Franck Saint-Marcoux

University of Limoges, Limages, Limousin, France

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Publications (58)173.27 Total impact

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    ABSTRACT: Modern LC-MS/MS instruments have sensitivity and scanning velocity high enough to analyze many different compounds in single runs. Consequently, the sample preparation procedure has become the bottleneck for developing efficient, rapid, and cheap multi-compound methods. Here, we examined one-step sample preparation based on quick, easy, cheap, effective, rugged, and safe (QuEChERS) salts to set up and validate a LC-MS/MS method for the simultaneous determination of 35 drugs of abuse and their metabolites in whole blood. Despite large differences in physicochemical properties, this simplified QuEChERS extraction method yielded satisfactory recoveries (until 96 %) for the 35 molecules. The amounts of QuEChERS salts had no influence on extraction yield. Chromatographic separation was obtained in less than 6 min. LLOD and LLOQ were 3 and 5 ng/mL, respectively. The procedure was successfully validated and then applied to 253 cases of driving under the influence of drugs (DUID), collected over a 6-month period.
    No preview · Article · Jan 2016 · Analytical and Bioanalytical Chemistry
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    ABSTRACT: Objectives: Ganciclovir is the most widely used treatment for cytomegalovirus infections. However, neutropenia is a frequent associated adverse effect leading to a decrease in the ganciclovir dose or discontinuation of the therapy, thereby favouring viral resistance. In the present study, the objectives were: (i) to describe the pharmacokinetics of blood and intracellular ganciclovir and its metabolites; and (ii) to explore the relationship between exposure to ganciclovir and/or its metabolites and evolution of the neutrophil count under treatment. Methods: Pharmacokinetic profiles (pre-dose and 1, 2, 3 and 5 h after dosing) of ganciclovir and its metabolites were measured in 22 adult renal transplant patients and further modelled by a non-parametric approach (PMetrics(®)). The relationship between exposure indices to ganciclovir and the slope of the neutrophil count was investigated using multiple linear regression. Results: A four-compartment open model was able to accurately describe ganciclovir and its intracellular forms. A significant association was found between intracellular ganciclovir triphosphate concentrations (AUC0-5) and the decrease in neutrophil count over the first 3 months of treatment (β = -0.0019 ± 5 × 10(-4); P < 0.01). Conclusions: In this population of renal transplant patients, the decrease in neutrophil count, used as a surrogate marker of haematological toxicity, was associated with ganciclovir triphosphate accumulation in blood cells. Further studies are needed to test this biomarker as a predictive factor for toxicity.
    No preview · Article · Nov 2015 · Journal of Antimicrobial Chemotherapy
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    ABSTRACT: Every transplant patient will, at least occasionally, miss immunosuppressive drug doses or take them outside the prescribed times. This study aims at quantifying the impact of poor execution on tacrolimus exposure in renal transplant patients. Validated pharmacokinetic tools applied in clinical setting were used to simulate the steady-state pharmacokinetic profiles of the drug when given as the immediate-release formulation to renal transplant patients, being CYP3A5 expressors or not, and who have reached either a standard or a minimized exposure. Situations of interruption due to a missed or delayed dose were simulated and the impact on drug exposure was explored. In case of a missed dose, it was observed that: (i) a single forgotten dose can greatly impact exposure: up to 49% decrease for tacrolimus trough concentration and 70% for AUC0-12h in patients with the highest clearance values; (ii) patients with a minimized exposure are the most affected by a missed dose; and (iii) a dose of 1.5 times the usual dose may be recommended after a total dose oversight. Considering that intra-patient exposure variability is a predictive factor of poor graft outcome, these modeling results may serve as recommendations for patients, both preventively and in response to their questions. Copyright © 2015. Published by Elsevier Ltd.
    No preview · Article · Aug 2015 · Pharmacological Research
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    ABSTRACT: Mycophenolic acid (MPA) area under the curve (AUC) has been associated with graft outcome. (1) to develop pharmacokinetic tools to optimize MPA inter-dose AUC estimation in heart transplant patients; and (2) to investigate the relationships between acute allograft rejection and MPA AUC, trough level (C0) or mycophenolate mofetil (MMF) dose. Two independent modeling approaches (parametric and non parametric) were used to fit 56 rich MPA pharmacokinetic (PK) profiles collected from 40 adult heart transplant recipients enrolled in the PIGREC study, receiving MMF and a calcineurin inhibitor (CNI), in the first year post-transplantation. In addition, associations between drug exposure (MPA C0, AUC and MMF dose) and acute rejection or MMF adverse events were investigated using time-dependent Cox models with stratification on the type of calcineurin inhibitor. Exposure threshold values were investigated using ROC curve analysis. The 2 models developed fit adequately the data and the use of their combination yielded 100% consistency with the measured AUC in terms of strategy of dose adjustment (maintain, increase or decrease). MPA measured AUC adjusted on CNI exposure was significantly associated with rejection (per unit increase: HR [95% CI]=0.97 [0.95-0.99], p=0.0122), while no effect was shown for adverse events attributable to MMF. An AUC threshold of 50mg×h/L was proposed (sensitivity=77%, specificity=25%) beyond which the risk of rejection was significantly increased (low vs. high: HR=3.48 [1.21-10.0], p=0.0204). The tools developed have already been made available to the heart transplant community on our ISBA website (https://pharmaco.chu-limoges.fr). Copyright © 2015. Published by Elsevier Ltd.
    No preview · Article · Jul 2015 · Pharmacological Research

  • No preview · Article · Jun 2015

  • No preview · Article · Apr 2015 · Fundamental and Clinical Pharmacology
  • P. Nolain · J. B. Woillard · P. Turlure · F. Saint-Marcoux

    No preview · Article · Apr 2015 · Fundamental and Clinical Pharmacology

  • No preview · Article · Apr 2015 · Fundamental and Clinical Pharmacology
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    ABSTRACT: Ganciclovir (GCV) is prescribed for cytomegalovirus infection which is a major issue in immunodepressed patients. It is however characterized by hematological toxicity. A better understanding of GCV concentration-effects relationships implies the measurement of intracellular forms. The objective of this study was to develop a method to measure GCV and its derivatives in cells. A four-stage procedure was developed with the following strategy: (1) to separate into different fractions the different intracellular forms of GCV (GCV itself and its phosphorylated forms) by solid-phase extraction (SPE) from blood cells, (2) to dephosphorylate the different phosphorylated forms into GCV, (3) to perform a second SPE to desalt samples and concentrate GCV, and (4) to measure GCV concentrations in the different extracts using a triple-quadrupole, linear ion trap mass spectrometer. Finally, the procedure was tested in 17 patients receiving GCV. From lysed cells, the different forms of GCV were fractionated, the phosphorylated forms were eluted with different KCl solutions, and the obtained fractions were treated with acid phosphatase to transform the phosphorylated metabolites back into GCV. The method was validated from 5 to 500 μg L(-1) with a limit of detection of 1 μg L(-1). The whole procedure was validated according to the US Food and Drug Administration guidelines and successfully applied in 17 patients receiving GCV. The method liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) allowing the measurement of GCV and its phosphorylated forms in blood cells was developed and can be used in developing clinical studies to explore the role of these biomarkers in the event of toxicity.
    No preview · Article · Feb 2015 · Analytical and Bioanalytical Chemistry
  • Franck Saint-Marcoux
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    ABSTRACT: Therapeutic drug monitoring can be defined as a multiple step activity involving: (i) the measurement of a drug; (ii) the interpretation of the concentration by taking into account the concentration-effect relationship; (iii) the individual dose adjustment. For over 15 years pharmacology-toxicology departments have implemented liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) on a daily basis. This article discusses the current position of this technology in TDM routine activity.
    No preview · Article · Feb 2015 · Annales de biologie clinique
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    ABSTRACT: Objective: The inter-dose area-under-the-curve (AUC) has been described as the best marker of exposure to Tacrolimus, suggesting its use for dose adjustment. In a population of Tunisian renal transplant patients, this study aimed (i) at building a population pharmacokinetic (PopPK) model for Tacrolimus, (ii) at identifying factors that explain inter-patient variability, and (iii) at developing a Bayesian estimator (MAP-BE) enabling the estimation of individual AUC. Patients and methods: Full-PK profiles were obtained from 20 stable renal transplant recipients given Prograf® and Tacrolimus blood concentrations were measured by a CMIA technique (ARCHITECT; Abott). PopPK analysis was performed using non linear mixed effects approach (NONMEM program). The following covariates were tested: age, weight, hematocrit, AST, ALT, albumin. PopPK parameters where then used as priors to develop a MAP-BE for the estimation of Tacrolimus AUC using a limited sampling strategy. The predictive performance of the MAP-BE were tested by (i) comparing the estimated AUC to that obtained by the trapezoidal rule; and (ii) its ability to provide similar dose adjustments to those obtained using all the available time-points. Validation was performed by both jackknife and bootstrapping methods. Results: Tacrolimus pharmacokinetics were well described by a two-compartment model combined with an Erlang distribution to describe the absorption phase: residual proportional error was 16% and imprecision parameter estimate was less than 15% (9.3 - 14.4%). Body weight was identified as a covariate influencing the apparent central volume of distribution (inter-patient variability decreased from 28 to 7.7%). MAP-BE based on three blood concentrations measured at 0, 1 and 3 h post-dose provided a good estimation of AUC with a mean bias -1 + 13.2% (-22 to 22%) with 85% of the patients having an AUC bias < 20%. The BE proposed similar doses to those proposed using all concentrations in 19out of 20 patients, with a maximum difference of 0.5 mg. Conclusion: A PopPK model and its associated Bayesian estimator providing good prediction of Tacrolimus exposure have been developed in Tunisian renal transplant recipients. These tools allow us to individualize Tacrolimus dosages based on the AUC using only three concentrations.
    No preview · Article · Jan 2015 · International Journal of Pharmacy and Pharmaceutical Sciences
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    ABSTRACT: Objective: The aim of this study was to identify a cyclosporine therapeutic range for kidney recipients. Materials and methods: The cyclosporine exposure level was based on the calculation of the mean area under the concentration-time curve AUC(0-12). The AUC(0-12) was estimated using a Bayesian estimator and a 3-point limited sampling strategy. Cyclosporine exposure levels were obtained from 3 blood samples: 0, 1, and 3h postdose; and analyses were performed using a liquid chromatography-tandem mass spectrometry method. The therapeutic window of cyclosporine was calculated by the Chebyshev's inequality method with a 99% guarantee (α=0.01) using the IBM SPSS Statistics 20 software. Results: It was found that the therapeutic window of cyclosporine estimated by the Chebyshev's inequality method and put on the AUC(0-12) exposure lies in the ranges from 2.84-3.13 mg h/L with the 99% confidence for the patients with the target AUC(0-12) exposure of 3.8 mg h/L (posttransplantation time >1 year). The therapeutic window of cyclosporine differs in different posttransplantation time groups: the estimated AUC exposure range in the group of patients who have a graft longer than 5 years is 2.70-2.98 mg h/L, and the estimated AUC exposure range in the group of patients who have a graft for 1-5 years is 3.05-3.75 mg h/L. Conclusions: Chebyshev's inequality could be an appropriate and more precise method to determine the therapeutic window for cyclosporine in kidney recipients than the target AUC(0-12) value and further studies should be conducted to evaluate patients with postoperative time <1 year.
    Full-text · Article · Dec 2014 · Medicina (Kaunas, Lithuania)

  • No preview · Article · May 2014 · Fundamental and Clinical Pharmacology

  • No preview · Article · Apr 2014 · The Journal of Heart and Lung Transplantation
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    Full-text · Article · Dec 2013 · Pediatric Rheumatology
  • M. Beaurain · F. Saint-Marcoux · J. B. Woillard · J. P. Rerolle · M. Essig · P. Marquet

    No preview · Article · Dec 2013 · Transplant International
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    ABSTRACT: Inadequate cyclosporine blood levels may cause acute rejection in transplanted renal graft, and its increase is accompanied with graft toxicity. These reasons settle that many years cyclosporine was monitored by determining through level, latter 2-hour peak level which was determined as not a suitable method (1). And mostly through level and 2-hour peak are used for counting area under the concentration time curve as the single points (2). The aim of this study was to identify cyclosporine therapeutic range for kidney recipients using 3-point limited sampling strategy. Methods. The cyclosporine exposure level was based on the calculation of the mean area under the concentration-time curve AUC (0-12). The AUC (0-12) was estimated using a Bayesian estimator and a 3-point limited sampling strategy. Cyclosporine exposure levels were obtained from 3 blood samples: 0, 1, and 3 hours post–dose; and analyses were performed using a liquid chromatography-tandem mass spectrometry method. The therapeutic window of cyclosporine was calculated by the Chebyshev's inequality method with a 99% guarantee (α=0.01) using the IBM SPSS Statistics 20 software. Results.It was found that the therapeutic window of cyclosporine estimated by the Chebyshev's inequality method and put on the AUC (0-12) exposure lies in the ranges from 2.84–3.13 mg h/L with the 99% confidence (the average AUC (0-12) exposure is 2.99 mg h/L, maximum 5.43 mg h/L, and minimum 1.39 mg h/L) for the patients with the target AUC (0-12) exposure of 3.8 mg h/L (post-transplantation time >1 year). The therapeutic window of cyclosporine differs in different post-transplantation time groups: the estimated AUC exposure range in the group of patients who have a graft longer than 5 years is 2.70–2.98 mg h/L (the average AUC (0-12) exposure is 2.84 mg h/L, maximum 4.38 mg h/L. and minimum 1.39 mg h/L), and the estimated AUC exposure range in the group of patients who have a graft for 1–5 years is 3.05–3.75 mg h/L (the average AUC (0-12) exposure is 3.60 mg h/L, maximum 5.43 mg h/L, and minimum 1.65 mg h/L).
    Full-text · Conference Paper · Jul 2013
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    Full-text · Conference Paper · May 2013
  • Franck Saint-Marcoux · Jean-Baptiste Woillard · Camille Jurado · Pierre Marquet
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    ABSTRACT: Objectives: Since 2007, a number of transplantation centers have been routinely using an expert system for tacrolimus (TAC) dose adjustment in kidney allograft recipients, based on PK modeling and Bayesian estimation for area-under-the-curve (AUC) determination. This has allowed the setting up of a large database of TAC pharmacokinetic profiles and AUC values, a part of which was analyzed here. Methods: We retrospectively studied 2030 requests posted by 21 different centers for routine TAC dose adjustment in 1000 different adult renal transplant patients (not enrolled in any kind of concentration-controlled clinical trial). For each request, the following information was obtained: time elapsed since transplantation, TAC daily dose, calculated AUC, and trough concentration (C0). Results: The dose-standardized exposure to TAC significantly and progressively increased in the months after transplantation: from month (M) 1 to M9 C0/dose increased from 2.33 to 3.44 mcg·L(1)·mg(1) and AUC/dose from 43.1 to 64.2 mcg·h(1)·L(1)·mg(1), respectively. On the contrary, in patients beyond the first year whose C0 or AUC was in the target range, the odds of remaining in this range were high for a long time period, suggesting a low intrapatient variability in the stable phase. Regression analyses showed that the correlation between C0 and AUC was better in the first 3-month period (r(2) = 0.76) than later on (r(2) ≤ 0.67). Using the regression equations obtained, AUC ranges corresponding to different applicable C0 targets were calculated. Conclusions: From a large number of kidney graft recipients, we have estimated the relationships between C0 and AUC, modeled the evolution of TAC exposure with time and defined AUC targets that could be useful to lead further controlled-concentration trials and improve routine TAC therapeutic drug monitoring.
    No preview · Article · May 2013 · Therapeutic drug monitoring
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    ABSTRACT: Mycophenolic acid (MPA) area under the curve (AUC) has been reported as an important marker of graft outcome. The aim of our study was to develop: (i) population pharmacokinetic (POPPK) models in adult heart transplant patients using a parametric (P) and a nonparametric (NP) approach; and (ii) two independent Bayesian estimators (BE) enabling AUC determination using a limited sampling strategy.Methods and MaterialsFifty-six MPA pharmacokinetic (PK) profiles were collected from 39 adult heart transplant patients given mycophenolate mofetil. POPPK analysis was performed using both the parametric iterative two-stage Bayesian method and the nonparametric adaptive grid approach (using Pmetrics R package). The PK profiles were fitted to a one-compartment model with first-order elimination combined to two gamma laws to describe the absorption phase.ResultsPK profiles were divided into a development dataset (n=37) and a validation dataset (n=19). For each approach, a POPPK model was developed that accurately fitted the observed data. In the validation group, the BE developed using each model yielded good AUC estimation performance (bias of -1.26±19.33% (P) and -1.12±19.34% (NP)) on the basis of a 20, 60, 180 and 360 minutes sampling schedule. Accordingly, dose adjustment (for a 45 mg.h/L target AUC) based on BE was similar to that proposed on the basis of the reference AUC (trapezoidal AUC using all the available concentrations) in 79% (P) and 84% (NP) of the patients.Conclusions The PK profiles of MPA in heart transplant patients are more complex than those observed in kidney graft recipients. Bayesian estimators allowing the determination of MPA AUC using a limited number of blood samples have been developed using 2 totally independent population modelling approaches, the combination of which now increase the accuracy of our results. They are now available on our ISBA website (https://pharmaco.chu-limoges.fr) for routine dose adjustment.
    No preview · Article · Apr 2013 · The Journal of Heart and Lung Transplantation