203 and its metabolite, EAPB0202, in rat plasma. Thereafter, the pharmacokinetic profiles of EAPB0203 were studied in rat after intravenous and intraperitoneal administrations. After intraperitoneal administration the absolute bioavailability remains limited (22.7%). In xenografted mouse, after intraperitoneal administration of 5 and 20 mg/kg, EAPB0203 is more potent than fotemustine. The survival time was increased up to 4 and 2 weeks compared to control mice and mice treated by fotemustine, respectively. The results of this study demonstrate the relationship between the dose of EAPB0203 and its effects on tumor growth. Thus, promising efficacy, tolerance and pharmacokinetic data of EAPB0203 encourage the development towards patient benefit

Étude de l'effet antitumoral de l'IFNg produit par transfert de gène et de son mécanisme d'action sur les cellules de mésothéliome humain

Le mésothéliome est une tumeur gravissime de la plèvre dont l'incidence ne cesse d'augmenter. Les thérapies conventionnelles sont inefficaces. Cette situation justifie le développement de thérapies innovantes. Ainsi, nous avons construit un adénovirus recombinant portant le gène de l'IFNy (Ad-IFNy). J'ai d'abord montré que le transfert de gène par l'Ad-IFNy était efficace dans les lignées cellulaires de mésothéliome humain (LCMH), in vitro et in vivo, et que l'IFNy était produit de manière prolongée. L'Ad-IFNy exerçait un effet antiprolifératif sur les LCMH in vitro et antitumoral sur des xénogreffes chez la souris nude. Dans un second temps, les mécanismes d'action de l'IFN-y recombinant humain et de l'Ad-IFNy sur les LCMH ont été abordés par la technique des puces à ADNc. Les gènes régulés variaient selon la LCMH et le traitement. Au vu des gènes régulés, l'Ad-IFNy pourrait exercer un effet antitumoral même si les cellules sont résistantes à l'effet antiprolifératif de l'IFNy.Mesothelioma is a fatal pleural tumor, with an increasing incidence. Conventionnai therapies are unefficient, justifying the development of innovative therapies. Thus, we have constructed a recombinant adenovirus carrying the IFNy gene (Ad-IFNy). I first showed that Ad-IFNy could efficiently transfer the IFNy gene to human mesothelioma cdl lines (HMCL), in vitro et in vivo, and that IFNy production was prolonged. Ad-IFNy exerted an antiproliferative effect on HMCL in vitro and an antiturnoral action in xenogenic tumors in nude mice. Secondly, the mechanisms involved in the action ofrecombinant human i and Ad-IFNy on HMCL were assessed by cDNA array. Differentiaily regulated genes varied depending on the HMCL and on the treatment, Regarding genes regulated, Ad-IFN could exert an antitumoral effect in mesothelioma, even though mesothelioma cells were resistant to the antiproliferative action of IFNy.PARIS12-CRETEIL BU Multidisc. (940282102) / SudocSudocFranceF

Les thérapies innovantes dans le traitement du mésothéliome pleural

PARIS-BIUP (751062107) / SudocSudocFranceF

Population pharmacokinetics of FOLFIRINOX: a review of studies and parameters

International audienceFOLFIRINOX regimen is commonly used in colorectal and more recently pancreatic cancer. However, FOLFIRINOX induces significant and dose-limiting toxic effects leading to empirical dose reduction and sometimes treatment discontinuation. Model-based FOLFIRINOX regimen optimization might help improving patients' outcome. As a first step, the current review aims at bringing together all published population pharmacokinetics models for FOLFIRINOX anticancer drugs

Population pharmacokinetic model of cefotaxime encompassing time-varying physiopathology: exploration of intra-individual variability of the renal function

International audienceBackground and objectivesCritically ill patients display pathophysiological features that cause high inter- and intra-individual pharmacokinetic (PK) variability, which can result in supra or sub-therapeutic drug concentrations. Among the factors involved in PK variability, renal clearance appears as an important contributor, whether as renal failure1 or augmented renal clearance2. Beta-lactams, and more specifically cefotaxime, are a good example of a drug commonly used in intensive care unit (ICU) patients, for which a high risk of not reaching the PK/PD target3 has been observed due to renal clearance changes. However, factors leading to intra-individual variability during the treatment course remain poorly described. A better integration of the evolution of renal function in ICU patients in population pharmacokinetic (PopPK) models is therefore suitable to guide a priori dose adjustment of cefotaxime. Materials and methodsIn a prospective, observational study, adult ICU patients (October 2015 - May 2017) were treated with a loading dose (2-4g/0.5h) followed by a continuous infusion (1-24g/24h) of cefotaxime. Cefotaxime concentrations 30 minutes after the loading dose, during the continuous infusion at day 1, 4 and 7 after drug initiation, and 4 hours after the end of the infusion, were measured by a validated HPLC-UV method. Demographic, clinical and biological data were collected at inclusion and throughout the study. Data were analysed by nonlinear mixed-effects modeling using MONOLIX version 2023R1. Data below the limit of quantification were treated as left-censored. The impact of covariates values at baseline was evaluated using the stepwise covariate model procedure. Time-varying covariates reflecting the evolution of renal function during the course of treatment were first included in the model as a regressor, then as a biomarker model.Results The study included 76 ICU hospitalized patients (31 females, 45 males, age 57.5 ± 17.6 years). 251 cefotaxime plasma concentrations were available for PK analysis. 597 serum creatinine levels were collected to monitor the renal function. A one-compartment model with linear elimination and proportional residual error best described the PK data. Inclusion of baseline serum creatinine concentration as a covariate on cefotaxime clearance significantly improved the model and reduced the unexplained inter-individual variability of clearance from 54 to 31%. Inclusion of time-varying serum creatinine as a regressor further improved the model. Backward interpolation of the regressor performed better than forward interpolation. In order to anticipate changes in kidney function, particularly from normal kidney function to kidney injury, a joint model with a biomarker model of serum creatinine impacting the cefotaxime PK model was developed. A mono-exponential increase followed by a mono-exponential decrease best described kidney injury and recovery. Conclusions A PopPK model of cefotaxime was developed, encompassing the variation of renal function over the treatment course. Serum creatinine concentration explained a significant part of the high inter- and intra-variability of cefotaxime PK in ICU patients. Since the impact of renal function might be similar for other β-lactams4, our approach might be applied to a common PopPK model for various β-lactams in order to optimize a priori dosing adjustment in the context of drug switches

Cefotaxime dosage optimization in intensive care patients by population pharmacokinetic analysis

National audienceBackground: Cefotaxime is a beta-lactam antibiotics commonly used in intensive care unit (ICU). In this population, pathophysiological modifications induce a high inter-individual and intra-individual pharmacokinetic variability. This variability can result in supra or sub-therapeutic concentrations of cefotaxime and adapted drug regimen are required. The aim of this study was to propose optimized cefotaxime treatment in ICU patients by a population pharmacokinetic approach. Methods: In this prospective, multicenter, observational study (October 2015 – May 2017), patients hospitalized in ICU received continuous administration of cefotaxime. The cefotaxime dosing regimen was a loading dose (2g-4g/0.5h) then a continuous infusion (1-24g/24h). Therapeutic drug monitoring allowed the measurement of cefotaxime concentration at day 1, 4 and 7 after drug initiation. Concentrations were assayed by a validated HPLC-UV method, and nonlinear mixed-effects modeling was performed (NONMEM version 7.4). After determination of the base model that best described the data set, the influence of several covariates was tested on the model. Simulations were realized to propose adapted dosing regimens allowing to achieve the PK/PD target, namely 100% of time during a dosing interval with the free drug concentration exceeding 4 times the Minimum Inhibitory Concentration (MIC).Results: From 77 ICU hospitalized patients (31 females, 45 males, age = 55.84 ± 18.1 years), 255 cefotaxime plasma concentrations were available for analysis. The data were best described by a one-compartment model with proportional residual error. The model was qualified based on goodness-of-fit plots and precision of the parameter estimates. Typical population clearance (11.4 L/min) and volume of distribution (27 L) were in line with previously published results in different adult and pediatric population. Model-based simulations were performed under various cefotaxime regimen to assess target attainment and identify optimal protocols. Conclusions: To our knowledge, we developed the first pharmacokinetic model of cefotaxime in critically ill adult population. After external evaluation, this model will allow to adapt empirical cefotaxime treatment dose to improve antibiotic exposure and PK/PD target attainment in ICU patients

Cefotaxime dosage optimization in intensive care patients by population pharmacokinetic analysis

International audienc

Cefotaxime dosage optimization in intensive care patients by population pharmacokinetic analysis

International audienc

Population pharmacokinetic model of cefotaxime encompassing time-varying physiopathology: exploration of intra-individual variability of the renal function

International audienceBackground and objectivesCritically ill patients display pathophysiological features that cause high inter- and intra-individual pharmacokinetic (PK) variability, which can result in supra or sub-therapeutic drug concentrations. Among the factors involved in PK variability, renal clearance appears as an important contributor, whether as renal failure1 or augmented renal clearance2. Beta-lactams, and more specifically cefotaxime, are a good example of a drug commonly used in intensive care unit (ICU) patients, for which a high risk of not reaching the PK/PD target3 has been observed due to renal clearance changes. However, factors leading to intra-individual variability during the treatment course remain poorly described. A better integration of the evolution of renal function in ICU patients in population pharmacokinetic (PopPK) models is therefore suitable to guide a priori dose adjustment of cefotaxime. Materials and methodsIn a prospective, observational study, adult ICU patients (October 2015 - May 2017) were treated with a loading dose (2-4g/0.5h) followed by a continuous infusion (1-24g/24h) of cefotaxime. Cefotaxime concentrations 30 minutes after the loading dose, during the continuous infusion at day 1, 4 and 7 after drug initiation, and 4 hours after the end of the infusion, were measured by a validated HPLC-UV method. Demographic, clinical and biological data were collected at inclusion and throughout the study. Data were analysed by nonlinear mixed-effects modeling using MONOLIX version 2023R1. Data below the limit of quantification were treated as left-censored. The impact of covariates values at baseline was evaluated using the stepwise covariate model procedure. Time-varying covariates reflecting the evolution of renal function during the course of treatment were first included in the model as a regressor, then as a biomarker model.Results The study included 76 ICU hospitalized patients (31 females, 45 males, age 57.5 ± 17.6 years). 251 cefotaxime plasma concentrations were available for PK analysis. 597 serum creatinine levels were collected to monitor the renal function. A one-compartment model with linear elimination and proportional residual error best described the PK data. Inclusion of baseline serum creatinine concentration as a covariate on cefotaxime clearance significantly improved the model and reduced the unexplained inter-individual variability of clearance from 54 to 31%. Inclusion of time-varying serum creatinine as a regressor further improved the model. Backward interpolation of the regressor performed better than forward interpolation. In order to anticipate changes in kidney function, particularly from normal kidney function to kidney injury, a joint model with a biomarker model of serum creatinine impacting the cefotaxime PK model was developed. A mono-exponential increase followed by a mono-exponential decrease best described kidney injury and recovery. Conclusions A PopPK model of cefotaxime was developed, encompassing the variation of renal function over the treatment course. Serum creatinine concentration explained a significant part of the high inter- and intra-variability of cefotaxime PK in ICU patients. Since the impact of renal function might be similar for other β-lactams4, our approach might be applied to a common PopPK model for various β-lactams in order to optimize a priori dosing adjustment in the context of drug switches