Franck Saint-Marcoux

University of Limoges, Limages, Limousin, France

Are you Franck Saint-Marcoux?

Claim your profile

Publications (35)103.78 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to identify a cyclosporine therapeutic range for kidney recipients.
    Medicina (Kaunas, Lithuania) 01/2014; 50(1):37-43. · 0.55 Impact Factor
  • [Show abstract] [Hide abstract]
    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·mg and AUC/dose from 43.1 to 64.2 mcg·h·L·mg, 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 (r² = 0.76) than later on (r² ≤ 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.
    Therapeutic drug monitoring 05/2013; · 2.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The adherence to medication in drug-resistant focal epilepsy (RFE) remains largely unknown. The present work aimed to assess the frequency of recent adherence to antiepileptic drugs (AEDs) in patients with RFE. This prospective observational study screened all patients with RFE, admitted to the Nancy University Hospital between April 2006 and September 2008, for a 5-day hospitalization without AED tapering. The adherence to AEDs was assessed by measuring serum drug levels on day 1 (reflecting the recent "at home" adherence) and day 5 (reflecting the individual reference concentration when drug ingestion was supervised). A patient was considered nonadherent if at least one of their serum drug levels was different between days 1 and 5. The day-1 value was considered different from day 5 when it was at least 30% lower (underdosed) or 30% higher (overdosed). Nonadherent patients were classified as under-consumers in the case of one or more underdosed day-1 values, over-consumers in the case of one or more overdosed day-1 values, or undefined if they exhibited both underdosed and overdosed day-1 values. Forty-four of the 48 screened patients were included. Eighteen (40.9%) of 44 patients were nonadherent. Among them, 12 (66.7%) were over-consumers, 4 (22.2%) were under-consumers, and 2 (11.1%) were undefined nonadherents. The study indicates that recent adherence to antiepileptic medication in this group of patients with RFE is poor. Overconsumption is the most frequent form of nonadherence in this population and should be specifically assessed to prevent its possible consequences in terms of AEDs dose-dependent adverse events.
    Epilepsia 11/2012; · 3.96 Impact Factor
  • Médecine et Maladies Infectieuses 10/2012; · 0.75 Impact Factor
  • Archives de Pédiatrie 06/2012; 19(6):647–648. · 0.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A sensitive and reliable method was developed and validated for the determination of five synthetic pyrethroid metabolites namely cis-Cl(2)CA, trans-Cl(2)CA, Br(2)CA, 3-PBA and 4-FPBA in human urine by liquid chromatography-tandem mass spectrometry. (2)D(6)-labelled trans-Cl(2)CA and (13)C(6)-labelled 3-PBA were used as internal standards. This method was based on a liquid-liquid extraction procedure in acidic conditions using hexane solvent with a basic purification, a chromatographic separation using a specific C18 column and mass spectrometric detection in the negative polarity. Suitable limits of detection (0.015μg/L for the five compounds) and quantification (from 0.020 to 0.030μg/L) were obtained for rendering the method usable for the biomonitoring of pyrethroids in the general population. The efficiency of the method was tested in 39 urine samples from French people without any known exposure to pyrethroids. At least three of the five metabolites were detected in each sample. The results of this study were compared to those obtained in previous ones and discussed.
    Toxicology Letters 08/2011; 210(2):248-53. · 3.15 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We report a feasibility study based on our large-scale experience with mycophenolate mofetil dose adjustment based on mycophenolic acid interdose area under the curve (AUC) in renal transplant patients. Between 2005 and 2010, 13,930 requests for 7090 different patients (outside any clinical trial) were posted by more than 30 different transplantation centers on a free, secure web site for mycophenolate mofetil dose recommendations using three plasma concentrations and Bayesian estimation. This retrospective study showed that 1) according to a consensually recommended 30- to 60-mg·h/L target, dose adjustment was needed for approximately 35% of the patients, 25% being underexposed with the highest proportion observed in the first weeks after transplantation; 2) when dose adjustment had been previously proposed, the subsequent AUC was significantly more often in the recommended range if the dose was applied than not at all posttransplantation periods (72-80% vs. 43-54%); and 3) the interindividual AUC variability in the "respected-dose" group was systematically lower than that in the "not respected-dose" group (depending on the posttransplantation periods; coefficient of variation %, 31-41% vs 49-70%, respectively). Further analysis suggested that mycophenolic acid AUC should best be monitored at least every 2 weeks during the first month, every 1 to 3 months between months 1 and 12, whereas in the stable phase, the odds to be still in the 30- to 60-mg·h/L range on the following visit was still 75% up to 1 year after the previous dose adjustment. This study showed that the monitoring of mycophenolate mofetil on the basis of AUC measurements is a clinically feasible approach, apparently acceptable by the patients, the nurses, and the physicians owing to its large use in routine clinics.
    Therapeutic drug monitoring 06/2011; 33(3):285-94. · 2.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Several analytical techniques with different performances are available for the measurement of tacrolimus blood concentrations. The performance of Bayesian estimators (MAP-BEs) allowing dose adjustments of tacrolimus is dependent on the precision of the analytical technique. Hence, any Bayesian estimator should only be used for concentration data obtained with the same assay employed for its development. The present study aimed at evaluating the feasibility of developing Bayesian estimators dedicated to different immunoassays, using the concentrations obtained with the reference high-performance liquid chromatography with mass spectrometric detection (LC-MS/MS) method and a simulation approach. One hundred thirty-five full pharmacokinetic profiles of tacrolimus were obtained from 45 renal transplant patients using 3 different analytical techniques: 2 immunoassays [enzyme-multiplied immunoassay technique (EMIT) and chemiluminescent microparticle immunoassay (CMIA)] and LC-MS/MS. In a first step, 3 MAP-BEs were developed using the concentrations measured with the 3 techniques. Taking into account the correlation equations between the concentrations obtained with each of the immunoassays and LC-MS/MS, as well as the analytical error of the techniques, 2 hybrid MAP-BEs dedicated to the immunoassays were then developed after simulation of 100 pharmacokinetic profiles. Their performances were compared with those of the respective MAP-BEs developed using the actual immunoassay concentrations. The mean concentrations measured over the dosing interval using EMIT and CMIA were significantly higher than those measured using LC-MS/MS (+15% and +11% in the AUC₀₋₂₄ h value, respectively, P < 0.0001), leading to differences in dose recommendations of -0.9 ± 1.1 and -0.7 ± 0.9 mg, respectively. When applying the MAP-BE developed from LC-MS/MS data for the EMIT or CMIA concentrations, tacrolimus AUC₀₋₂₄ h was estimated with an imprecision >20% in 33% and 27% of the patients, respectively. In contrast, the "CMIA" and "EMIT" hybrid MAP-BEs provided a good AUC₀₋₂₄ h estimation in 85%-93% of the patients. This study showed the impact of the analytical technique on the performance of Bayesian estimators dedicated to tacrolimus dose adjustment and the feasibility to develop MAP-BE for a specific assay using results from a different assay, based on a limited method comparison study. This methodology could offer clinicians the opportunity to dose adjust tacrolimus whatever the assay used in their center.
    Therapeutic drug monitoring 03/2011; 33(2):171-7. · 2.43 Impact Factor
  • Françoise Goirand, Bernard Royer, Anne Hulin, Franck Saint-Marcoux
    [Show abstract] [Hide abstract]
    ABSTRACT: Everolimus has proven efficacy for prevention of rejection in adult de novo renal and cardiac transplant recipient in combination with ciclosporine and corticosteroids. Therapeutic drug monitoring (TDM) with target trough concentration (C0) value from 3 to 8 µg/L has been proposed. Through a systematic review of the literature, this work explored a level of recommendation for this TDM. Everolimus exhibits both wide interindividual pharmacokinetic variability and poor relationship between dose and exposure. A good relationship has been reported between C0 values and global exposure to the drug (i.e. AUC). Although C0 > 3 µg/L has been associated with a decreased incidence of rejection, the upper limit of 8 µg/L has never been formally validated. No clinical trial testing other exposure indices or comparing efficacy and/or toxicity of everolimus therapy with and without TDM has been published so far. Consequently the level of recommendation for everolimus monitoring is "recommended".
    Thérapie 01/2011; 66(1):57-61. · 0.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A rapid and sensitive LC/electrospray ionization-MS/MS method has been developed for the determination of dodine in fruit samples. Based on a liquid-liquid extraction of 10 g solid fruit homogenate using an acetone-dichloromethane-hexane mixture and acetate ammonium buffer (pH 4.5), this LC/MS/MS procedure was characterized by recoveries above 50%, with good intra-assay precision (RSD < 13%) and interassay precision (RSD < 18%) for seven different matrixes (apple, apricot, cherry, peach, pear, plum, and quince). This method was validated from 5 to 500 microg/kg according to standard guidelines. Its LOD (1 microg/kg) and LOQ (5 microg/kg) were in accordance with recommendations of the European legislation defined for infant food [maximum residue level (MRL) = 10 microg/kg]. The whole procedure was finally tested on 1022 fruit samples intended for commercialization, both infant food samples and samples not intended in particular for babies. In this study, dodine was detected in 27 samples; none exhibited a concentration higher than the MRL.
    Journal of AOAC International 01/2011; 94(1):300-6. · 1.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The use of mycophenolate mofetil (MMF) in children with idiopathic nephrotic syndrome (INS) is increasing. However, the clinical benefit of its monitoring has been scarcely studied, and little is known about its pharmacokinetics in this context. The objectives of the present study were: (i) to study and model the pharmacokinetics of mycophenolic acid (MPA; the active moiety of MMF) in paediatric patients with INS given MMF, at all stages of the disease; (ii) to develop a Bayesian estimator (MAP-BE) for individual inter-dose area under the concentration-time curve (AUC) prediction in this population, using a limited blood sampling strategy (LSS). Full-pharmacokinetic (PK) profiles of MPA collected in paediatric inpatients with INS already treated with a maintenance immunosuppressive therapy based on MMF (with no calcineurin inhibitors; CNI) were studied. A classical iterative two-stage (ITS) method was applied to model the data and develop MAP-BEs using a one-compartment open model where the absorption is described by a double gamma law allowing the description of a potential enterohepatic recirculation. The performance of the MAP-BE developed for individual exposure assessment was evaluated by the bias and precision of predicted AUCs with respect to measured, trapezoidal AUCs (reference value), and by the proportion of predicted AUCs with absolute error >20%. These PK tools were tested in an independent group of patients. Sixty PK profiles of MPA from children receiving MMF in association to corticosteroids or given alone were included in the study. Forty-five of these PK profiles were used to develop a PK model and a MAP-BE, and 15 for their validation. In the building group, the PK model fitted accurately the PK profiles of MPA: mean residual error of modelled vs. reference AUC was m±SD=-0.015±0.092 (range: -0.153 to 0.204). The MAP-BE which allowed the estimation of MPA AUC on the basis of a 20 min-60 min-180 min LSS was then developed. In the independent group of patients, its mean residual error vs. reference AUCs was m±SD=-0.036±0.145 (range: -0.205 to 0.189). Thus, a PK model and its derived MAP-BE for MMF (without any associated CNI) when given to children with INS have been developed. Clinical trials using these PK tools could test the potential impact of the therapeutic drug monitoring of MMF based on the AUC on the clinical evolution of INS.
    Pharmacological Research 01/2011; 63(5):423-31. · 4.35 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This article summarizes part of a consensus meeting about mycophenolate (MPA) therapeutic drug monitoring held in Rome under the auspices of The Transplantation Society in November 2008 (Clin J Am Soc Nephrol. 2010;5:341-358). This part of the meeting focused on the clinical pharmacokinetics of MPA and included discussion on how to measure MPA (active drug) exposure and the differences between the currently available formulations. SUMMARY POINTS: Because of variability in the dose-concentration relationship, MPA exposure should be measured and doses should be adjusted accordingly to achieve optimal clinical outcomes. Suggested therapeutic exposures derived for MPA from mycophenolate mofetil (MMF) may differ to those that could be useful for MPA from enteric-coated mycophenolate sodium (EC-MPS), particularly if limited sampling strategies or single concentration, especially trough concentrations, is used, as the concentration-time profiles of MPA from the 2 formulations are quite different. The 2 MPA formulations cannot be considered as bioequivalent. The area under the concentration-time curve (AUC 0-12) is considered the criterion standard for monitoring of MPA, which is a reflection of exposure to the drug over the entire dosing period. If a limited sampling protocol coupled with multilinear regression or Bayesian estimation is used to estimate this parameter, it should be used only for the population in which the model has been developed and should preferably include at least one time point after 4 hours (preferably around 8 or 9 hours after MMF dosing). If a single time point is to be used as a surrogate for an AUC 0-12, trough concentration of MPA may be the most practical but, from a pharmacokinetic standpoint, is not the most informative time point to choose. Because limited sampling strategies to estimate MPA exposure from EC-MPS have not yet been well developed and fully evaluated, nor have accurate Bayesian estimators been reported, AUC 0-12 measurement is still necessary to obtain reliable estimates of MPA exposure in patients treated with EC-MPS. The measurement of MPA trough concentrations should not be used at all for MPA exposure assessment following administration of EC-MPS. Because limited sampling strategies to estimate MPA exposure from EC-MPS have not yet been well developed and fully evaluated, nor have accurate Bayesian estimators been reported, AUC 0-12 measurement is still necessary to obtain reliable estimates of MPA exposure in patients treated with EC-MPS. The measurement of MPA trough concentrations should not be used at all for MPA exposure assessment following administration of EC-MPS. Lower (or higher) than expected total MPA exposure in patients with severe renal impairment may still indicate sufficient free MPA exposure. Mycophenolate free exposure measurement/estimation is likely to be beneficial in patients with severe renal impairment (creatinine clearance b25 mL/min) to guide dosage estimation, especially because renal function changes over time after transplant, while recognizing that robust prospective studies to show the clinical advantage of measuring free MPA exposure are still required. Lower total measured MPA exposure in patients with hypoalbuminemia may still indicate sufficient free MPA exposure. Mycophenolate free concentration measurement and estimation of exposure are likely to be beneficial in patients with a serum albumin less than or equal to 31 g/L to guide interpretation of MPA exposure. A 1.5-g twice-daily starting dose of MMF rather than a 1-g twice-daily starting dose of MMF is more likely to achieve the minimum target MPA exposure in adult transplant recipients receiving concomitant cyclosporine therapy. Because the cyclosporine dose is progressively tapered following transplantation, MPA exposure should be measured repeatedly and MMF should be doses adjusted accordingly to achieve optimal clinical outcome. Mycophenolate exposure should be measured in the first week after transplant, then each week for the first month, each month until month 3, and subsequently every 3 months up to 1 year with appropriate dosage adjustment, as AUC is likely to increase over time. After 1 year, if dosage requirement has stabilized, MPA exposure can be assessed each time the immunosuppressive regimen is changed or a potentially interacting drug is introduced or withdrawn. Assessment of UGT1A9 single nucleotide polymorphisms (-275TNA, -2152CNT, -440CNT, -331TNC) should be considered before transplantation to assist in dosing decisions to achieve optimal MPA exposure immediately after transplant. Consideration of the points summarized above should lead to more effective dosage adjustment based on sound applied pharmacokinetic and pharmacodynamic principles.
    Transplantation reviews (Orlando, Fla.) 12/2010; 25(2):47-57.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Advagraf is a new extended-release once-daily formulation of tacrolimus, a potent immunosuppressant widely used in renal transplantation. The aims of his study were (i) to develop a population pharmacokinetic model for once-daily tacrolimus in adult renal transplant patients; and (ii) to develop a Bayesian estimator able to reliably estimate individual pharmacokinetic parameters and exposure indices. Full pharmacokinetic profiles obtained from 41 adult renal transplant patients who had been switched from ciclosporin to a single daily dose of the new once-daily tacrolimus formulation for more than 6 months were analysed. Tacrolimus concentrations were measured using validated turbulent flow chromatography-tandem mass spectrometry methods. Population parameters were computed using nonlinear mixed-effect modelling software (NONMEM Version VI). The patients were randomly divided into (i) a model-building test group (n = 29); and (ii) a validation group (n = 12). Population pharmacokinetic analysis was performed to estimate the effects on tacrolimus pharmacokinetics of demographic characteristics (sex, bodyweight, age), drug interaction with prednisolone, laboratory test results (the haematocrit, haemaglobin level and serum creatinine level) and cytochrome P450 (CYP) 3A5 (CYP3A5) genetic polymorphism. The population pharmacokinetic model was further refined by taking into account all of the data from the 41 patients, and the final model was validated using a bootstrap and a visual predictive check. For Bayesian estimation, the best limited-sampling strategy was determined on the basis of the D-optimality criterion and validation performed in the validation group. The trapezoidal area under the whole-blood concentration time curve from 0 to 24 hours (AUC(24)) of tacrolimus varied by up to 50% for the same trough concentration value. The pharmacokinetics of once-daily tacrolimus were well described by a two-compartment model combined with an Erlang distribution to describe the absorption phase. The CYP3A5 genotype was the only covariate retained in the final model. The apparent clearance of tacrolimus was 2-fold higher in expressers (with the CYP3A5*1/*1 and CYP3A5*1/*3 genotypes) than in non-expressers (with the CYP3A5*3/*3 genotype). This factor explained around 25% of the interindividual variability in the apparent clearance. A posteriori Bayesian estimation allowed accurate prediction of the AUC(24) of once-daily tacrolimus, using just three sampling times (0, 1 and 3 hours post-dose) with a nonsignificant mean bias of 0.7% (range 16-20%) and good precision (root mean square error 9%). Population pharmacokinetic analysis of once-daily tacrolimus in renal transplant recipients resulted in identification of the CYP3A5*1/*3 genotype as a significant covariate on the apparent clearance of tacrolimus, and the design of an accurate maximum a posteriori Bayesian estimator based on three blood concentration measurements and this covariate. Such a tool could be helpful for comparing different exposure indices or different target levels. It could contribute to improvement of the efficacy and tolerability of once-daily tacrolimus in some patients.
    Clinical Pharmacokinetics 10/2010; 49(10):683-92. · 5.49 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The once-daily formulation of tacrolimus has been reported to exhibit the same efficacy and safety profile as compared with the immediate-release form administered twice daily. However, as a result of differences in their pharmacokinetic (PK) profile, the PK models or Bayesian estimators (MAP-BE) previously developed for the immediate-release formulation cannot be used for the new once-daily formulation. Using the PK information obtained from a Phase II trial, the aim of this study was to explore the feasibility of developing a PK model and a MAP-BE able to estimate, on the basis of a routinely applicable limited sampling strategy, tacrolimus individual PK parameters and AUC0-24h in de novo renal transplant patients given the once-daily formulation. Twelve de novo kidney transplant recipients receiving once-daily tacrolimus as part of their immunosuppressive regimen provided full PK profiles (17 concentration time points over 24 hours) on Days 14 and 42 posttransplantation. On the basis of a one-compartment open model with absorption described as following a double gamma distribution, a classic iterative two-stage method was applied to develop MAP-BEs. All the limited sampling strategies with a maximum of three sampling times within 4 hours postdose were tested for Bayesian forecasting with the aim of accurately estimating the AUC0-24h. Once-daily tacrolimus exhibited a high interpatient PK variability with coefficients of variation of 34.3% and 36.2% for AUC0-24h/dose (mg/kg) on Days 14 and 42, respectively. Regression analysis between C0 and AUC0-24h yielded r = 0.68 and 0.76 at these two periods, respectively. The iterative two-stage approach led to the development of a different MAP-BE for each posttransplantation period, which allowed estimation of once-daily tacrolimus pharmacokinetics and AUC0-24h on the basis of a C0-C1h-C3h sampling schedule. The mean bias of the Bayesian versus reference (trapezoidal) AUCs was 4.2% +/- 6.1% (range, -11.8% to +11.2%; root mean square error = 7.1%) on Day 14 and 0.2% +/- 7.9% (range, -12.9% to +14.1%; root mean square error = 7.8%) on Day 42. A PK model and Bayesian estimators allowing estimation of tacrolimus AUC0-24h based on a routinely applicable limited sampling strategy were developed for once-daily tacrolimus in renal transplantation. Further validation in independent groups of patients is required to confirm their applicability for optimizing the monitoring of once-daily tacrolimus in routine clinical practice or to conduct observational or comparative therapeutic drug monitoring clinical trials.
    Therapeutic drug monitoring 04/2010; 32(2):129-35. · 2.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Tacrolimus-based immunosuppression is the most frequently prescribed immunosuppression for kidney-transplant (KT) patients. Because tacrolimus has a narrow therapeutic window, drug monitoring is mandatory. Of the many methods used to assess whole-blood trough levels, antibody-conjugated magnetic immunoassay (ACMIA) is popular because, compared with microparticle enzyme-linked immunoassays (MEIA), there is no need to pretreat samples, thus reducing time taken by the laboratory technician. Herein, we report on a KT tacrolimus-treated patient who experienced falsely elevated whole-blood tacrolimus concentrations after using the ACMIA method. ACMIA gave trough levels of 24 ng/ml, whereas the actual trough level, when measured by enzyme-multiplied immunoassay technique (EMIT) and high-performance liquid chromatography coupled with mass spectrometry (LC-MS/MS), was nil. After a workup we only found one factor that might have caused the elevated concentration: positive anti-double stranded DNA autoantibodies. We conclude that, when ACMIA produces surprisingly high tacrolimus concentrations in organ-transplant patients, these should be reassessed immediately using either LC-MS/MS or another immunoassay in order to eliminate falsely elevated results.
    Transplant International 09/2009; 23(2):227-30. · 3.16 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: LC coupled to single (LC-MS) and tandem (LC-MS/MS) mass spectrometry is recognized as the most powerful analytical tools for metabolic studies in drug discovery. In this article, we describe five cases illustrating the utility of screening xenobiotic metabolites in routine analysis of forensic samples using LC-MS/MS. Analyses were performed using a previously published LC-MS/MS general unknown screening (GUS) procedure developed using a hybrid linear IT-tandem mass spectrometer. In each of the cases presented, the presence of metabolites of xenobiotics was suspected after analyzing urine samples. In two cases, the parent drug was also detected and the metabolites were merely useful to confirm drug intake, but in three other cases, metabolite detection was of actual forensic interest. The presented results indicate that: (i) the GUS procedure developed is useful to detect a large variety of drug metabolites, which would have been hardly detected using targeted methods in the context of clinical or forensic toxicology; (ii) metabolite structure can generally be inferred from their "enhanced" product ion scan spectra; and (iii) structure confirmation can be achieved through in vitro metabolic experiments or through the analysis of urine samples from individuals taking the parent drug.
    Journal of Separation Science 09/2009; 32(18):3074-83. · 2.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Therapeutic drug monitoring of mycophenolate mofetil (MMF) was found to be beneficial in preventing acute rejection after kidney transplantation. The aim of this pilot prospective study was to evaluate the efficacy of MMF dose adjustment in de novo liver transplant patients receiving MMF at fixed versus concentration-controlled doses [ie, adapted to mycophenolic acid (MPA) AUC0-12h] and tacrolimus during the first 12 months posttransplant. Twenty-nine patients received steroids only up to day 10, induction therapy by lymphoglobulins followed by tacrolimus and MMF. In all patients, MPA AUC0-12h were measured on posttransplant days 7 and 14 and at months 1, 2, 3, 6, and 12. From March 2006 to March 2007, 15 patients received MMF at a fixed dose of 1 g twice a day for 12 months. From April 2007 to December 2007, MMF was given to 14 patients at a dose of 1 g twice a day until day 7 and was then adapted to reach an MPA AUC0-12h target of 30-60 mg x h/L. The proportion of MPA AUC0-12h values within the target range was similar in both groups. The proportion of patients with MPA AUC0-12h below 30 mg x h/L tended to be higher in the fixed dose group within the first month posttransplant. However, MMF dose did not differ significantly between the 2 groups at any period except month 1. MPA AUC0-12h tended to be higher in the concentration-controlled group at day 14 and month 2 and was significantly so at month 1. Tacrolimus trough concentrations tended to be lower in the concentration-controlled group at all study periods and was significantly so at month 3. At 12 months posttransplant, patient and graft survivals, acute rejection rate, and adverse events were similar in both groups. We concluded that adapting the dose of MMF resulted in a significant increase in MPA AUC0-12h at month 1. There was a trend toward a lower proportion of patients with MPA AUC0-12h below 30 mg x h/L in the concentration-controlled group. No difference in outcome was found between both groups.
    Therapeutic drug monitoring 07/2009; 31(4):451-6. · 2.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A new mycophenolate (MPA) assay based on the enzymatic activity of recombinant type II inosine monophosphate dehydrogenase (the pharmacological target of MPA) with excellent correlation with high-performance liquid chromatography has recently been released for the measurement of MPA plasma levels. This study aimed to (1) compare this new assay with liquid chromatography tandem mass spectrometry (LC-MS/MS) for MPA pharmacokinetic (PK) studies in different populations of allograft recipients given mycophenolate mofetil, (2) develop specific Bayesian estimators for this inhibition assay and test their accuracy, and (3) compare the resulting MPA area under the curve (AUC0-12h) estimates with those of Bayesian estimators developed based on the LC-MS/MS results. Sixty-four adult or pediatric, renal or lung transplant patients who were administered mycophenolate mofetil in association with cyclosporine, tacrolimus, or sirolimus at different post-transplant periods were enrolled as part of different PK studies. Eight hundred ninety-four patients' samples were analyzed in parallel with the enzymatic MPA assay and a reference LC-MS/MS method. Repeated analysis of quality control samples showed a mean difference of 6% between the 2 assays, whereas the results obtained in different populations of transplanted patients showed excellent correlation (r2 > 0.96) and small mean relative differences (2.0%-16.9%). The full profiles obtained with both assays were adequately fitted using either a 2-compartment model with 1 "gamma" absorption phase or a 1-compartment model with 2 gamma inputs. Several PK parameters were significantly affected by the analytical method used. Accurate Bayesian estimators could be specifically developed for the enzymatic MPA assay, using the same 3 concentration-time points (20 minutes, 1 hour, and 3 hours post dose) as with LC-MS/MS, with a median bias versus reference (trapezoidal) AUC0-12h values of -1.3% (range -45.2% to 40.4%), and 83% of the patients within +/-20% of the reference. These Bayesian estimates were significantly higher than those obtained with LC-MS/MS in patients on cyclosporine or sirolimus, but not in patients on tacrolimus.
    Therapeutic drug monitoring 07/2009; 31(4):443-50. · 2.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mycophenolate mofetil, a prodrug of mycophenolic acid (MPA), is used during non-myeloablative and reduced-intensity conditioning haematopoetic stem cell transplantation (HCT) to improve engraftment and reduce graft-versus-host disease (GVHD). However, information about MPA pharmacokinetics is sparse in this context and its use is still empirical. To perform a pilot pharmacokinetic study and to develop maximum a posteriori Bayesian estimators (MAP-BEs) for the estimation of MPA exposure in HCT. Fourteen patients administered oral mycophenolate mofetil 15 g/kg three times daily were included. Two consecutive 8-hour pharmacokinetic profiles were performed on the same day, 3 days before and 4 days after the HCT. One 8-hour pharmacokinetic profile was performed on day 27 after transplantation. For these 8-hour pharmacokinetic profiles, blood samples were collected predose and 20, 40, 60, 90 minutes and 2, 4, 6 and 8 hours post-dose. Using the iterative two-stage (ITS) method, two different one-compartment open pharmacokinetic models with first-order elimination were developed to describe the data: one with two gamma laws and one with three gamma laws to describe the absorption phase. For each pharmacokinetic profile, the Akaike information criterion (AIC) was calculated to evaluate model fitting. On the basis of the population pharmacokinetic parameters, MAP-BEs were developed for the estimation of MPA pharmacokinetics and area under the plasma concentration-time curve (AUC) from 0 to 8 hours at the different studied periods using a limited-sampling strategy. These MAP-BEs were then validated using a data-splitting method. The ITS approach allowed the development of MAP-BEs based either on 'double-gamma' or 'triple-gamma' models, the combination of which allowed correct estimation of MPA pharmacokinetics and AUC on the basis of a 20 minute-90 minute-240 minute sampling schedule. The mean bias of the Bayesian versus reference (trapezoidal) AUCs was <5% with <16% of the patients with absolute bias on AUC >20%. AIC was systematically calculated for the choice of the most appropriate model fitting the data. Pharmacokinetic models and MAP-BEs for mycophenolate mofetil when administered to HCT patients have been developed. In the studied population, they allowed the estimation of MPA exposure based on three blood samples, which could be helpful in conducting clinical trials for the optimization of MPA in reduced-intensity HCT. However, prior studies will be needed to validate them in larger populations.
    Clinical Pharmacokinetics 01/2009; 48(10):667-75. · 5.49 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Monitoring of the area under the plasma concentration-time curve (AUC) of mycophenolic acid (MPA) has been developed for individual dose adjustment of mycophenolate mofetil (MMF) in renal allograft recipients. MMF is currently used as an off-label drug in the treatment of systemic lupus erythematosus (SLE), but factors of its exposition may be different in these patients and need to be determined for therapeutic drug monitoring (TDM) purposes. The aim of the study was to develop a maximum a posteriori probability (MAP) Bayesian estimator of MPA exposition in patients with SLE, with the objective of TDM based on a limited sample strategy. Twenty adult patients with SLE given a stable 1 g/day, 2 g/day or 3 g/day dose of MMF orally for at least 10 weeks were included in the study. MPA was measured by high-performance liquid chromatography (HPLC) coupled to a photodiode array detector (11 plasma measurements over 12 hours post-dose per patient). Free MPA concentrations were measured by HPLC with fluorescence detection. Two different one-compartment models with first-order elimination were tested to fit the data: one convoluted with a double gamma distribution to describe secondary concentrations peaks, and one convoluted with a triple gamma distribution to model a third, later peak. A large interindividual variability in MPA concentration-time profiles was observed. The mean maximum plasma concentration, trough plasma concentration, time to reach the maximum plasma concentration and AUC from 0 to 12 hours (AUC(12)) were 13.6 +/- 8.4 microg/mL, 1.4 +/- 1.2 microg/mL, 1.1 +/- 1.2 hours and 32.2 +/- 17.1microg . h/mL, respectively. The mean free fraction of MPA was 1.7%. The one-compartment model with first-order elimination convoluted with a triple gamma distribution best fitted the data. Accurate Bayesian estimates of the AUC(12) were obtained using three blood samples collected at 40 minutes, 2 hours and 3 hours, with a coefficient of correlation (R) = 0.95 between the observed and predicted AUC(12) and with a difference of <20% in 16 of the 20 patients. A specific pharmacokinetic model was built to accurately fit MPA blood concentration-time profiles after MMF oral dosing in SLE patients, which allowed development of an accurate Bayesian estimator of MPA exposure that should allow MMF monitoring based on the AUC(12) in these patients. The predictive value of targeting one specific or different AUC values on patients' outcome using this estimator in SLE will need to be evaluated.
    Clinical Pharmacokinetics 01/2008; 47(4):277-84. · 5.49 Impact Factor