Pharmacokinetic Modelling and Development of Bayesian Estimators for Therapeutic Drug Monitoring of Mycophenolate Mofetil in Reduced-Intensity Haematopoietic Stem Cell Transplantation
| Autor: | Eric Deconinck, Franck Saint-Marcoux, Jean-Pierre Kantelip, Jean Debord, Faezeh Legrand, Fabrice Larosa, Pierre Marquet, Bernard Royer |
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| Přispěvatelé: | 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, Service de Pharmacologie, toxicologie et pharmacovigilance [CHU Limoges], CHU Limoges, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Université de Limoges (UNILIM), Service d'hématologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Marquet, Pierre, 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) |
| Rok vydání: | 2009 |
| Předmět: |
Male
Pilot Projects Pharmacology Mycophenolate 030226 pharmacology & pharmacy 0302 clinical medicine MESH: Drug Monitoring Prodrugs Pharmacology (medical) MESH: Models Theoretical education.field_of_study MESH: Middle Aged medicine.diagnostic_test Anti-Inflammatory Agents Non-Steroidal Mycophenolate mofetil Hematopoietic Stem Cell Transplantation MESH: Pharmacokinetics Middle Aged [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences haematopoietic cell transplantation MESH: Anti-Inflammatory Agents Non-Steroidal 3. Good health [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences MESH: Young Adult Area Under Curve 030220 oncology & carcinogenesis Female Drug Monitoring medicine.drug Adult medicine.medical_specialty MESH: Bayes Theorem Population Urology Context (language use) Biology Article Mycophenolic acid Young Adult 03 medical and health sciences Pharmacokinetics medicine Humans education MESH: Hematopoietic Stem Cell Transplantation MESH: Mycophenolic Acid MESH: Humans Bayes Theorem MESH: Adult Models Theoretical Mycophenolic Acid Bayesian estimation MESH: Pilot Projects clinical pharmacokinetics MESH: Male Transplantation Therapeutic drug monitoring MESH: Area Under Curve MESH: Prodrugs Akaike information criterion MESH: Female |
| Zdroj: | Clinical Pharmacokinetics Clinical Pharmacokinetics, Springer Verlag, 2009, 48 (10), pp.667-75. ⟨10.2165/11317140-000000000-00000⟩ |
| ISSN: | 0312-5963 1179-1926 |
| DOI: | 10.2165/11317140-000000000-00000 |
| Popis: | International audience; BACKGROUND: Mycophenolate mofetil, a prodrug of mycophenolic acid (MPA), is used during non-myeloablative and reduced-intensity conditioning haematopoetic stem cell transplantation (HCT) to improve engraftment and reduce graft-versus-host disease (GVHD). However, information about MPA pharmacokinetics is sparse in this context and its use is still empirical. OBJECTIVES: To perform a pilot pharmacokinetic study and to develop maximum a posteriori Bayesian estimators (MAP-BEs) for the estimation of MPA exposure in HCT. PATIENTS AND METHODS: Fourteen patients administered oral mycophenolate mofetil 15 g/kg three times daily were included. Two consecutive 8-hour pharmacokinetic profiles were performed on the same day, 3 days before and 4 days after the HCT. One 8-hour pharmacokinetic profile was performed on day 27 after transplantation. For these 8-hour pharmacokinetic profiles, blood samples were collected predose and 20, 40, 60, 90 minutes and 2, 4, 6 and 8 hours post-dose. Using the iterative two-stage (ITS) method, two different one-compartment open pharmacokinetic models with first-order elimination were developed to describe the data: one with two gamma laws and one with three gamma laws to describe the absorption phase. For each pharmacokinetic profile, the Akaike information criterion (AIC) was calculated to evaluate model fitting. On the basis of the population pharmacokinetic parameters, MAP-BEs were developed for the estimation of MPA pharmacokinetics and area under the plasma concentration-time curve (AUC) from 0 to 8 hours at the different studied periods using a limited-sampling strategy. These MAP-BEs were then validated using a data-splitting method. RESULTS: The ITS approach allowed the development of MAP-BEs based either on 'double-gamma' or 'triple-gamma' models, the combination of which allowed correct estimation of MPA pharmacokinetics and AUC on the basis of a 20 minute-90 minute-240 minute sampling schedule. The mean bias of the Bayesian versus reference (trapezoidal) AUCs was 20%. AIC was systematically calculated for the choice of the most appropriate model fitting the data. CONCLUSION: Pharmacokinetic models and MAP-BEs for mycophenolate mofetil when administered to HCT patients have been developed. In the studied population, they allowed the estimation of MPA exposure based on three blood samples, which could be helpful in conducting clinical trials for the optimization of MPA in reduced-intensity HCT. However, prior studies will be needed to validate them in larger populations. |
| Databáze: | OpenAIRE |
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