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1. Adaptative Strategy of Immunosuppressive Drugs Dosage Adjustments When Combined With Nirmatrelvir/Ritonavir in Solid Organ Transplant Recipients With COVID-19

Author

Lidvine Boland, Arnaud Devresse, Caroline Monchaud, Sébastien Briol, Stéphanie Belaiche, Baptiste Giguet, Lionel Couzi, Olivier Thaunat, Laure Esposito, Magdalena Meszaros, Ana Roussoulieres, Vincent Haufroid, Yannick Le Meur, and Florian Lemaitre

Subjects
drug-drug interactions, drug monitoring, nirmatrelvir/ritonavir, pharmacokinetic modelling, tacrolimus, Specialties of internal medicine, RC581-951
Abstract

Nirmatrelvir/ritonavir is a promising option for preventing severe COVID-19 in solid organ transplant recipients with SARS-CoV-2 infection. However, concerns have arisen regarding potential drug interactions with calcineurin inhibitors (CNI). This two-phase multicentre retrospective study, involving 113 patients on tacrolimus and 13 on cyclosporine A, aimed to assess the feasibility and outcomes of recommendations issued by The French societies of transplantation (SFT) and pharmacology (SFPT) for CNI management in this context. The study first evaluated adherence to recommendations, CNI exposure, and clinical outcomes. Notably, 96.5% of patients on tacrolimus adhered to the recommendations, maintaining stable tacrolimus trough concentrations (C0) during nirmatrelvir/ritonavir treatment. After reintroduction, most patients experienced increased C0, with 42.9% surpassing 15 ng/mL, including three patients exceeding 40 ng/mL. Similar trends were observed in cyclosporine A patients, with no COVID-19-related hospitalizations. Moreover, data from 22 patients were used to refine the reintroduction strategy. Modelling analyses suggested reintroducing tacrolimus at 50% of the initial dose on day 8, and then at 100% from day 9 as the optimal approach. In conclusion, the current strategy effectively maintains consistent tacrolimus exposure during nirmatrelvir/ritonavir treatment, and a stepwise reintroduction of tacrolimus may be better suited to the low CYP3A recovery.

Published
2024
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2. Transient Lactic Acidosis and Elevation of Transaminases after the Introduction of Remdesivir in a Patient with Acute Kidney Injury

Author

Elise André, Florian Lemaitre, Marie-Clémence Verdier, Vincent Haufroid, João Pinto Pereira, and Philippe Hantson

Subjects
Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

A 56-year-old woman was transferred to the intensive care unit (ICU) two days after an allogeneic stem cell transplantation (ASCT) when she presented acute respiratory distress due to the relapse of a SARS-CoV-2 infection. Following that, she received two intravenous doses of 100 mg remdesivir. Subsequently, the patient developed multiple instances of diarrhea, progressing to oliguria and acute kidney injury, necessitating continuous venovenous hemofiltration (CVVH). Despite the absence of signs of hypoxemia or cardiocirculatory failure requiring vasopressor intervention, a progressive lactic acidosis emerged. Two days after the onset of lactic acidosis, a significant rise in aminotransferases and lactate dehydrogenase occurred, in the absence of encephalopathy and coagulation disorders. Remdesivir therapy had been interrupted upon the initial signs of lactic acidosis. Despite an improvement in liver function tests and lactic acidosis, the patient’s condition deteriorated, ultimately leading to her demise on day 29 due to newly arising hematological complications.

Published
2024
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3. The need for area under the curve measurements in the field of ganciclovir therapeutic drug monitoring in children: a case report

Author

Xavier Duval, Florian Lemaitre, Sophie Pertuisel, Jamie Probert, Virginie Gandemer, Marie-Clémence Verdier, and Camille Tron

Subjects
Therapeutic drug monitoring, Antiviral therapy, Cytomegalovirus (CMV), Pharmacokinetics, Hematopoietic stem cell transplantation, Pediatrics, Infectious and parasitic diseases, RC109-216
Abstract

Abstract Background Ganciclovir pharmacokinetics is characterized by a high variability in drug exposure. Usually, monitoring of ganciclovir exposure is performed by measuring trough concentration. However, due to the specificity of pediatric pharmacokinetics, trough concentration measurements may not be a relevant surrogate of ganciclovir exposure. Area under the curve of concentration (AUC) may be a more appropriate biomarker. Case presentation We report the case of 3.6-year-old boy with Emberger syndrome with a cytomegalovirus reactivation occurring after allogenic hematopoietic stem cell transplantation. After a few days of treatment with intravenous ganciclovir, sub-therapeutic trough ganciclovir concentrations were measured (

Published
2021
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4. Therapeutic drug monitoring in oncology - What’s out there: A bibliometric evaluation on the topic

Author

Jana Stojanova, Jane E. Carland, Bridin Murnion, Vincent Seah, Jim Siderov, and Florian Lemaitre

Subjects
therapeutic drug monitoring, pharmacokinetic, antineoplastic agents, kinase inhibitors, bibliometric analysis, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Pharmacological therapy is the mainstay of treatment for cancer patients. Despite wide interpatient variability in systemic drug concentrations for numerous antineoplastics, dosing based on body size remains the predominant approach. Therapeutic drug monitoring (TDM) is used for few antineoplastics in specific scenarios. We conducted a rapid bibliometric evaluation of TDM in oncology to capture a snapshot of research in this area over time and explore topics that reflect development in the field. Reports with the composite, indexed term ‘therapeutic drug monitoring’ in the title and abstract were extracted from MEDLINE (inception to August 2021). Reports related to applications in cancer were selected for inclusion and were tagged by study design, antineoplastic drugs and concepts related to TDM. We present a timeline from 1980 to the present indicating the year of first report of antineoplastic agents and key terms. The reports in our sample primarily reflected development and validation of analytical methods with few relating to clinical outcomes to support implementation. Our work emphasises evidence gaps that may contribute to poor uptake of TDM in oncology.

Published
2022
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5. Amoxicillin-Induced Neurotoxicity: Contribution of a Healthcare Data Warehouse to the Determination of a Toxic Concentration Threshold

Author

Sébastien Lalanne, Guillaume Bouzillé, Camille Tron, Matthieu Revest, Elisabeth Polard, Eric Bellissant, Marie-Clémence Verdier, and Florian Lemaitre

Subjects
amoxicillin, neurotoxicity, concentrations, Therapeutics. Pharmacology, RM1-950
Abstract

Background: Amoxicillin (AMX)-induced neurotoxicity is well described and may be associated with AMX overexposure. No neurotoxic concentration threshold has been determined thus far. A better knowledge of maximum tolerable AMX concentrations is of importance to improve the safety of high doses of AMX. Methods: We conducted a retrospective study using the local hospital data warehouse EhOP® to generate a specific query related to AMX neurotoxicity symptomatology. All patient medical reports containing a mention of neurotoxicity clinical symptoms coupled with AMX plasma concentration measurements were explored. Patients were classified into two groups according to the imputability of AMX in the onset of their neurotoxicity, on the basis of chronological and semiological criteria. A receiver-operating characteristic curve was performed to identify an AMX neurotoxic steady-state concentration (Css) threshold. Results: The query identified 101 patients among 2054 patients benefiting from AMX TDM. Patients received a median daily dose of 9 g AMX, with a median creatinine clearance of 51 mL/min. A total of 17 of the 101 patients exhibited neurotoxicity attributed to AMX. The mean Css was higher for patients with neurotoxicity attributed to AMX (118 ± 62 mg/L) than those without 74 ± 48 mg/L (p = 0.002). A threshold AMX concentration of 109.7 mg/L predicted the occurrence of neurotoxicity. Conclusions: This study identified, for the first time, an AMX Css threshold of 109.7 mg/L associated with an excess risk of neurotoxicity. This approach needs to be confirmed by a prospective study with systematic neurological evaluation and TDM.

Published
2023
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6. Optimization of the treatment with beta-lactam antibiotics in critically ill patients—guidelines from the French Society of Pharmacology and Therapeutics (Société Française de Pharmacologie et Thérapeutique—SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (Société Française d’Anesthésie et Réanimation—SFAR)

Author

Romain Guilhaumou, Sihem Benaboud, Youssef Bennis, Claire Dahyot-Fizelier, Eric Dailly, Peggy Gandia, Sylvain Goutelle, Sandrine Lefeuvre, Nicolas Mongardon, Claire Roger, Julien Scala-Bertola, Florian Lemaitre, and Marc Garnier

Subjects
Beta-lactam antibiotics, Pharmacokinetics, Pharmacodynamics, Continuous infusion, Dosage, Therapeutic drug monitoring, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background Beta-lactam antibiotics (βLA) are the most commonly used antibiotics in the intensive care unit (ICU). ICU patients present many pathophysiological features that cause pharmacokinetic (PK) and pharmacodynamic (PD) specificities, leading to the risk of underdosage. The French Society of Pharmacology and Therapeutics (SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (SFAR) have joined forces to provide guidelines on the optimization of beta-lactam treatment in ICU patients. Methods A consensus committee of 18 experts from the two societies had the mission of producing these guidelines. The entire process was conducted independently of any industry funding. A list of questions formulated according to the PICO model (Population, Intervention, Comparison, and Outcomes) was drawn-up by the experts. Then, two bibliographic experts analysed the literature published since January 2000 using predefined keywords according to PRISMA recommendations. The quality of the data identified from the literature was assessed using the GRADE® methodology. Due to the lack of powerful studies having used mortality as main judgement criteria, it was decided, before drafting the recommendations, to formulate only “optional” recommendations. Results After two rounds of rating and one amendment, a strong agreement was reached by the SFPT-SFAR guideline panel for 21 optional recommendations and a recapitulative algorithm for care covering four areas: (i) pharmacokinetic variability, (ii) PK-PD relationship, (iii) administration modalities, and (iv) therapeutic drug monitoring (TDM). The most important recommendations regarding βLA administration in ICU patients concerned (i) the consideration of the many sources of PK variability in this population; (ii) the definition of free plasma concentration between four and eight times the Minimal Inhibitory Concentration (MIC) of the causative bacteria for 100% of the dosing interval as PK-PD target to maximize bacteriological and clinical responses; (iii) the use of continuous or prolonged administration of βLA in the most severe patients, in case of high MIC bacteria and in case of lower respiratory tract infection to improve clinical cure; and (iv) the use of TDM to improve PK-PD target achievement. Conclusions The experts strongly suggest the use of personalized dosing, continuous or prolonged infusion and therapeutic drug monitoring when administering βLA in critically ill patients.

Published
2019
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7. Pharmacogenetic-Whole blood and intracellular pharmacokinetic-Pharmacodynamic (PG-PK2-PD) relationship of tacrolimus in liver transplant recipients.

Author

Camille Tron, Jean-Baptiste Woillard, Pauline Houssel-Debry, Véronique David, Caroline Jezequel, Michel Rayar, David Balakirouchenane, Benoit Blanchet, Jean Debord, Antoine Petitcollin, Mickaël Roussel, Marie-Clémence Verdier, Eric Bellissant, and Florian Lemaitre

Subjects
Medicine, Science
Abstract

Tacrolimus (TAC) is the cornerstone of immunosuppressive therapy in liver transplantation. This study aimed at elucidating the interplay between pharmacogenetic determinants of TAC whole blood and intracellular exposures as well as the pharmacokinetic-pharmacodynamic relationship of TAC in both compartments. Complete pharmacokinetic profiles (Predose, and 20 min, 40 min, 1h, 2h, 3h, 4h, 6h, 8h, 12h post drug intake) of twice daily TAC in whole blood and peripheral blood mononuclear cells (PBMC) were collected in 32 liver transplanted patients in the first ten days post transplantation. A non-parametric population pharmacokinetic model was applied to explore TAC pharmacokinetics in blood and PBMC. Concurrently, calcineurin activity was measured in PBMC. Influence of donor and recipient genetic polymorphisms of ABCB1, CYP3A4 and CYP3A5 on TAC exposure was assessed. Recipient ABCB1 polymorphisms 1199G>A could influence TAC whole blood and intracellular exposure (p

Published
2020
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8. The Role of Intra-Patient Variability of Tacrolimus Drug Concentrations in Solid Organ Transplantation: A Focus on Liver, Heart, Lung and Pancreas

Author

Gwendal Coste and Florian Lemaitre

Subjects
intra-patient variability, drug, monitoring, pharmacokinetics, tacrolimus, liver transplantation, Pharmacy and materia medica, RS1-441
Abstract

Tacrolimus, the keystone immunosuppressive drug administered after solid organ transplantation, presents a narrow therapeutic index and wide inter- and intra-patient pharmacokinetic variability (IPV). The latter has been fairly studied in kidney transplantation, where it could impact outcomes. However, literature about other transplanted organ recipients remains inconclusive. This review aimed at summarizing the evidence about the IPV of tacrolimus concentrations outside of the scope of kidney transplantation. First, factors influencing IPV will be presented. Then, the potential of IPV as a biomarker predictive of graft outcomes will be discussed in liver, heart, lung and pancreas transplantation. Lastly, strategies to reduce IPV will be reviewed, with the ultimate objective being ready-to-implement solutions in clinical practice by transplantation professionals.

Published
2022
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20. Contribution of voriconazole N‐oxide plasma concentration measurements to voriconazole therapeutic drug monitoring in patients with invasive fungal infection

Author

Christelle Boglione‐Kerrien, Jeff Morcet, Lucie‐Marie Scailteux, François Bénézit, Christophe Camus, Jean‐Baptiste Mear, Jean‐Pierre Gangneux, Eric Bellissant, Camille Tron, Marie‐Clémence Verdier, Florian Lemaitre, CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and École des Hautes Études en Santé Publique [EHESP] (EHESP)

Subjects
phenotyping, Infectious Diseases, pharmacokinetic variability, metabolic ratio, therapeutic drug monitoring, voriconazole N-oxide, [SDV]Life Sciences [q-bio], voriconazole, Dermatology, General Medicine, Antifungal, invasive fungal infection
Abstract

International audience; BACKGROUND: Voriconazole (VRC), a widely used triazole antifungal, exhibits significant inter- and intra-individual pharmacokinetic variability. The main metabolite voriconazole N-oxide (NOX) can provide information on the patient’s drug metabolism capacity. OBJECTIVES: Our objectives were to implement routine measurement of NOX concentrations and to describe the metabolic ratio (MR), and the contribution of the MR to VRC therapeutic drug monitoring (TDM) by proposing a suggested dosage-adjustment algorithm. PATIENTS AND METHODS: Sixty-one patients treated with VRC were prospectively included in the study, and VRC and NOX levels were assayed by LC-MS/MS. A mixed logistic model on repeated measures was implemented to analyze risk factors for the patient’s concentration to be outside the therapeutic range. RESULTS: Based on 225 measurements, the median and interquartile range were 2.4 μg/mL (1.2; 4.2), 2.1 μg/mL (1.5; 3.0), and 1.0 (0.6; 1.9) for VRC, NOX, and the MR, respectively. VRC C(min) 1.15 and

Published
2023
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23. TDM Is Alive and Kicking!

Author

Florian Lemaitre, Dennis A. Hesselink, Internal Medicine, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], and Erasmus University Medical Center [Rotterdam] (Erasmus MC)

Subjects
Pharmacology, [SDV]Life Sciences [q-bio], Pharmacology (medical)
Abstract

International audience

Published
2023
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24. Pharmaco-toxico : a very bad trip ?

Author

Mehdi Oualha, Nicolas Tournier, Sébastien Préau, Nicolas Grégoire, Guillaume Voiriot, Alexandre Pierre, Jérémie Joffre, Alexandre Gaudet, Youenn Jouan, Hatem Kallel, Peter Radermacher, Benjamine Sarton, Laure Stiel, Nicolas Bréchot, Florian Lemaitre, Dominique Vodovar, De la SRLF CRT, and Partenaire SFPT

Subjects
Emergency Medicine, Emergency Nursing
Abstract

La septième édition du séminaire annuel de la Commission de la Recherche Translationnelle de la SRLF a permis un nouveau moment d’échange unique entre chercheurs et cliniciens autour des dernières données issues de la recherche translationnelle en pharmaco-toxicologie. Les études pharmacologiques et toxicologiques, chez les patients en situation critique, se sont longtemps résumées à des mesures de concentrations plasmatiques. Leur interprétation clinique étaient souvent limitées par les méthodes de dosage elles-mêmes, mais aussi par les différents mécanismes conduisant à une variation individuelle de l’absorption, de la distribution, du métabolisme ou de l’élimination des médicaments ou du toxique. Les évolutions récentes des méthodes de dosage, la meilleure compréhension des mécanismes de diffusion et de clairance des médicaments/toxiques dans les tissus ainsi que l’utilisation de techniques innovantes basées sur l’imagerie pharmacologique et les modélisations pharmacocinétiques, permettent une meilleure interprétation des dosages mais aussi de prédire des échecs ou la survenue d’une toxicité en lien avec un médicament ou un toxique. Les actes du séminaire ont été rédigés par les membres de la Commission de la Recherche Translationnelle de la SRLF et validés par les orateurs.

Published
2022
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25. Pharmacokinetic Interactions Between Abiraterone, Apalutamide, Darolutamide or Enzalutamide and Antithrombotic Drugs: Prediction of Clinical Events and Review of Pharmacological Information

Author

François Boujonnier, Florian Lemaitre, Lucie-Marie Scailteux, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), CHU Pontchaillou [Rennes], and This study was supported by the French National Agency for Drug Safety (Agence Nationale de Sécurité du Médicament) as part of the ‘AANETH’ project.

Subjects
Pharmacology, Antithrombotic, [SDV]Life Sciences [q-bio], Apalutamide, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Darolutamide enzalutamide, Pharmacology (medical), CYP450, General Medicine, P-glycoprotein, Cardiology and Cardiovascular Medicine, Abiraterone, Drug-drug interaction
Abstract

International audience; PURPOSE: Abiraterone, apalutamide, darolutamide and enzalutamide are second-generation hormone therapies used for advanced prostate cancer; the majority of patients receiving these treatments are elderly, poly-medicated patients. Since their first market authorizations, their pharmacokinetic (PK) characteristics are increasingly well known. A potential risk of drug-drug interaction (DDI), especially with cardiovascular drugs, needs to be considered. In the case of antithrombotics, treatment imbalance can lead to severe consequences. OBJECTIVES: To describe PK profiles of hormone therapies and antithrombotics and to predict DDIs and potentially related clinical events. METHODS: PK profiles (CYP450 and P-gp substrate, inducer or inhibitor) are described by cross-referencing data sources (summary of product characteristics, European public assessment reports, PubMed database, Micromedex(®), etc.); a description of the potential interactions with anti-cancer drugs for each DDI and related clinical events is provided. We discuss management recommendations, including those set out in international guidelines. RESULTS: Antithrombotics are mainly metabolized by CYP 2C9, 2C19 or 3A4. For abiraterone (CYP 2C8, 2D6 inhibitor) and darolutamide (CYP 3A4 inducer), no interaction was identified with antithrombotics. For apalutamide (CYP 2C9, 2C19, 3A4 and P-gp inducer) and enzalutamide (CYP 2C9, 2C19, 3A4 inducer and P-gp inhibitor), several PK interactions were identified with antithrombotics, which could lead to various clinical events (haemorrhage or thromboembolism). CONCLUSION: Numerous interactions are expected between enzalutamide or apalutamide and antithrombotics, for which management should be deployed on a case-by-case basis. PK and pharmaco-epidemiological studies could shed light on whether or not there are clinically significant events related to DDIs with antithrombotics.

Published
2023
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26. Antimicrobial Exposure: Do Not Forget the Patient's Condition Beneath the Extracorporeal Membrane Oxygenation Support!

Author

Pierre Fillatre, Florian Lemaitre, Nicolas Nesseler, François Legay, Nicolas Massart, CHU de Saint-Brieuc, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), and CHU Pontchaillou [Rennes]

Subjects
Pulmonary and Respiratory Medicine, [SDV]Life Sciences [q-bio], Critical Care and Intensive Care Medicine
Published
2023
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27. Auteurs de la 5e édition

Author

Benoît, Allenet, primary, Thomas, Aparicio, additional, Xavier, Armoiry, additional, Nathalie, Asseray, additional, Gilles, Aulagner, additional, Astrid, Bacle, additional, Jean-Didier, Bardet, additional, Aurélie, Barrail-Tran, additional, Marie, Batisse, additional, Magalie, Baudrant, additional, Pierrick, Bedouch, additional, Yannick, Béjot, additional, Johnny, Beney, additional, Lise, Bernard, additional, Florian, Bernard-Arnoux, additional, Philippe, Bertin, additional, Marie-Anne, Bertrand, additional, Guillaume, Binson, additional, Thomas, Bochaton, additional, Laurence, Bonhomme-Faivre, additional, Pascal, Bonnabry, additional, Aurélie, Bonvin, additional, Roselyne, Boulieu, additional, Mathieu, Boulin, additional, Elsa, Bourcier, additional, Olivier, Bourdon, additional, Amélie, Boursier, additional, Michel, Brazier, additional, Valentine, Bréant, additional, Dominique, Breilh, additional, Françoise, Brion, additional, Olivier, Bugnon, additional, Cécile, Burgos Leon, additional, Marion, Buyse, additional, Jean, Calop, additional, Nathalie, Calop, additional, Pauline, Calvet, additional, Aude, Capelle, additional, Philippe, Caron, additional, Audrey, Castet-Nicolas, additional, Jean-Louis, Cazin, additional, Philippe, Cestac, additional, Sébastien, Chanoine, additional, Claire, Chapuis, additional, Alexandre, Charmillon, additional, Fiona, Chautant, additional, Hacène, Chekroud, additional, Anne-Laure, Clairet, additional, Chantal, Csajka, additional, Béatrice, Demoré, additional, François, Derimay, additional, Jean-Luc, Diehl, additional, Thierry, Dine, additional, Xavier, Dode, additional, Virginie, Dousset, additional, Antoine, Dupuis, additional, Raphaël, Duval, additional, Philippe, Fagnoni, additional, Patrice, Fardellone, additional, Christine, Fernandez, additional, Alexandra, Fournel, additional, Blandine, Gérard, additional, Stéphane, Gibaud, additional, François, Goehringer, additional, Marion, Grare, additional, Jean, Grellet, additional, Pauline, Gueneau, additional, Bertrand, Guignard, additional, Aline, Hajj, additional, Souheil, Hallit, additional, Sylvie, Hansel-Esteller, additional, Raoul, Herbrecht, additional, Patrick, Hindlet, additional, Stéphane, Honoré, additional, Jean-François, Huon, additional, Audrey, Janoly-Dumenil, additional, Jeremy, Jost, additional, Pierre, Jouanny, additional, Jean-Daniel, Kaiser, additional, Laurent, Kodjikian, additional, Diane, Korb, additional, Virginie, Korb-Savoldelli, additional, Charlotte, Laborde, additional, Magali, Larger, additional, Gwenaël, Le Moal, additional, Paul, Le Turnier, additional, François, Lebargy, additional, Audrey, Lehmann, additional, Florian, Lemaitre, additional, Joël, Leroy, additional, Dominique, Levêque, additional, Samuel, Limat, additional, Louise, Malet, additional, Marine, Manuelli, additional, Nicolas, Marie, additional, Aurélien, Mary, additional, Martial, Mercié, additional, Florence, Meyer, additional, Frédéric, Mille, additional, Pauline, Mondoloni, additional, Céline, Mongaret Kossmann, additional, Tess, Monnot, additional, David, Montani, additional, Jean-François, Mornex, additional, Philippe, Moulin, additional, Florian, Naudet, additional, Dominique, Navas, additional, Virginie, Nerich, additional, Yasmine, Nivoix, additional, Hélène, Ottomani, additional, Arnaud, Pagès, additional, Hélène, Peyrière, additional, Isabelle, Pin, additional, Christophe, Pison, additional, Stéphane, Ploteau, additional, Laudine, Potie, additional, Sophie, Potin, additional, Sonia, Prot-Labarthe, additional, Florent, Puisset, additional, Céline, Pulcini, additional, Pauline, Quillet, additional, Alain, Ragon, additional, Stéphanie, Ragot, additional, Voa, Ratsimbazafy, additional, Philippe, Reix, additional, Pierre, Renaudin, additional, Anne, Rouault, additional, Laure, Rouch, additional, Matthieu, Roustit, additional, Brigitte, Sabatier, additional, Hala, Sacre, additional, Pascale, Salameh, additional, Brigitte, Sallerin, additional, Valérie, Sautou, additional, Pascale, Sebahoun, additional, Laurent, Sebbag, additional, Igor, Tauveron, additional, Aurélie, Terrier-Lenglet, additional, Camille, Tron, additional, Hervé, Trout, additional, Geneviève, Ubeaud-Séquier, additional, Nicolas, Venisse, additional, Sandrine, Venisse, additional, Pascale, Vergne-Salle, additional, and Sandra, Vukusic, additional

Published
2018
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29. Nirmatrelvir/ritonavir (Paxlovid®): French pharmacovigilance survey 2022

Author

Kevin Bihan, Lorène Lipszyc, Florian Lemaitre, Anne Dautriche, Sophie Fédrizzi, Marina Atzenhoffer, Aurélie Vitores, Annabelle Page, Bénédicte Lebrun-Vignes, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Henri Mondor [Créteil], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Service Hospitalo-Universitaire de Pharmaco-Toxicologie [Bron] (CEIP), Hospices Civils de Lyon (HCL)-Groupement Hospitalier Est [Bron], Agence nationale de sécurité du médicament et des produits de santé [Saint-Denis] (ANSM), and None

Subjects
Drug drug interaction, Pharmacovigilance, Nirmatrelvir/ritonavir, [SDV]Life Sciences [q-bio], [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, COVID-19, Pharmacology (medical)
Abstract

International audience; INTRODUCTION: Nirmatrelvir/ritonavir (Paxlovid®) is currently one of the few therapeutic options for coronavirus disease 2019 (COVID-19) curative treatment in non-oxygen-requiring adult patients at-high risk of progressing to severe disease. This recently approved boosted antiviral therapy presents a significant risk of drug-drug interactions (DDI). As part of the enhanced surveillance program in France for COVID-19 drugs and vaccines, the French national pharmacovigilance database (BNPV [base nationale de pharmacovigilance]) was queried in order to better characterize the drug safety profile, with a special focus on DDI. The aim of the study was to describe the adverse drug reactions reported through the BNPV. METHOD: All nirmatrelvir/ritonavir reports validated in the BNPV from the first authorization in France (January, 20th 2022) to December, 3rd 2022 (date of the query) were considered. An analysis of the scientific literature (PubMed®) and from the WHO pharmacovigilance database (Vigibase) was also performed. RESULTS: Over this period (11 months), 228 reports (40% of serious reports) were registered with a sex ratio of 1.9 female/1 male and a mean age of 66 years old. DDI reports account for more than 13% of reports (n=30) and were mainly related to immunosuppressive drugs overexposure (n=16). A total of 10/228 reports with fatal outcomes were reported in complex clinical settings. The main reported unexpected adverse drug reaction (ADRs) were high blood pressure (n=7), confusion (n=5), acute kidney injuries (AKI, n=7) and various skin reactions (n=22). Apart from situations of disease recurrence (not found in this analysis), data from Pubmed® and Vigibase also reported the above-mentioned events of interest. CONCLUSION: Overall, this analysis shows that nirmatrelvir/ritonavir safety profile was conform to current summary of product characteristics (SmPC). The main concern was the risk of DDI. Therefore, SmPC and expert recommendations should be systematically consulted before initiation of this antiviral, which is particularly indicated in polypharmacy patients. A case-by-case multidisciplinary approach including a clinical pharmacologist is required in these complex situations. Blood pressure elevation, confusion, cutaneous reactions and AKIs were the main unexpected ADRs of interest to follow, but need to be confirmed with a qualitative approach over time and new reports.

Published
2023
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30. A pharmacist-led intervention to improve kidney transplant recipient outcomes and identify patients at risk of highly variable trough tacrolimus levels: a cohort study

Author

Roxane Lhermitte, Brendan Le Daré, Florian Laval, Florian Lemaitre, Barbara Troussier, Marie-Pascale Morin, Cécile Vigneau, Jonathan M Chemouny, Astrid Bacle, CHU Pontchaillou [Rennes], Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and École des Hautes Études en Santé Publique [EHESP] (EHESP)

Subjects
PHARMACY SERVICE, Evidence-Based Medicine, Professional Competence, TRANSPLANTATION, [SDV]Life Sciences [q-bio], Clinical Competence, General Pharmacology, Toxicology and Pharmaceutics, Drug Monitoring, Kidney Transplantation, HOSPITAL, NEPHROLOGY
Abstract

International audience; ObjectivesGiven the positive impact of appropriate medication management on graft outcome and therefore of patient survival and graft function, the pharmacist's role in the kidney transplantation team has evolved over recent decades. The primary objective of this study was to determine whether pharmacist-led intervention after kidney transplantation is associated with a lower graft rejection rate and intra-patient variation in tacrolimus trough concentrations (C-min). The study's secondary objective was to develop a questionnaire to identify patients at risk for highly variable C-min. MethodsWe retrospectively analysed kidney transplant recipients at Rennes University Hospital (France) between January 2013 and December 2020. Patients who received pharmacist-led education (intervention group, n=139) were compared with patients who did not (control group, n=131), according to graft survival at 1 year post-transplant, coefficient of variation (%CV) for the tacrolimus C-min, age, sex, length of hospital stay post-transplantation, body mass index, and Charlson Comorbidity Index. In the intervention group, a questionnaire assessing patient knowledge was introduced to compare scores with the %CV. ResultsIn the intervention group, 1 year post-transplant graft survival was higher (95.7% vs 88.5%, p=0.0289) and patients had fewer variabilities in C-min. The %CV was correlated with questionnaire scores (r=-0.9758, p

Published
2023
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31. Comment on: Population pharmacokinetics of the rilpivirine long-acting formulation after intramuscular dosing in healthy subjects and people living with HIV

Author

Sihem Benaboud, Caroline Solas, Stephane Bouchet, Matthieu Gregoire, Florian Lemaitre, Nicolas Venisse, Minh Patrick Lê, Patrice Muret, Francois Parant, Nadege Neant, Sana Boujafaar, Jennifer Lagoutte-Renosi, Rodolphe Garraffo, Gilles Peytavin, Pharmacologie et évaluations thérapeutiques chez l'enfant et la femme enceinte (URP_7323), Université Paris Cité (UPCité), Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cibles et Médicaments des Infections et de l'Immunité (IICiMed), Nantes Université - UFR des Sciences Pharmaceutiques et Biologiques (Nantes Univ - UFR Pharmacie), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire de Nice (CHU Nice), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord

Subjects
Pharmacology, Microbiology (medical), Infectious Diseases, [SDV]Life Sciences [q-bio], Pharmacology (medical)
Abstract

International audience

Published
2023
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32. Lactic acidosis after allogeneic haematopoietic stem cell transplantation potentially related to letermovir

Author

Bérénice Manczak, Marie‐Clémence Verdier, Joseph P. Dewulf, Florian Lemaitre, Vincent Haufroid, Philippe Hantson, UCL - SSS/IREC/LTAP - Louvain Centre for Toxicology and Applied Pharmacology, UCL - SSS/IREC/MEDA - Pôle de médecine aiguë, UCL - (SLuc) Service de biochimie médicale, UCL - (SLuc) Service d'anesthésiologie, UCL - (SLuc) Service de soins intensifs, Cliniques Universitaires Saint-Luc [Bruxelles], CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), and Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Pharmacology, Liver-Specific Organic Anion Transporter 1, [SDV]Life Sciences [q-bio], haematopoietic stem cell transplantation, Hematopoietic Stem Cell Transplantation, Middle Aged, Acetates, Antiviral Agents, letermovir, SLCO1B1 gene polymorphism, lactic acidosis, Cytomegalovirus Infections, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Humans, Pharmacology (medical), Female, Acidosis, Lactic, pharmacokinetics
Abstract

International audience; A 53-year-old woman with a history of acute myeloid leukaemia received a second allogeneic haematopoietic stem cell transplant and was prescribed, among other medications, acyclovir and letermovir (480-mg daily oral dose) for prophylaxis of, respectively, herpes simplex and cytomegalovirus infection. The patient was admitted in the intensive care unit for dyspnoea and oliguria. Laboratory investigations revealed acute kidney injury but also a severe and progressive lactic acidosis. Liver function tests were within normal range. The combination of lactic acidosis, hypoglycaemia and acylcarnitine profile in plasma raised the suspicion of mitochondrial toxicity. Letermovir therapy was interrupted, and determination of plasma letermovir pharmacokinetics revealed a prolonged terminal half-life (38.7 h) that was not significantly influenced by continuous venovenous haemofiltration. Exploration for genetic polymorphisms revealed that the patient was SLCO1B1*5/*15 (c.521T>C homozygous carrier and c.388A>G heterozygous carrier) with a predicted nonfunctional organic anion transporting polypeptide 1B1 protein. The relationship between letermovir accumulation and development of lactic acidosis requires further observations.

Published
2023
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33. LACTIC ACIDOSIS AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION AND POSSIBLE INFLUENCE OF ANTIVIRAL DRUGS

Author

Bérénice Manczak, Marie-Clémence Verdier, Joseph Dewulf, Florian Lemaitre, Vincent Haufroid, and Philippe Hantson

Abstract

A 53-year-old woman with a history of acute myeloid leukemia received a second allogenic hematopoietic stem cell transplant (HSCT) and was prescribed, among other medications, acyclovir and letermovir (480 mg daily oral dose) for prophylaxis of respectively herpes simplex and cytomegalovirus infection. The patient was admitted in the intensive care unit (ICU) for dyspnea and oliguria. Laboratory investigations revealed acute kidney injury, but also a severe and progressive lactic acidosis. Liver function tests were within normal range. The combination of lactic acidosis, hypoglycaemia and acylcarnitine profile in plasma suspected a mitochondrial toxicity. Letermovir therapy was interrupted and determination of plasma letermovir pharmacokinetics revealed a prolonged terminal half-life (40.7 h) that was not significantly influenced by continuous venovenous hemofiltration. Exploration for genetic polymorphisms revealed that the patient was SLCO1B1*5/*15 (c.521T>C homozygous carrier and c.388A>G heterozygous carrier) with a predicted non-functional OATP1B1 protein. The relationship between letermovir accumulation and development of lactic acidosis requires further observations.

Published
2022
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35. A Case Report of Safe Coadministration of Amiodarone with Short-Term Treatment Nirmatrelvir-Ritonavir

Author

Alice Sluijters, Florian Lemaitre, Leïla Belkhir, Lidvine Boland, Vincent Haufroid, Julien De Greef, Cliniques Universitaires Saint-Luc [Bruxelles], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Catholique de Louvain = Catholic University of Louvain (UCL), None, UCL - SSS/IREC/LTAP - Louvain Centre for Toxicology and Applied Pharmacology, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de biochimie médicale, and UCL - (SLuc) Service de médecine interne générale

Subjects
Pharmacology, [SDV]Life Sciences [q-bio], [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Pharmacology (medical)
Abstract

International audience

Published
2022
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36. Blood, cellular, and tissular calcineurin inhibitors pharmacokinetic-pharmacodynamic relationship in heart transplant recipients: the INTRACAR study

Author

Gwendal, Coste, Céline, Chabanne, Camille, Tron, Bernard, Lelong, Marie-Clémence, Verdier, Mikael, Roussel, François, Le Gall, Bruno, Turlin, Mireille, Desille-Dugast, Erwan, Flécher, Bruno, Laviolle, Florian, Lemaitre, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération Hospitalo-universitaire SUrvival oPtimization in ORgan Transplantation (FHU SUPORT), Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques (RESINFIT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Cellules Dendritiques, Immunomodulation et Greffes, Université de Tours (UT)-Université de Tours (UT)-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Institut National de la Santé et de la Recherche Médicale (INSERM), The authors acknowledge the Centre de Ressources Biologiques (CRB) Santé of Rennes BB-0033- 00056 for managing patient samples., and Jonchère, Laurent

Subjects
[SDV.IB] Life Sciences [q-bio]/Bioengineering, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Pharmacology, Pharmacology (medical), [SDV.IB]Life Sciences [q-bio]/Bioengineering, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences
Abstract

International audience; BACKGROUND: After heart transplantation, calcineurin inhibitors (CNI) (cyclosporin A and tacrolimus) are key immunosuppressive drugs to prevent graft rejection. Whole-blood concentration (Cblood)-guided therapeutic drug monitoring (TDM) is systematically performed to improve graft outcomes. However, some patients will still experience graft rejection and/or adverse events despite CNI Cblood within the therapeutic range. Other pharmacokinetic parameters, such as the intra-graft, or intracellular concentration at the CNI site of action could refine their TDM. Nonetheless, these remain to be explored. The objective of the INTRACAR study was to describe the relationship between whole blood, intra-graft, and intracellular CNI concentrations as well as their efficacy in heart transplant recipients (HTR). METHODS: In a cohort of HTR, protocol endomyocardial biopsies (EMB) were collected to assess rejection by anatomopathological analysis. Part of the EMB was used to measure the intra-graft concentrations of CNI (CEMB). Cblood, and the concentration inside peripheral blood mononuclear cells (CPBMC), a cellular fraction enriched with lymphocytes, were also monitored. Concentrations in the three matrices were compared between patients with and without biopsy-proven acute rejection (BPAR). RESULTS: Thirty-four HTR were included, representing nearly 100 pharmacokinetic (PK) samples for each CNI. Cblood, CEMB and CPBMC correlated for both CNI. BPAR was observed in 74 biopsies (39.6 %) from 26 patients (76.5 %), all except one of low-grade. None of the PK parameters (Cblood, CEMB, CPBMC, CEMB/blood and CPBMC/blood) was associated with BPAR. CONCLUSION: In this cohort of well-immunosuppressed patients, no association was observed for any of the PK parameters including Cblood, with the occurrence of BPAR. However, a trend was noticed for the CEMB and CEMB/blood of cyclosporin A. Further studies in higher-risk patients may help optimize the use of CEMB and CPBMC for CNI TDM in HTR.

Published
2022
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37. Le suivi des patients greffés

Author

Anaïs Bonneau, Caroline Monchaud, and Florian Lemaitre

Subjects
Pharmacology, 03 medical and health sciences, 0302 clinical medicine, 030232 urology & nephrology, Pharmacology (medical), 030226 pharmacology & pharmacy
Abstract

La prise en charge d’un patient transplante requiert une surveillance clinique et biologique parfois complexe. L’adaptation de la posologie des immunosuppresseurs est frequente, en particulier en debut de greffe. Elle s’appuie notamment sur le suivi therapeutique pharmacologique, necessaire pour apprecier la variabilite pharmacocinetique des immunosuppresseurs, mais qui peut s’averer contraignant pour le patient.

Published
2021
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38. Quantification of infliximab and adalimumab in human plasma by a liquid chromatography tandem mass spectrometry kit and comparison with two ELISA methods

Author

Camille Tron, Florian Lemaitre, Pauline Bros, Claire Goulvestre, Bénédicte Franck, Nicolas Mouton, Sandrine Bagnos, Romain Coriat, Nihel Khoudour, Dorothée Lebert, Benoit Blanchet, CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), École des Hautes Études en Santé Publique [EHESP] (EHESP), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), PROteomics and METabolomics Platform [Grenoble] (PROMETHEE), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Cibles Thérapeutiques et conception de médicaments (CiTCoM - UMR 8038), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), P Bros, S Bagnos N Mouton and D Lebert are employed by Promise Proteomics. B Blanchet has received honoraria from Promise Proteomics for consulting services. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed., and Jonchère, Laurent

Subjects
musculoskeletal diseases, therapeutic drug monitoring, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Enzyme-Linked Immunosorbent Assay, General Medicine, MS, Analytical Chemistry, LC-MS, [SDV] Life Sciences [q-bio], Medical Laboratory Technology, Tandem Mass Spectrometry, adalimumab, Humans, ELISA, General Pharmacology, Toxicology and Pharmaceutics, skin and connective tissue diseases, infliximab, Chromatography, Liquid
Abstract

International audience; Background: This study compared the performance of plasma infliximab and adalimumab quantification using a commercially available kit (mAbXmise kit) and mass spectrometry readout to that of two ELISA methods in patients treated for inflammatory bowel disease. Methods and results: The mAbXmise method based on liquid chromatography tandem mass spectrometry (LC-MS/MS) was linear from 2 to 100 mu g/ml. It was validated according to international guidelines. Regarding cross-validation for infliximab (n = 70), the mean bias with LC-MS/MS assay was approximately threefold higher with the commercial ELISA assay compared with the in-house ELISA (-6.1 vs -1.8 mu g/ml, respectively). The mean bias between the LC-MS/MS assay and in-house ELISA was -1.2 mu g/ml for adalimumab (n = 35). Conclusion: The LC-MS/MS method is a powerful alternative to immunoassays to monitor concentrations of infliximab and adalimumab.

Published
2022
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39. Comparison of different equations for renal function evaluation as proxies for antibiotic drug clearance: the examples of amoxicillin and cloxacillin

Author

Xavier Duval, Bénédicte Franck, Matthieu Revest, Camille Tron, Jonathan M. Chemouny, Sébastien Lalanne, Roch Houot, Marie-Clémence Verdier, Florian Lemaitre, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], ARN régulateurs bactériens et médecine (BRM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), and Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Betalactams, Antibiotics, [SDV]Life Sciences [q-bio], Chronic Kidney Disease, Clinical Biochemistry, Pharmacokinetics, General Medicine, Drug Monitoring
Abstract

International audience; The most appropriate renal function estimation equation to predict drug clearance is a matter of debate. In this study, we compare the Modification of Diet in Renal Disease (MDRD), the Chronic Kidney Disease Epidemiology collaboration (CKD-EPI) and the Cockroft-Gault (CG) equations to predict amoxicillin and cloxacillin clearance among hospitalized patients receiving high doses of these antibiotic treatments. This study aimed to compare different equations used to predict amoxicillin and cloxacillin clearance among hospitalized patients receiving amoxicillin or cloxacillin treatments outside the intensive care unit. Data from 128 patients contributing 268 plasma samples was analyzed, and correlations between the equations and the amoxicillin and cloxacillin antibiotic clearance rates were calculated. We found a correlation between antibiotic clearance and all the renal function estimation equations, CG being the best, with a R(2) of 0.35 for amoxicillin and 0.29 for cloxacillin (compared to 0.26 and 0.21 for MDRD and 0.12 and 0.24 for CKD-EPI). CG should be preferentially used as a proxy for amoxicillin and cloxacillin drug clearance, but the use of completely different tools such as therapeutic drug monitoring could help individualize antibiotic dosage.

Published
2022
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40. Management of drug-drug interactions with nirmatrelvir/ritonavir in patients treated for Covid-19: Guidelines from the French Society of Pharmacology and Therapeutics (SFPT)

Author

Florian Lemaitre, Matthieu Grégoire, Caroline Monchaud, Stéphane Bouchet, Béatrice Saint-Salvi, Elisabeth Polard, Sihem Benaboud, Laurent Chouchana, Jean-Luc Cracowski, Milou-Daniel Drici, Rodolphe Garraffo, Romain Guilhaumou, Annie-Pierre Jonville-Bera, Mathieu Molimard, Patric Muret, Gilles Peytavin, Vincent Richard, Caroline Solas, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], The Enteric Nervous System in gut and brain disorders [U1235] (TENS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre hospitalier universitaire de Nantes (CHU Nantes), Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Agence nationale de sécurité du médicament et des produits de santé [Saint-Denis] (ANSM), and Jonchère, Laurent

Subjects
Ritonavir, SARS-CoV-2, [SDV]Life Sciences [q-bio], Paxlovid, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Antiviral Agents, Drug monitoring, COVID-19 Drug Treatment, [SDV] Life Sciences [q-bio], [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Pharmacodynamics, Cysteine Proteases, Chymotrypsin, Humans, Drug Interactions, Pharmacology (medical), Pharmacokinetics, Antiviral
Abstract

International audience; OBJECTIVES: Nirmatrelvir in association with ritonavir (PAXLOVID™, Pfizer) is an antiviral agent targeting the 3-chymotrypsin-like cysteine protease enzyme (3C-like protease or Mpro) which is a key enzyme of the viral cycle of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This combination with a well-known pharmacokinetic enhancer leads to a high risk for drug-drug interactions in a polymedicated elected population for treatment. The aim of this work was to provide recommendations on behalf of the national French society of pharmacology (French Society of Pharmacology and Therapeutics; SFPT), by suggesting optimal and pragmatic therapeutic strategies if nirmatrelvir/ritonavir is to be given together with drugs commonly used, in order to ensure secured physicians’ prescription. METHODS: Six clinical pharmacologists search the scientific literature to provide a first draft of recommendations. Thereafter, twelve other clinical pharmacologists verified the recommendations and proposed modifications. The final draft was then validated by all 18 participants. RESULTS: Five distinct recommendations were issued: i) contra-indications, ii) "PAXLOVID™ not recommended with the comedication", iii) "PAXLOVID™ possible whether the comedication is discontinued", iv) "PAXLOVID™ possible only after an expert advice" and v) "PAXLOVID™ possible without modification of the associated treatment". The final document comprises recommendations for 171 drugs/therapeutic classes aiming to secure prescription. In complex situations, clinicians are advised to contact their pharmacology department to obtain specific recommendations on the management of drug-drug interactions with nirmatrelvir/ritonavir. CONCLUSION: These recommendations intend to be a help for clinicians willing to prescribe nirmatrelvir/ritonavir and to prevent drug-drug interactions leading to adverse drug reactions or loss of efficacy. They constitute a guideline for primary care situations. Of course, some complex situations may require expert advices and here, again, clinical pharmacologists are at the forefront in providing therapeutic advice.

Published
2022
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41. Synthèse des recommandations de l’International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) sur le suivi thérapeutique pharmacologique du tacrolimus

Author

Nicolas Picard, Pierre Marquet, Florian Lemaitre, Jean-Baptiste Woillard, Caroline Monchaud, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), CHU Limoges, Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
medicine.medical_specialty, [SDV]Life Sciences [q-bio], medicine.medical_treatment, chemical and pharmacologic phenomena, Liver transplantation, Rejection, 030226 pharmacology & pharmacy, 03 medical and health sciences, 0302 clinical medicine, Calcineurin inhibitors, Transplantation Pharmacocinétique, medicine, Pharmacokinetics, Pharmacology (medical), Rejet, Intensive care medicine, Adverse effect, Transplantation, medicine.diagnostic_test, business.industry, Area under the curve, Effets indésirables, Tacrolimus, 3. Good health, Calcineurin, surgical procedures, operative, Therapeutic drug monitoring, Adverse events, Inhibiteur de calcineurine, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, business, Pharmacogenetics, 030215 immunology
Abstract

National audience; Recently, the International Association of Therapeutic Drug Monitoring (IATDMCT), that is the learning society for biological pharmacology and toxicology, issued recommendations on the therapeutic drug monitoring (TDM) of tacrolimus. This is the second consensus after the one issued in 2009. In this document, the role of tacrolimus TDM for the four principal transplanted organs is discussed. The analytical aspects, pharmacogenetics, TDM alternative approaches and the positioning of biomarkers are also presented. Stronger recommendations are about trough concentration targets in kidney and liver transplantation and for other indication of tacrolimus use. For the first time, an area under the curve of tacrolimus concentrations target is recommended for recipients management. Eventually, another set of recommendations are proposed for pharmacodynamic biomarkers used in patients’ follow-up.

Published
2020
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42. Measuring Intracellular Concentrations of Calcineurin Inhibitors

Author

Nils Tore Vethe, Ida Robertsen, Brenda C. M. de Winter, Birgit C. P. Koch, Mercè Brunet, Pierre Wallemacq, Florian Lemaitre, Amedeo Denicolo, Teun van Gelder, Dennis A. Hesselink, Stein Bergan, Raman Venkataramanan, Antonio D'Avolio, Camille Tron, Pharmacy, Internal Medicine, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Université de Rennes 1 - Faculté de Médecine (UR1 Médecine), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Oslo University Hospital [Oslo], University of Turin, University of Oslo (UiO), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Harvard Medical School AIDS Initiative in Vietnam (HAIVN), Harvard Medical School [Boston] (HMS), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Cliniques universitaires St Luc [Bruxelles], Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes - Faculté de Médecine (UR Médecine), and Université de Rennes (UR)

Subjects
Graft Rejection, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Calcineurin Inhibitors, Pharmacology, 030226 pharmacology & pharmacy, Tacrolimus, 03 medical and health sciences, 0302 clinical medicine, Therapeutic index, Pharmacokinetics, Cyclosporin a, Medicine, Humans, Pharmacology (medical), medicine.diagnostic_test, business.industry, Organ Transplantation, 3. Good health, Transplantation, Calcineurin, Immunosuppressive drug, Therapeutic drug monitoring, Cyclosporine, Drug Monitoring, business, Immunosuppressive Agents
Abstract

Background Therapeutic drug monitoring (TDM) of the two calcineurin inhibitors (CNIs), tacrolimus (TAC) and cyclosporine A (CsA), has resulted in improvements in the management of patients who have undergone solid organ transplantation. As a result of TDM, acute rejection rates and treatment-related toxicities have been reduced. Irrespective, acute rejection and toxicity still occur in patients who have undergone transplantation showing blood CNI concentrations within the therapeutic range. Moreover, the acute rejection rate is no longer decreasing. Hence, smarter TDM approaches are necessary. As CNIs exert their action inside T-lymphocytes, intracellular CNIs may be a promising candidate for improving therapeutic outcomes. Intracellular CNI concentration may be more directly related to drug effect and has been favorably compared with the standard, whole-blood TDM for TAC in liver transplant recipients. However, measuring intracellular CNIs concentrations is not without pitfalls at both the pre-analytical and analytical stages, and standardization appears essential in this area. To date, there are no guidelines for the TDM of intracellular CNI concentrations. Methods Under the auspices of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology and its Immunosuppressive Drug committees, a group of leading investigators in this field have shared experiences and have presented pre-analytical and analytical recommendations for measuring intracellular CNI concentrations.

Published
2020
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43. Potential drug–drug interactions associated with drugs currently proposed for COVID‐19 treatment in patients receiving other treatments

Author

Elisabeth Polard, Chantal Barin-Le Guellec, Caroline Solas, Agnès Sommet, Laurence Lagarce, Florian Lemaitre, Matthieu Grégoire, Michel Tod, Béatrice Saint-Salvi, Laure Elens, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Marseille (APHM), Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre hospitalier universitaire de Nantes (CHU Nantes), The Enteric Nervous System in gut and brain disorders [U1235] (TENS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Université Catholique de Louvain = Catholic University of Louvain (UCL), Agence nationale de sécurité du médicament et des produits de santé [Saint-Denis] (ANSM), Centre d'Investigation Clinique 1426 (CIC 1426), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Institut des Sciences Pharmaceutiques et Biologiques (ISPB), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), UCL - SSS/LDRI - Louvain Drug Research Institute, UCL - SSS/IREC/LTAP - Louvain Centre for Toxicology and Applied Pharmacology, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Jonchère, Laurent

Subjects
Anti-Inflammatory Agents, Antitubercular Agents, Review Article, 030226 pharmacology & pharmacy, Lopinavir, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Drug Interactions, Pharmacology (medical), Anti-Asthmatic Agents, Review Articles, Hypolipidemic Agents, media_common, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Analgesics, education.field_of_study, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, medicine.diagnostic_test, Anti-Bacterial Agents, 3. Good health, Editorial, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Coronavirus Infections, Risk assessment, Interferon beta-1b, Hydroxychloroquine, medicine.drug, Drug, Thyroid Hormones, medicine.medical_specialty, Prescription Drugs, Coronavirus disease 2019 (COVID-19), media_common.quotation_subject, Pneumonia, Viral, Population, MEDLINE, Antineoplastic Agents, Therapeutic drug monitoring, Risk Assessment, Antiviral Agents, Betacoronavirus, 03 medical and health sciences, Pharmacokinetics, medicine, Hypoglycemic Agents, Humans, In patient, education, Intensive care medicine, Adverse effect, Pandemics, Pharmacology, Psychotropic Drugs, SARS-CoV-2, business.industry, Anticoagulants, COVID-19, Outbreak, Cardiovascular Agents, Receptors, Interleukin, COVID-19 Drug Treatment, Clinical trial, Pharmacodynamics, Adverse events, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, business, 030217 neurology & neurosurgery
Abstract

International audience; Patients with COVID-19 are sometimes already being treated for one or more other chronic conditions, especially if they are elderly. Introducing a treatment against COVID-19, either on an outpatient basis or during hospitalization for more severe cases, raises the question of potential drug-drug interactions. Here, we analyzed the potential or proven risk of the co-administration of drugs used for the most common chronic diseases and those currently offered as treatment or undergoing therapeutic trials for COVID-19. Practical recommendations are offered, where possible.

Published
2020
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44. Clinical trials during pandemics and beyond: time for a more efficient pharmacological strategy

Author

Florian Naudet, Clara Locher, Florian Lemaitre, Marie-Clémence Verdier, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), CHU Pontchaillou [Rennes], Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Microbiology (medical), medicine.medical_specialty, [SDV]Life Sciences [q-bio], Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), MEDLINE, 030204 cardiovascular system & hematology, Antiviral Agents, Efficacy, 03 medical and health sciences, Viewpoint, 0302 clinical medicine, Animal model, Pandemic, AcademicSubjects/MED00740, Animals, Humans, Medicine, Pharmacology (medical), National level, 030212 general & internal medicine, Intensive care medicine, Pandemics, Pharmacology, Clinical Trials as Topic, SARS-CoV-2, business.industry, COVID-19, Limiting, 3. Good health, Clinical trial, AcademicSubjects/MED00290, Infectious Diseases, AcademicSubjects/MED00230, business
Abstract

During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, clinical trials on antiviral or symptomatic drugs have been conducted very rapidly even for drugs with a poor pharmacological rationale for efficacy on SARS-CoV-2. Despite lacking basic pharmacological information, most of these clinical trials were also extremely redundant. Applying simple rules, (such as identifying a mechanistic rationale, confirming the ability to reach exposure targets at therapeutic dosage and ensuring tests show drug efficacy in appropriate in vitro and animal models before entering clinical trials) might have saved considerable amounts of time and money, and might have avoided useless research. Moreover, combining these simple rules with the implementation of a relevant policy at both an international and a national level, by limiting studies with a poor methodological/scientific approach and aggregating studies with similar design into single clinical trials, is potentially a far more-efficient strategy.

Published
2021
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45. Development of a dosing-adjustment tool for fluoroquinolones in osteoarticular infections: The Fluo-pop study

Author

Florian, Lemaitre, Fabien, Fily, Jean-Baptiste, Foulquier, Matthieu, Revest, Vincent, Jullien, Antoine, Petitcollin, Pierre, Tattevin, Camille, Tron, Jean-Louis, Polard, Marie-Clémence, Verdier, Emmanuelle, Comets, Denis, Huten, Cédric, Arvieux, Eric, Bellissant, Bruno, Laviolle, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Epicentre [Paris] [Médecins Sans Frontières], Hôpital Broussais, ARN régulateurs bactériens et médecine (BRM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Paris 13 (UP13), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de référence des Infections Ostéo-articulaires du Grand Ouest [Nantes] (CRIOGO - Nantes), Centre hospitalier universitaire de Nantes (CHU Nantes), This work was supported by a local research grant (COmité de la REcherche Clinique et Translationnelle, CORECT, Rennes University Hospital, Rennes, France)., The authors want to thank the COmité de la REcherche Clinique et Translationnelle, CORECT from the Rennes University Hospital for their support., Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Jonchère, Laurent

Subjects
Adult, Male, Ofloxacin, Staphylococcus, Levofloxacin, RM1-950, Models, Biological, Joint infection, Young Adult, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Humans, Pharmacokinetics, Prospective Studies, Aged, Aged, 80 and over, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Modeling, Middle Aged, Bone Diseases, Infectious, Anti-Bacterial Agents, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Female, Therapeutics. Pharmacology, Joint Diseases, Monte Carlo Method, Bone infection, Fluoroquinolones
Abstract

International audience; Fluoroquinolones efficacy depend on both the drug exposure and the level of drug resistance of the bacteria responsible for the infection. Specifically for the Staphylococcus species, which is the microorganism mainly involved in osteoarticular infections (OAI), in-vitro data reported that an AUC/MIC ratio above 115 h maximizes drug efficacy. However, data on OAI patients are lacking and a simple approach to access AUCs is still a clinical issue. We conducted a prospective, single-center study in 30 OAI patients hospitalized in the Rennes University Hospital to model ofloxacin pharmacokinetics and to define a limited sampling strategy (LSS) suitable for ofloxacin and levofloxacin treatments. Modeling was conducted with the Monolix software. The final model was externally validated using levofloxacin data. Monte-Carlo simulations were used to evaluate the probability of target attainment (PTA) of different dosing regimens. Two hundred and ninety-seven (297) ofloxacin concentrations were available for the pharmacokinetic modeling. Ofloxacin pharmacokinetics was best described using a bicompartmental model with a first order elimination, and a transit compartment model absorption. CKD-EPI and sex explained half of ofloxacin pharmacokinetic variability. For LSS, the 0, 1 h and 3 h sampling scheme resulted in the best approach both for BID and TID dosages (R(2) adjusted = 91.1% and 95.0%, outliers = 4.8% and 5.0%, respectively). PTA allows choosing the best drug and dosage according to various hypotheses. A simple 3-sample protocol (pre-dose, 1 h after intake and 3 h after intake) to estimate ofloxacin and levofloxacin AUC allows optimal drug dosage for the treatment of osteoarticular infections.

Published
2021
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46. Drug transporters are implicated in the diffusion of tacrolimus into the T lymphocyte in kidney and liver transplant recipients: Genetic, mRNA, protein expression, and functionality

Author

Gwendal Coste, Fabien Robin, Jonathan Chemouny, Camille Tron, Jérôme Le Priol, Régis Bouvet, Marc Le Vée, Pauline Houssel-Debry, Michel Rayar, Marie-Clémence Verdier, Mikael Roussel, Marie-Dominique Galibert, Edouard Bardou-Jacquet, Olivier Fardel, Cécile Vigneau, Karim Boudjema, Bruno Laviolle, Florian Lemaitre, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Laboratoire de génétique moléculaire et génomique médicale [CHU Rennes], Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and This work was partly supported by a research grant by Sandoz and the bourse Ouest Transplant. The funding source had no involvement in any part of the study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the article for publication.

Subjects
Pharmacology, T-Lymphocytes, [SDV]Life Sciences [q-bio], Pharmaceutical Science, Drug transporter, Therapeutic drug monitoring, Kidney, Personalized medicine, Tacrolimus, Liver Transplantation, Solid organ transplantation, Leukocytes, Mononuclear, Humans, Cytochrome P-450 CYP3A, Pharmacokinetics, Pharmacology (medical), RNA, Messenger, Immunosuppressive Agents
Abstract

International audience; Because of a narrow therapeutic index and a wide inter- and intra-patient variability, therapeutic drug monitoring of the immunosuppressant drug tacrolimus (TAC) based on whole-blood concentrations (C) is mandatory in solid organ transplant recipients. Using peripheral blood mononuclear cells concentrations (C) could improve patient outcomes. The poor correlation between C and C makes hypothesize that drug transporters are implicated in the intracellular accumulation of TAC. The aim of this work was therefore to clinically study: i) the role of genetic variants and ii) the effect of mRNA and protein expression of 4 drug transporters on the TAC C ratio. In addition, functional in vitro experiments were performed to mechanistically validate the clinical observations. Genetic variants of ABCB1/P-gp and SLC28A3/CNT3 did not influence TAC C in liver transplant recipients (LTR). ABCC2/MRP2 at the mRNA level; ABCB1/P-gp, SLC28A3/CNT3 and SLC29A1/ENT1 at the protein level; correlated with the C in kidney and LTR. In vitro results suing transporter-expressing cells confirmed that TAC is substrate of P-gp but not MRP2, whereas experiments remained inconclusive for CNT3 and ENT1. In conclusion, the genetic-transcription-protein-functional approach presented in this work provides new insights in the understanding of TAC transport at the T lymphocyte plasma membrane.

Published
2022
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47. Has the Time Come for Systematic Therapeutic Drug Monitoring of First-Line and WHO Group A Antituberculosis Drugs?

Author

Florian Lemaitre, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), École des Hautes Études en Santé Publique [EHESP] (EHESP), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Chard-Hutchinson, Xavier

Subjects
Drug, medicine.medical_specialty, isoniazid, Tuberculosis, pyrazinamide, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Extensively Drug-Resistant Tuberculosis, antituberculous, Antitubercular Agents, ethambutol, linezolid, rifampicin, World Health Organization, 030226 pharmacology & pharmacy, Group A, 03 medical and health sciences, 0302 clinical medicine, Anti tuberculosis, Tuberculosis, Multidrug-Resistant, medicine, Global health, pharmacodynamics, Humans, Pharmacology (medical), fluoroquinolones, bedaquiline, Intensive care medicine, media_common, Pharmacology, 0303 health sciences, medicine.diagnostic_test, 030306 microbiology, business.industry, Area under the curve, Mycobacterium tuberculosis, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Therapeutic drug monitoring, Infectious disease (medical specialty), exposure, Drug Monitoring, business, pharmacokinetics
Abstract

International audience; Tuberculosis (TB) is a major global health issue, with approximately 10 million people being infected each year, and is the leading cause of mortality from infectious disease, with 1.5 million deaths a year. Optimal TB treatment requires a combination of drugs for an adequate treatment duration owing to persistent organisms, hardly accessible infection sites, and a high risk of resistance selection. Long-term therapy increases the risk of patients’ loss of adherence, adverse drug reactions, and drug-drug interactions, potentially leading to treatment failure. The high inter-patient variability of TB drug exposure is another point eliciting interest in therapeutic drug monitoring (TDM) to optimize treatment. Studies reporting clinically relevant exposure thresholds, which might be proposed as targets toward treatment personalization, are discussed. Practical TDM strategies have also been reported to circumvent issues related to delayed drug absorption and the need for multiple samples when evaluating the area under the curve of drug concentrations. The need for treatment individualization is further emphasized because of the development of multi-drug resistant TB, or extensively drug resistant TB. Finally, the willingness to shorten the treatment duration while maintaining success is also a driver for ensuring adequate exposure to TB drugs with TDM. The aim of the present review is to underline the role of TDM in drug-susceptible TB and World Health Organization group A TB drugs.

Published
2021
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48. Determination of amoxicillin and cotrimoxazole concentrations in sputum of patients with cystic fibrosis

Author

Chantal Belleguic, Marie-Clémence Verdier, E. Deneuville, Samer Kayal, Florian Lemaitre, Caroline Piau, Eric Bellissant, Charles Ricordel, Camille Tron, G. Brinchault, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], None, Jonchère, Laurent, Université d'Angers (UA)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
medicine.medical_specialty, high performance liquid chromatography, therapeutic drug monitoring, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Context (language use), 030226 pharmacology & pharmacy, Biochemistry, Cystic fibrosis, Gastroenterology, Analytical Chemistry, cystic fibrosis, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Limit of Detection, Internal medicine, Drug Discovery, Trimethoprim, Sulfamethoxazole Drug Combination, medicine, Humans, Molecular Biology, Chromatography, High Pressure Liquid, Pharmacology, 0303 health sciences, Chromatography, medicine.diagnostic_test, 030306 microbiology, Chemistry, Sulfamethoxazole, Amoxicillin, Reproducibility of Results, sputum, General Medicine, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, medicine.disease, Trimethoprim, cotrimoxazole, 3. Good health, [SDV] Life Sciences [q-bio], [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Therapeutic drug monitoring, Amoxcillin, Linear Models, Sputum, medicine.symptom, Drug Monitoring, medicine.drug
Abstract

International audience; In the management of cystic fibrosis, treatments against Staphylococcus aureus and Haemophilus influenzae such as amoxicillin or cotrimoxazole have to be prescribed and the antibiotherapy efficacy may be linked to the concentration that reaches the infected site. As cystic fibrosis patients present disturbed pharmacokinetics parameters, a drug monitoring would be relevant to assess lungs distribution of antibiotics and to optimize dosing regimens. In this context, the aim of the study was to develop and validate HPLC-based methods for the determination of both antibiotics in bronchial sputum from cystic fibrosis patients, in order to assess drugs distribution into lungs. Plasma proteins were precipitated by acetonitrile, amoxicillin concentrations in sputum were determined by HPLC coupled with tandem-mass spectrometry. Following a liquid extraction with ethyl acetate, cotrimoxazole was quantified by HPLC using ultraviolet detection. Both methods were found rapid, specific, accurate and reproducible. The method was applied to patient’s samples. In three treated patients, concentration of amoxicillin in sputum were closed and below the lower limit of quantification (0.1 μg/g) and in six patients, sputum concentrations up to 11.1 μg/g and 6.4 μg/g were measured for sulfamethoxazole and trimethoprim respectively.

Published
2021
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49. COVID-19 in Patient with Sarcoidosis Receiving Long-Term Hydroxychloroquine Treatment, France, 2020

Author

Stéphane Jouneau, Pierre Axel Lentz, Solène Patrat-Delon, François Bénézit, Florian Lemaitre, Audrey Le Bot, Charlotte Pronier, Pierre Tattevin, Matthieu Revest, Vincent Thibault, CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), ARN régulateurs bactériens et médecine (BRM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Jonchère, Laurent, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)

Subjects
Microbiology (medical), medicine.medical_specialty, hydroxychloroquine, Coronavirus disease 2019 (COVID-19), Epidemiology, [SDV]Life Sciences [q-bio], 030231 tropical medicine, coronavirus, plasma concentration, lcsh:Medicine, lcsh:Infectious and parasitic diseases, 2019 novel coronavirus disease, respiratory infections, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Research Letter, medicine, lcsh:RC109-216, viruses, In patient, sarcoidosis, 030212 general & internal medicine, COVID-19 in Patient with Sarcoidosis Receiving Long-Term Hydroxychloroquine Treatment, France, 2020, SARS-CoV-2, business.industry, lcsh:R, COVID-19, Hydroxychloroquine, medicine.disease, zoonoses, 3. Good health, [SDV] Life Sciences [q-bio], Infectious Diseases, Tomography x ray computed, coronavirus disease, Curative treatment, Plasma concentration, France, Sarcoidosis, business, Coronavirus Infections, severe acute respiratory syndrome coronavirus 2, medicine.drug
Abstract

International audience; Because of in vitro studies, hydroxychloroquine has been evaluated as a preexposure or postexposure prophylaxis for coronavirus disease (COVID-19) and as a possible COVID-19 curative treatment. We report a case of COVID-19 in a patient with sarcoidosis who was receiving long-term hydroxychloroquine treatment and contracted COVID-19 despite adequate plasma concentrations.

Published
2020
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50. Mega randomized clinical trials: a definitive solution or a double-edged sword?

Author

Florian Lemaitre, Bruno Laviolle, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Jonchère, Laurent

Subjects
medicine.medical_specialty, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, Mega, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, SWORD, Intensive care medicine, Pandemics, Point of View, ComputingMilieux_MISCELLANEOUS, Randomized Controlled Trials as Topic, Pharmacology, SARS-CoV-2, business.industry, General Medicine, COVID-19 Drug Treatment, 3. Good health, [SDV] Life Sciences [q-bio], Research Design, Sample Size, business
Abstract

International audience

Published
2021
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