Pierre Marquet

University of Limoges, Limages, Limousin, France

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Publications (267)841.97 Total impact

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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.
    Pharmacological Research 08/2015; DOI:10.1016/j.phrs.2015.08.020 · 4.41 Impact Factor
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    ABSTRACT: We investigated the associations between variants in genes coding for enzymes and transporters related to the 6-mercaptopurine pathway and clinical outcomes in pediatric patients with acute lymphoblastic leukemia. Statistical association between gender, age and genotypes of selected SNPs, and the risks of hematological toxicity and relapse were investigated using a Cox proportional hazard model in 70 acute lymphoblastic leukemia patients from upper Egypt. We found significant associations between ITPA, IMPDH1, SLC29A1, SLC28A2, SLC28A3 and ABCC4 SNPs and one or more of the hematological toxicity manifestations (neutropenia, agranulocytosis and leukopenia); age was significantly related to relapse. Genetic polymorphisms in enzymes and transporters involved in the 6-mercaptopurine pathway should be considered during its use to avoid hematological toxicity.
    Pharmacogenomics 08/2015; DOI:10.2217/PGS.15.62 · 3.43 Impact Factor
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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.
    Pharmacological Research 07/2015; DOI:10.1016/j.phrs.2015.07.012 · 4.41 Impact Factor
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    ABSTRACT: Hepatitis C virus-related B-cell proliferation is a model of virus-driven autoimmune/neoplastic disorder leading to mixed cryoglobulinemia and/or B-cell non Hodgkin lymphoma. These lymphomas are often marginal zone lymphomas or diffuse large B-cell lymphomas. Peginterferon/Ribavirin therapy has proved its crucial role in the cure of these non-Hodgkin lymphomas, but data are lacking concerning new direct anti-viral agents. We report five cases of Hepatitis C virus-associated B-cell non Hodgkin lymphoma treated with direct anti-viral agents: two marginal zone lymphomas received direct anti-viral agents alone (one with a leukemic phase only, one with splenic and deep lymph nodes localizations); one renal marginal zone lymphoma with renal insufficiency received direct anti-viral agents and 4 rituximab infusions simultaneously; two diffuse large B-cell lymphomas were treated with direct ant-viral agents following chemotherapy. Sustained virological response was obtained in all patients, and complete remission of NHL was noted six months after cessation of any treatment except for one patient with a persistent small leukemic phase. Direct anti-viral agents might be proposed as a first-line treatment in marginal zone lymphomas in the case of no life-threatening complications with the precaution of a long-term follow-up. In the setting of diffuse large B-cell lymphomas, well-tolerated direct anti-viral agents could potentially be introduced very early not only to prevent relapse of these lymphomas but also to limit the liver toxicity of chemotherapy and rituximab by preventing outbreaks of viral load. New observations and trials should support these assumptions. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 06/2015; DOI:10.1111/liv.12897 · 4.41 Impact Factor
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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.
    Analytical and Bioanalytical Chemistry 02/2015; 407(12). DOI:10.1007/s00216-015-8554-0 · 3.58 Impact Factor
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    ABSTRACT: Personalized medicine is based on: 1) improved clinical or non-clinical methods (including biomarkers) for a more discriminating and precise diagnosis of diseases; 2) targeted therapies of the choice or the best drug for each patient among those available; 3) dose adjustment methods to optimize the benefit-risk ratio of the drugs chosen; 4) biomarkers of efficacy, toxicity, treatment discontinuation, relapse, etc. Unfortunately, it is still too often a theoretical concept because of the lack of convenient diagnostic methods or treatments, particularly of drugs corresponding to each subtype of pathology, hence to each patient. Stratified medicine is a component of personalized medicine employing biomarkers and companion diagnostics to target the patients likely to present the best benefit-risk balance for a given active compound. The concept of targeted therapy, mostly used in cancer treatment, relies on the existence of a defined molecular target, involved or not in the pathological process, and/or on the existence of a biomarker able to identify the target population, which should logically be small as compared to the population presenting the disease considered. Targeted therapies and biomarkers represent important stakes for the pharmaceutical industry, in terms of market access, of return on investment and of image among the prescribers. At the same time, they probably represent only the first generation of products resulting from the combination of clinical, pathophysiological and molecular research, i.e. of translational research. © 2015 Société Française de Pharmacologie et de Thérapeutique.
    Thérapie 02/2015; 70(1). DOI:10.2515/therapie/2014231 · 0.40 Impact Factor
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    ABSTRACT: La transplantation utérine (TU) est un traitement potentiel de l’infertilité utérine (IU). La demande concernant ce traitement est toutefois méconnue.
    Gynécologie Obstétrique & Fertilité 01/2015; 43(2). DOI:10.1016/j.gyobfe.2014.12.005 · 0.58 Impact Factor
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    ABSTRACT: To study the demand there is for uterus transplantation (UTx). Recent media coverage of developments in UTx prompted associations of patients with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome and of women suffering from UI to contact us. We sent them anonymous questionnaires devised to sound out their attitude towards UTx and towards adoption and gestational surrogacy (GS). A clinical psychologist also carried out a qualitative discourse analysis. Sixty patients answered the questionnaire. Thirty-eight patients were married or living with a male partner. Seven patients had had a hysterectomy. Fifty-one patients had uterine agenesis. Of the 60 patients, 19 and 21, respectively, had ruled out the option of adoption or GS, and 11 would not envisage either possibility. Thirty-five patients were willing to take part in a clinical study into UTx despite the uncertainty of the outcome and the potential risks involved. Of these 35 volunteers, 23 were in a heterosexual relationship and aged ≤35 years. For women with UI the condition is all the more distressing because there is no medical solution for it. UTx could hold out hope for some of these patients despite the complexity of the procedure and the attendant risks. Because of the feelings of vulnerability engendered by UI, any UTx programme should provide full information to patients and ensure they are carefully screened and selected. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
    Gynécologie Obstétrique & Fertilité 01/2015; · 0.58 Impact Factor
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    Thérapie 01/2015; 70(1). DOI:10.2515/therapie/2014230 · 0.40 Impact Factor
  • T Gauthier · P Piver · N Pichon · M Essig · P Marquet · Y Aubard
    Gynécologie Obstétrique & Fertilité 11/2014; 42(11):741-3. DOI:10.1016/j.gyobfe.2014.09.010 · 0.58 Impact Factor
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    ABSTRACT: BACKGROUND: Although therapeutic drug monitoring has improved the clinical use of immunosuppressive drugs, there is still interpatient variability in efficacy and toxicity that pharmacodynamic monitoring may help to reduce. To select the best biomarkers of tacrolimus pharmacodynamics, we explored the strength and variability of signal transduction and the influence of polymorphisms along the calcineurin pathway. METHODS: Peripheral blood mononuclear cells from 35 healthy volunteers were incubated with tacrolimus (0.1-50 ng/mL) and stimulated ex vivo. Inhibition of NFAT1 (nuclear factor of activated T cells 1) translocation to the nucleus and intracellular expression of interleukin-2 in CD4(+) and CD8(+) T cells and the surface activation marker CD25 in CD3(+) cells were measured by flow cytometry. We sequenced the promoter regions of immunophilins and calcineurin subunits and characterized selected single nucleotide polymorphisms in the genes of the calcineurin pathway with allelic discrimination assays. RESULTS: All responses closely fitted an I/Imax sigmoid model. Large interindividual variability (n = 30) in I-0 and IC50 was found for all biomarkers. Moreover, strong and statistically significant associations were found between tacrolimus pharmacodynamic parameters and polymorphisms in the genes coding cyclophilin A, the calcineurin catalytic subunit alpha isoenzyme, and CD25. CONCLUSIONS: This study demonstrates the consistency and large interindividual variability of signal transduction along the calcineurin pathway, as well as the strong influence of pharmacogenetic polymorphisms in the calcineurin cascade on both the physiological activity of this route and tacrolimus pharmacodynamics. (C) 2014 American Association for Clinical Chemistry
    Clinical Chemistry 08/2014; 60(10). DOI:10.1373/clinchem.2014.223511 · 7.77 Impact Factor
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    ABSTRACT: A time to event model was developed to study predictive factors of immunosuppressive efficacy in renal transplant patients and to investigate longitudinal calcineurin inhibitors (CNIs) and mycophenolic acid (MPA) co-exposures, and patient characteristics as potential covariates. The efficacy endpoint included acute rejection, graft loss and death.Data from 222 patients were analyzed: 23 events were observed in 126 patients receiving cyclosporine against 15 in 96 patients receiving tacrolimus (p=0.61) in the two first years post-transplantation. Each 1mg.h/L increase of MPA AUC was associated with a 4% decreased risk of event (hazard ratio (HR) 95% confidence interval (CI): 0.93-0.99). The onset of cytomegalovirus infection/disease significantly increased this risk (HR=10.9; 95% CI: 6.5-21.7). Within the observed ranges, CNIs exposures were not significantly associated with efficacy (i.e. acute rejection, graft loss and death). This work advocates for the avoidance of unnecessary high CNIs dosing and puts forward new arguments for MPA concentration monitoring.Clinical Pharmacology & Therapeutics (2014); Accepted article preview online 26 June 2014; doi:10.1038/clpt.2014.140.
    Clinical Pharmacology &#38 Therapeutics 06/2014; 96(4). DOI:10.1038/clpt.2014.140 · 7.39 Impact Factor
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    ABSTRACT: In lung transplantation, diverse clinical events may impact patient outcome. In clinical trials comparing intervention strategies, single primary endpoints require large populations, or long study durations, whereas composite endpoints (CEPs) do not take into account the respective impact of their components on patient survival. The objective of this study was to propose consensus recommendations on endpoints for clinical trials on immunosuppressants in lung transplantation. The consensus process was managed through the Internet using the Delphi method. Forty experts were invited by the pilot group with the help of the International Society for Heart and Lung Transplantation and The Transplantation Society. In the first round, a questionnaire was made available to the experts to complete, and the responses were analyzed. In each next round, a new questionnaire was developed from the previous responses and sent to the panel members. Consensus between 17 experts was achieved after five rounds. Two score-type CEPs were defined for immunosuppressive drug efficacy (7 items) and for toxicity (15 items). Death related to graft loss or immunosuppressive drug toxicity was attributed a maximum weight of 100. The weights of the items included in the efficacy and toxicity CEPs ranged between 10 and 80 and between 25 and 70, respectively. The CEP scores are calculated by adding the weights of all the items composing them, without exceeding 90 as long as the patient is alive. This consensus conference proposed two score-type CEPs including relevant endpoints. After validation, they should allow clinical trials with higher statistical power, improving the evaluation of the interventions tested.
    Transplantation 06/2014; 98(12). DOI:10.1097/TP.0000000000000235 · 3.78 Impact Factor
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    ABSTRACT: Purpose The aims of the present study were (1) to investigate the impact of great age on pharmacokinetics of capecitabine and its metabolites and (2) to evaluate the exposure–effect relationship of capecitabine in elderly patients. Methods Data collected from 20 elderly patients (75–92 years old) with breast or colorectal cancer who received oral capecitabine were analyzed. In order to study the old age effect on pharmacokinetics, data collected from two phase I studies involving 40 younger adults (<75 years old) with metastatic cancer who received oral capecitabine were added in the database. The population pharmacokinetic analysis was based on a four-compartment model describing the sequence of capecitabine and three of its metabolites. Results The absorption rate constant was found lower in the oldest patient group (≥75 years) compared with the youngest group, and the constant rate elimination of the 5-fluorouracil metabolite was found decreased over time (i.e., after 2 consecutive weeks of capecitabine administration). This time effect was not found different between the two age groups. In elderly patients, the exposure-safety analysis showed, from the second cycle of chemotherapy, significantly higher median exposures of capecitabine and its metabolites (5′-deoxy-5-fluorocytidine, 5′-deoxy-5-fluorouridine and 5-fluorouracil) in patients who experienced hand-foot syndrome compared with patients who did not. Conclusion This study puts forward new arguments for the treatment of elderly cancer patients who could benefit from capecitabine chemotherapy with acceptable toxicity.
    Cancer Chemotherapy and Pharmacology 06/2014; 73(6). DOI:10.1007/s00280-014-2466-0 · 2.57 Impact Factor
  • Journal of Cystic Fibrosis 06/2014; 13:S107. DOI:10.1016/S1569-1993(14)60371-4 · 3.82 Impact Factor
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    ABSTRACT: Objective: To describe the feasibility of human uterus retrieval after donation after brain death. Design: Single-center, prospective study. Setting: University hospital. Patient(s): Female brain dead donors. Intervention(s): The families of female brain dead donors were informed about consent to uterus donation. A specific organ retrieval procedure was performed. At the end of the procedure the uterus was removed together with the hypogastric vessels, parametria, and vaginal fornix. The tolerance of the uterus to cold ischemia was evaluated with histology and TUNEL reaction up to 24 hours. Main Outcome Measure(s): Rate of uterus donation refusal. Result(s): Between August 1, 2012 and July 31, 2013, seven uteri were retrieved from 14 female multiorgan donors. No refusal to uterus donation occurred. Our surgical protocol did not interfere with vital organ retrieval and was readily accepted by the other transplantation teams. The hypogastric vessels could be preserved in all cases but for one vein loss in the first retrieval. Histology studies did not find major morphologic changes after 24 hours of cold ischemia. Apoptosis was rare. Conclusion(s): Uterus retrieval could be part of a reproducible multiorgan procurement procedure. Uterus donation seems readily accepted. This preliminary study is a necessary step before any transplantation project. (C) 2014 by American Society for Reproductive Medicine.
    Fertility and Sterility 05/2014; 102(2). DOI:10.1016/j.fertnstert.2014.04.016 · 4.59 Impact Factor
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    ABSTRACT: AimsCyclosporine A (CsA) is used in the prophylaxis and treatment of acute and chronic graft-versus-host disease after hematopoietic stem cell (HCT) transplantation. Our objective were to build and compare three independent Bayesian estimators (BE) of CsA area under the curve (AUC) using a limited sampling strategy (LSS), to assist in dose adjustment.Methods The BEs were developed using in parallel: two independent parametric modeling approaches (NONMEM® and iterative two stage (ITS) Bayesian modeling) and the nonparametric adaptive grid method (Pmetrics®). Seventy-two full pharmacokinetic profiles (at pre-dose and 0.33, 0.66, 1, 2, 3, 4, 6, 8 and 12h after dosing) collected from 40 HCT patients given CsA were used to build the pharmacokinetic models, while 15 other profiles (n=7) were kept for validation. For each BE, AUCs estimated using the full profiles were compared to AUCs estimated using 3 samples.ResultsThe pharmacokinetic profiles were well fitted using a two-compartment model with first-order elimination, combined with a gamma function for the absorption phase with ITS and Pmetrics or an Erlang distribution with NONMEM. The derived BE based on a C0-C1h-C4h sampling schedule (best LSS) accurately estimated CsA AUC0-12h in the validation group (n=15; NONMEM: bias (mean ± SD)/RMSE=2.05%±13.31%/13.02%; ITS: 4.61%±10.56%/11.20%; Pmetrics: 0.30%±10.12%/10.47%). The dose chosen confronting the 3 results led to a pertinent dose proposal.ConclusionsBEs developed were all able to predict cyclosporine AUC0-12h in HCT patients using only three blood with minimal bias and may be combined to increase the reliability of CsA dose adjustment in routine.
    British Journal of Clinical Pharmacology 04/2014; 78(4). DOI:10.1111/bcp.12394 · 3.69 Impact Factor
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    ABSTRACT: AimsThe use of mycophenolate mofetil (MMF) in children with Systemic Lupus Erythematosus (SLE) 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 describe mycophenolic acid (MPA; the active moiety of MMF) pharmacokinetics; (ii) to develop a Bayesian estimator (BE) allowing the determination AUC (Area under the curve) from a limited number of blood samples; and (ii) to explore the relationships between exposure indices to MPA and the clinical status in children with SLE.Methods This was a retrospective study including 36 children with SLE, extracted from the expert system ISBA, for whom full- pharmacokinetic profiles of MPA were collected together with clinical data. A pharmacokinetic model and a BE were developed using an iterative two-stage Bayesian approach. ROC curve analyses and logistic regressions was used to investigate the association of exposure and active disease.ResultsA pharmacokinetic model and a BE were developed that allowed good AUC estimation performance (bias±SD=-0.02±0.15). ROC curve analyses showed that AUC/dose<0.06 and AUC<44 mg*h/L were associated with a good sensitivity and specificity for active disease (78%/94% and 94%/56% respectively). When introduced in a logistic regression model, AUC<44 mg.h/L and AUC/dose<0.06 were associated with an increased risk of active disease (OR=21.2[2.3-196.1], p=0.007; and OR [95%CI]=59.5[5.9-588.2], p=0.0005 respectively).Conclusions The developed pharmacokinetics BE could be used to prospectively test the interest of MPA monitoring for limiting relapse of the disease or its progression.
    British Journal of Clinical Pharmacology 04/2014; 78(4). DOI:10.1111/bcp.12392 · 3.69 Impact Factor
  • The Journal of Heart and Lung Transplantation 04/2014; 33(4):S280-S281. DOI:10.1016/j.healun.2014.01.747 · 5.61 Impact Factor
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    ABSTRACT: Different associations between single nucleotide polymorphisms (SNPs) in cellular target, metabolism enzymes or transport proteins, and biopsy-proven acute rejection (BPAR) or adverse events have been reported in transplant patients receiving mycophenolate mofetil. This work aimed to study these in patients on enteric-coated mycophenolate sodium (EC-MPS). The study included 189 renal transplant patients from the DOMINOS trial. Fifteen SNPs in IMPDH2, IMPDH1, ABCC2, SLCO1B3, UGT1A8, UGT1A9, UGT2B7, CYP2C8, HUS1, and IL12A were genotyped in all patients. Associations between SNPs and the first event of BPAR or diarrhea were investigated using multivariate logistic regressions. Associations between SNPs and leukopenia or anemia at nine different visits between days 0 and 190 after transplantation were studied using time-dependent Cox proportional hazards regression models. Multivariate analyses showed that the CYP2C8 rs11572076 wild-type genotype was associated significantly with a lower risk of leukopenia [GG vs. GA: hazard ratio (95% confidence interval) 0.14 (0.03, 0.59), P=0.00783]. Higher EC-MPS doses and the UGT2B7 c.-840 G>A variant allele were associated with an increased risk of anemia [EC-MPS per unit dose increase: 1.004 (1.003, 1.005), P<0.0001; UGT2B7 GA vs. AA: 1.65 (1.12, 2.43), P=0.01043; GG vs. AA: 1.88 (1.23, 2.88), P=0.00343]. However, no significant association was found between any of the SNPs studied and diarrhea or BPAR. Two pharmacogenetic associations reported previously with mycophenolate mofetil were found in a population of 189 renal transplant patients treated with EC-MPS.
    Pharmacogenetics and Genomics 03/2014; 24. DOI:10.1097/FPC.0000000000000045 · 3.45 Impact Factor

Publication Stats

5k Citations
841.97 Total Impact Points

Institutions

  • 1997–2015
    • University of Limoges
      • Faculté de Médecine
      Limages, Limousin, France
  • 2013–2014
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2007–2013
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2011
    • Columbia University
      New York, New York, United States
  • 2002–2008
    • Centre Hospitalier Universitaire de Limoges
      Limages, Limousin, France
  • 2005
    • University of Tours
      Tours, Centre, France
  • 1990
    • Centre Hospitalier Régional Universitaire de Lille
      Lille, Nord-Pas-de-Calais, France