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1. Pharmacokinetics and tissue diffusion of ganciclovir in mice and rats

Author

Pierre Gressens, Homa Adle-Biassette, Natacha Teissier, May Fakhoury, Evelyne Jacqz-Aigrain, Imene Boujemla, Marie Françoise Hurteaud, Michel N. Nassar, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pharmacologie Pédiatrique et Pharmacogénétique [Robert Debré, Paris], 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), Service d'hématologie pédiatrique [Robert-Debré, Paris], Department of Division of Imaging Sciences and Biomedical Engineering [London], Centre for the Developing Brain [London], King‘s College London-St Thomas' Hospital [London]-King‘s College London-St Thomas' Hospital [London], This work was supported by the INSERM, Paris Diderot University, and Grace de Monaco Foundation., and Teissier, Natacha

Subjects
0301 basic medicine, Ganciclovir, Mouse, ganciclovir, medicine.medical_treatment, Intraperitoneal injection, Biological Availability, Pharmacology, Antiviral Agents, Injections, Blood cell, Mice, 03 medical and health sciences, Pharmacokinetics, Pregnancy, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Virology, medicine, Animals, Tissue Distribution, Platelet, business.industry, Age Factors, Transplacental, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, medicine.disease, Pathophysiology, Rats, congenital CMV, 3. Good health, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, 030104 developmental biology, medicine.anatomical_structure, Immunology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, Sensorineural hearing loss, business, Biomarkers, medicine.drug
Abstract

Background Congenital cytomegalovirus (CMV) infection is the leading infectious cause of birth defects, mental retardation and non-genetic sensorineural hearing loss. Murine models have been developed in order to understand the pathophysiological mechanisms underlying these lesions. These models are being proposed for the validation of therapeutic protocols for clinical use. The aim of this preclinical study was to assess the pharmacokinetics of the reference antiviral molecule, ganciclovir, in order to optimize these protocols and confirm the diffusion of the molecule to the appropriate target zones. Methods Transplacental and intracochlear diffusion of ganciclovir was evaluated in mice and rats. Pharmacokinetics was assessed in adult mice and pups after 5 consecutive days of intraperitoneal injection of ganciclovir. The occurrence of hematological side effects of ganciclovir was evaluated in the different blood cell lineages. Results In adult rats, the intracochlear diffusion of ganciclovir was shown to achieve the same concentration as in blood. In gestating mice, transplacental diffusion was observed, with a fetal-to-maternal blood ratio of 0.5. In newborn mice, the plasma concentration profile of ganciclovir showed a peak at 2 h followed by a gradual decrease. In adult mice, the concentration peaked at 1 h, but became undetectable by 2 h after injection. Counts of white blood cells, red blood cells and platelets decreased significantly in ganciclovir-treated newborn mice. Conclusion Our data provide evidence for the intracochlear diffusion of the molecule, which may be relevant for the treatment of sensorineural hearing loss in congenitally-infected children.

Published
2016

2. A Computer Prescribing Order Entry–Clinical Decision Support system designed for neonatal care: results of the ‘preselected prescription’ concept at the bedside

Author

E. Saliba, A. Pignolet, Silvia Iacobelli, Catherine Quantin, Béatrice Gouyon, Jean-Bernard Gouyon, Evelyne Jacqz-Aigrain, Centre d'Études Périnatales de l'Océan Indien (CEPOI), Université de La Réunion (UR)-Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Service Biostatistiques et Informatique Médicale (CHU de Dijon) (DIM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Pharmacologie Pédiatrique et Pharmacogénétique [Robert Debré, Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Drug, Male, medicine.medical_specialty, drug error, Prescription Drugs, Drug-Related Side Effects and Adverse Reactions, Adverse drug effects, media_common.quotation_subject, premature infants, Pilot Projects, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Body weight, Clinical decision support system, Drug Prescriptions, Computer Prescribing Order Entry, computerized decision support, Order entry, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, Intensive care, Intensive Care Units, Neonatal, medicine, Périnatalité, Humans, Medication Errors, Pharmacology (medical), 030212 general & internal medicine, Formulary, Medical prescription, Intensive care medicine, media_common, Pharmacology, business.industry, Infant, Newborn, dose regimen, Neonates, Decision Support Systems, Clinical, 3. Good health, Female, overdose, business
Abstract

SummaryWhat is known The neonatal intensive care units (NICUs) are at the highest risk of drug dose error of all hospital wards. NICUs also have the most complicated prescription modalities. The computerization of the prescription process is currently recommended to decrease the risk of preventable adverse drug effects (pADEs) in NICUs. However, Computer Prescribing Order Entry–Clinical Decision Support (C.P.O.E./C.D.S.) systems have been poorly studied in NICUs, and their technical compatibility with neonatal specificities has been limited. Objectives We set up a performance study of the preselected prescription of drugs for neonates, which limited the role of the prescriber to choosing the drugs and their indications. Methods A single 29 bed neonatal ward used this neonatal C.P.O.E./C.D.S. system for all prescriptions of all hospitalized newborns over an 18-month period. The preselected prescription of drugs was based on the indication, gestational age, body weight and post-natal age. The therapeutic protocols were provided by a formulary reference (330 drugs) that had been specifically designed for newborns. The preselected prescription also gave complete information about preparation and administration of drugs by nurses. The prescriber was allowed to modify the preselected prescription but alarms provided warning when the prescription was outside the recommended range. The main clinical characteristics and all items of each line of prescription were stored in a data warehouse, thus enabling this study to take place. Results Seven hundred and sixty successive newborns (from 24 to 42 weeks’ gestation) were prescribed 52 392 lines of prescription corresponding to 65 drugs; About 30·4% of neonates had at least one out of licensed prescription; A prescription out of the recommended range for daily dose was recorded for 1·0% of all drug prescriptions. What is new? The C.P.O.E./C.D.S. systems can currently provide a complete preselected prescription in NICUs according to dose rules, which are specific to newborns and also comply with local specificities (therapeutic protocols and formulation of drugs). The role of the prescriber is limited to the choice of drugs and their indications. The prescriber still retains the possibility of modifying each item of the prescription, with all other prescription items being calculated by the C.P.O.E. system. In these conditions, the prescribers rarely modified the preselected prescription and the rate of out of range prescription was low. A multicentric study is required to confirm and extend these observations. Conclusions This study showed the feasibility of preselected prescription in NICUs and a low rate of out of range prescriptions. The preselected prescription could play a key role in lowering the dose error rate in NICUs.

Published
2017

3. A Population and Developmental Pharmacokinetic Analysis To Evaluate and Optimize Cefotaxime Dosing Regimen in Neonates and Young Infants

Author

Stéphanie Leroux, Valérie Biran, Evelyne Jacqz-Aigrain, Hao Zheng, Jean-Bernard Gouyon, Jean-Michel Roué, Wei Zhao, Evaluation thérapeutique et pharmacologie périnatale et pédiatrique (EA_7323), Université Paris Descartes - Paris 5 (UPD5), CHU Pontchaillou [Rennes], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHRU de Brest - Département de Pédiatrie (CHU BREST Pédiatrie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre d'Études Périnatales de l'Océan Indien (CEPOI), Université de La Réunion (UR)-Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Service de Pharmacologie Pédiatrique et Pharmacogénétique [Robert Debré, Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Evaluation thérapeutique et pharmacologie périnatale et pédiatrique ( EA 7323 ), Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ), CHRU de Brest - Département de Pédiatrie ( CHU BREST Pédiatrie ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Centre d'Études Périnatales de l'Océan Indien ( CEPOI ), and Université de la Réunion ( UR ) -Centre Hospitalier Universitaire de La Réunion ( CHU La Réunion )

Subjects
0301 basic medicine, Male, Pediatrics, Cefotaxime, [ SDV.MHEP.PED ] Life Sciences [q-bio]/Human health and pathology/Pediatrics, 030226 pharmacology & pharmacy, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Tandem Mass Spectrometry, Pharmacology (medical), Drug Dosage Calculations, Chromatography, High Pressure Liquid, Volume of distribution, education.field_of_study, Gestational age, 3. Good health, Anti-Bacterial Agents, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Intensive Care Units, Infectious Diseases, Female, Monte Carlo Method, medicine.drug, medicine.medical_specialty, 030106 microbiology, Population, Gestational Age, Drug Administration Schedule, 03 medical and health sciences, Pharmacokinetics, Sepsis, Périnatalité, medicine, Humans, Computer Simulation, Dosing, education, Pharmacology, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Models, Statistical, business.industry, Body Weight, Infant, Newborn, [ SDV.SP.PHARMA ] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Infant, NONMEM, Pharmacodynamics, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, business, Gram-Negative Bacterial Infections
Abstract

Cefotaxime is one of the most frequently prescribed antibiotics for the treatment of Gram-negative bacterial sepsis in neonates. However, the dosing regimens routinely used in clinical practice vary considerably. The objective of the present study was to conduct a population pharmacokinetic study of cefotaxime in neonates and young infants in order to evaluate and optimize the dosing regimen. An opportunistic sampling strategy combined with population pharmacokinetic analysis using NONMEM software was performed. Cefotaxime concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. Developmental pharmacokinetics-pharmacodynamics, the microbiological pathogens, and safety aspects were taken into account to optimize the dose. The pharmacokinetic data from 100 neonates (gestational age [GA] range, 23 to 42 weeks) were modeled with an allometric two-compartment model with first-order elimination. The median values for clearance and the volume of distribution at steady state were 0.12 liter/h/kg of body weight and 0.64 liter/kg, respectively. The covariate analysis showed that current weight, GA, and postnatal age (PNA) had significant impacts on cefotaxime pharmacokinetics. Monte Carlo simulations demonstrated that the current dose recommendations underdosed older newborns. A model-based dosing regimen of 50 mg/kg twice a day to four times a day, according to GA and PNA, was established. The associated risk of overdose for the proposed dosing regimen was 0.01%. We determined the population pharmacokinetics of cefotaxime and established a model-based dosing regimen to optimize treatment for neonates and young infants.

Published
2016

4. Clinical Utility and Safety of a Model-Based Patient-Tailored Dose of Vancomycin in Neonates

Author

Valérie Biran, Evelyne Jacqz-Aigrain, Doriane Madeleneau, Stéphane Rioualen, Elodie Zana-Taïeb, Emmanuel Lopez, Stéphanie Leroux, Anne-Laure Virlouvet, Camille Wallon, Wei Zhao, Evaluation thérapeutique et pharmacologie périnatale et pédiatrique (EA_7323), Université Paris Descartes - Paris 5 (UPD5), CHU Pontchaillou [Rennes], Service de Pharmacologie Pédiatrique et Pharmacogénétique [Robert Debré, Paris], 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), 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], Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Shandong Jiaotong University [Jinan], This work was supported by the Fundamental Research Funds and Young Scholars Program of Shandong University, the GRIP (Global Research in Pediatrics, European Commission FP7 project, grant agreement number 261060), and NeoVanc (European Commission FP7 project, grant agree-ment number 602041)., Evaluation thérapeutique et pharmacologie périnatale et pédiatrique ( EA 7323 ), Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ), 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)-Hôpital Robert Debré, CHRU Tours, and Jonchère, Laurent

Subjects
Male, Methicillin-Resistant Staphylococcus aureus, medicine.medical_specialty, Pediatrics, Population, [ SDV.MHEP.PED ] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Gestational Age, 030226 pharmacology & pharmacy, Drug Administration Schedule, Nephrotoxicity, 03 medical and health sciences, Patient safety, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, 0302 clinical medicine, Pharmacokinetics, Vancomycin, Intensive care, Intensive Care Units, Neonatal, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Dosing, Precision Medicine, Intensive care medicine, education, Pharmacology, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, education.field_of_study, Models, Statistical, medicine.diagnostic_test, business.industry, Infant, Newborn, [ SDV.SP.PHARMA ] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Infant, Staphylococcal Infections, 3. Good health, Anti-Bacterial Agents, Infectious Diseases, Therapeutic drug monitoring, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Female, Patient Safety, Drug Monitoring, business, medicine.drug
Abstract

Pharmacokinetic modeling has often been applied to evaluate vancomycin pharmacokinetics in neonates. However, clinical application of the model-based personalized vancomycin therapy is still limited. The objective of the present study was to evaluate the clinical utility and safety of a model-based patient-tailored dose of vancomycin in neonates. A model-based vancomycin dosing calculator, developed from a population pharmacokinetic study, has been integrated into the routine clinical care in 3 neonatal intensive care units (Robert Debré, Cochin Port Royal, and Clocheville hospitals) between 2012 and 2014. The target attainment rate, defined as the percentage of patients with a first therapeutic drug monitoring serum vancomycin concentration achieving the target window of 15 to 25 mg/liter, was selected as an endpoint for evaluating the clinical utility. The safety evaluation was focused on nephrotoxicity. The clinical application of the model-based patient-tailored dose of vancomycin has been demonstrated in 190 neonates. The mean (standard deviation) gestational and postnatal ages of the study population were 31.1 (4.9) weeks and 16.7 (21.7) days, respectively. The target attainment rate increased from 41% to 72% without any case of vancomycin-related nephrotoxicity. This proof-of-concept study provides evidence for integrating model-based antimicrobial therapy in neonatal routine care.

Published
2015

5. Feasibility of, and critical paths for mycophenolate mofetil Bayesian dose adjustment: Pharmacological re-appraisal of a concentration-controlled versus fixed-dose trial in renal transplant recipients

Author

Aurélie Prémaud, Guillaume Hoizey, Lionel Hary, Patricia Compagnon, C. Loichot, Alexandra Rousseau, Pierre Marquet, D. Debruyne, Evelyne Jacqz-Aigrain, S. Saivin, Nicolas Venisse, Y. Le Meur, Alain Turcant, Pharmacologie des Immunosuppresseurs et de la Transplantation (PIST), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Limoges (UNILIM), CHRU Brest - Service de Nephrologie (CHU - BREST - Nephrologie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Modélisations pharmacocinétiques-pharmacodynamiques pour un meilleur usage des anti-infectieux, Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Milétrie, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Groupe d'Étude des Interactions Hôte-Pathogène (GEIHP), Université d'Angers (UA), Université de Reims Champagne-Ardenne (URCA), Pharmacologie des Dysfonctionnements Endotheliaux et Myocardiques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Développements Méthodologiques en Tomographie par Emission de Positons (LDM-TEP), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Service de Pharmacologie Pédiatrique et Pharmacogénétique [Robert Debré, Paris], 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Université de Limoges (UNILIM)-CHU Limoges, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers, Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT)

Subjects
Graft Rejection, medicine.medical_specialty, Time Factors, Concentration-controlled versus fixed-dose trial, [SDV]Life Sciences [q-bio], Bayesian probability, Urology, 030230 surgery, Mycophenolate, 030226 pharmacology & pharmacy, Fixed dose, Mycophenolic acid, 03 medical and health sciences, 0302 clinical medicine, Dose adjustment, Linear regression, Humans, Medicine, Drug Dosage Calculations, Practice Patterns, Physicians', Randomized Controlled Trials as Topic, Retrospective Studies, Pharmacology, Dose-Response Relationship, Drug, business.industry, Graft Survival, Mycophenolate mofetil, Bayes Theorem, Renal transplantation, Mycophenolic Acid, Kidney Transplantation, 3. Good health, Surgery, Treatment Outcome, Renal transplant, Area Under Curve, Acute Disease, Practice Guidelines as Topic, Linear Models, Feasibility Studies, France, Guideline Adherence, Drug Monitoring, business, Immunosuppressive Agents, Bayesian dose adjustment, Blood sampling, medicine.drug
Abstract

LDM TEP COLL; International audience; The aim of this study was to analyze retrospectively and critically the different steps of the individual dose adjustment procedure employed in the concentration-controlled (CC) versus fixed-dose trial Apomygre, which showed that mycophenolate mofetil (MMF) dose adjustment using a limited sampling strategy significantly reduced the risk of treatment failures and acute rejection in renal transplants at one year posttransplantation.The number of AUCs performed during the study and circumstances of collection, time of blood sampling, Bayesian mycophenolic acid (MPA) area-under-the-curve (AUC) estimation procedures and physicians’ compliance with MMF dose recommendations were retrospectively analyzed. 92% of AUCs scheduled over the study were actually performed. Sampling times were very well respected. Bayesian estimation of MPA exposure was done by the pharmacologists locally in accordance with the protocol instructions and the AUC estimates obtained were virtually all confirmed a posteriori. On the other hand, a second AUC estimated by multiple linear regression could only be provided for 84% of the profiles and showed a large overestimation with respect to Bayesian estimates for AUC values between 10 and 55 mg h/L. In the CC arm, a very good physicians’ compliance was observed (85%) and application of the dose recommendations led to higher values of AUCs (42.1 ± 14.6 mg h/L versus 36.7 ± 16.3 mg h/L, p = 0.0035) and to more AUCs in the target range (69% versus 56%, p = 0.0343) than when dose recommendations were not applied. By analyzing in detail the feasibility criteria of MMF Bayesian dose adjustment, this study highlighted the requirements for successful extrapolation of the Apomygre trial results to routine practice: (i) respect of the PK sampling time-windows; (ii) use of relevant tools for accurate drug exposure estimation and dose adjustment calculation; and (iii) good compliance of the physicians with regard to the recommended doses.

Published
2010

6. Cost-Effectiveness Analysis of Individualized Mycophenolate Mofetil Dosing in Kidney Transplant Patients in the APOMYGRE Trial

Author

Marie-Laure Laroche, Nicolas Venisse, Mathias Büchler, Claire Villeneuve, Guillaume Hoizey, Pierre Marquet, Yannick Le Meur, Lionel Hary, Evelyne Jacqz-Aigrain, Patricia Compagnon, Annick Rousseau, Sylvie Saivin, Danièle Debruyne, Alain Vergnenègre, Cecile Loichot-Roselmac, Alain Turcant, Pharmacologie des Immunosuppresseurs et de la Transplantation (PIST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Université de Limoges (UNILIM)-CHU Limoges, Université de Limoges (UNILIM), Equipe de Recherche Médicale Appliquée (ERMA), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Modélisations pharmacocinétiques-pharmacodynamiques pour un meilleur usage des anti-infectieux, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers, Hôpital de la Milétrie, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Groupe d'Étude des Interactions Hôte-Pathogène (GEIHP), Université d'Angers (UA), Université de Reims Champagne-Ardenne (URCA), Pharmacologie des Dysfonctionnements Endotheliaux et Myocardiques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Développements Méthodologiques en Tomographie par Emission de Positons (LDM-TEP), Service Hospitalier Frédéric Joliot (SHFJ), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier Universitaire de Purpan (CHU Purpan), Service de Pharmacologie Pédiatrique et Pharmacogénétique [Robert Debré, Paris], 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), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Université Francois Rabelais [Tours], Service de Pathologie respiratoire et allergologie [CHU Limoges], CHU Limoges, Service de Néphrologie, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Université de Limoges (UNILIM)-CHU Limoges, Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)

Subjects
Adult, Graft Rejection, Male, Reoperation, medicine.medical_specialty, Basiliximab, Cost effectiveness, Recombinant Fusion Proteins, [SDV]Life Sciences [q-bio], Population, 030230 surgery, 030226 pharmacology & pharmacy, Mycophenolic acid, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Adrenal Cortex Hormones, Internal medicine, medicine, Ambulatory Care, Humans, Treatment Failure, education, health care economics and organizations, Aged, Immunosuppression Therapy, Transplantation, education.field_of_study, business.industry, Histocompatibility Testing, Antibodies, Monoclonal, Cost-effectiveness analysis, Middle Aged, Mycophenolic Acid, Kidney Transplantation, Confidence interval, 3. Good health, Discontinuation, Female, business, Immunosuppressive Agents, Switzerland, medicine.drug
Abstract

LDM TEP COLL; International audience; BACKGROUND:In the prospective, randomized, multicenter APOMYGRE trial conducted in France, concentration-controlled mycophenolate mofetil (MMF) dosing based on mycophenolic acid (MPA) exposure significantly reduced the treatment failure and acute rejection during the first posttransplantation year compared with fixed-dose MMF. This analysis investigated the cost effectiveness of dose individualization.METHOD:The study included 65 patients per group (intent-to-treat population). Treatment failure (primary efficacy endpoint) was defined as death, graft loss, acute rejection, or MMF discontinuation because of adverse effects. Data on hospitalizations, drugs prescribed, physicians' fees, laboratory expenses, ambulatory visits, and transportation were retrieved. Costs were calculated from the French National Health System perspective.RESULTS:The mean (95% confidence interval) total yearly cost per patient was Euro 47,477 (Euro 43,933; Euro 51,020) in the concentration-controlled group and Euro 46,783 ( Euro 44,152; Euro 49,414) in the fixed-dose group (P=0.7). The observed incremental cost-effectiveness ratio was Euro 3757 per treatment failure (Purchasing Power Parities United States/France: $4129). Hospitalization and drug costs accounted for approximately 50% and 25% of total costs, respectively. The cost for MPA area under the concentration-time curve and dose calculation was Euro 452 per patient, less than 1% of the total cost.CONCLUSION:In the APOMYGRE trial, therapeutic MPA monitoring using a limited sampling strategy reduced the risk of treatment failure and acute rejection in renal allograft recipients during the first 12 months posttransplantation, at neutral cost.

Published
2010

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