Quentin Beaulieu1, Daolun Zhang1, Isabelle Melki2,3,4, Véronique Baudouin5, Lauriane Goldwirst1, Jean-Baptiste Woillard6,7,8, Evelyne Jacqz-Aigrain9,10,11. 1. Paediatric Pharmacology, Department of Biological Pharmacology, Saint-Louis University Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France. 2. General Pediatrics, Infectious Disease and Internal Medicine Department, Robert Debre University Hospital, Reference Center for Rheumatic, AutoImmune and Systemic Diseases in Children (RAISE), AP-HP, Paris, France. 3. Pediatric Hematology-Immunology and Rheumatology Department, Necker-Enfants Malades University Hospital, Reference center for Rheumatic, AutoImmune and Systemic Diseases in Children (RAISE), AP-HP, Paris, France. 4. Laboratory of Neurogenetics and Neuroinflammation, Imagine Institute, Paris, France. 5. Department of Pediatric Nephrology, Robert Debré University Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France. 6. IPPRITT, INSERM, U1248, Limoges, France. 7. IPPRITT, University of Limoges, Limoges, France. 8. Department of Pharmacology and Toxicology, CHU Limoges, Limoges, France. 9. Paediatric Pharmacology, Department of Biological Pharmacology, Saint-Louis University Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France. evelyne.jacqz-aigrain@aphp.fr. 10. University of Paris, Paris, France. evelyne.jacqz-aigrain@aphp.fr. 11. Department of Biological Pharmacology, Saint-Louis University Hospital, Assistance Publique - Hôpitaux de Paris, FranceHôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, 1 avenue Charles Vellefaux, Paris, 75010, France. evelyne.jacqz-aigrain@aphp.fr.
Abstract
INTRODUCTION: Mycophenolate mofetil (MMF), a pro-drug of mycophenolic acid (MPA), has become a major therapeutic option in juvenile systemic lupus erythematosus (jSLE). Monitoring MPA exposure using area under curve (AUC) has proved its value to increase efficacy and safety in solid organ transplantation both in children and adults, but additional data are required in patients with autoimmune diseases. In order to facilitate MMF therapeutic drug monitoring (TDM) in children, Bayesian estimators (BE) of MPA AUC0-12 h using limited sampling strategies (LSS) have been developed. Our aim was to conduct an external validation of these LSS using rich pharmacokinetics and compare their predictive performance. METHODS: Pharmacokinetic blood samples were collected from jSLE treated by MMF and MPA plasma concentrations were determined using high-performance liquid chromatography system with ultraviolet detection (HPLC-UV). Individual AUC0-12 h at steady state was calculated using the trapezoid rule and compared with two LSS: (1) ISBA, a two-stage Bayesian approach developed for jSLE and (2) ADAPT, a non-linear mixed effects model with a parametric maximum likelihood approach developed with data from renal transplanted adults. RESULTS: We received 41 rich pediatric PK at steady state from jSLE and calculated individual AUC0-12 h. The external validation MPA AUC0-12 h was conducted by selecting the concentration-time points adapted to ISBA and ADAPT: (1) ISBA showed good accuracy (bias: - 0.8 mg h/L), (2) ADAPT resulted in a bias of 6.7 mg L/h. The corresponding relative root mean square prediction error (RSME) was 23% and 43% respectively. CONCLUSION: According to our external validation of two LSS of drug exposure, the ISBA model is recommended for Bayesian estimation of MPA AUC0-12 h in jSLE. In the literature focusing on MMF TDM, an efficacy cut-off for MPA AUC0-12 h between 30 and 45 mg h/L is proposed in jSLE but this requires additional validation.
INTRODUCTION: Mycophenolate mofetil (MMF), a pro-drug of mycophenolic acid (MPA), has become a major therapeutic option in juvenile systemic lupus erythematosus (jSLE). Monitoring MPA exposure using area under curve (AUC) has proved its value to increase efficacy and safety in solid organ transplantation both in children and adults, but additional data are required in patients with autoimmune diseases. In order to facilitate MMF therapeutic drug monitoring (TDM) in children, Bayesian estimators (BE) of MPA AUC0-12 h using limited sampling strategies (LSS) have been developed. Our aim was to conduct an external validation of these LSS using rich pharmacokinetics and compare their predictive performance. METHODS: Pharmacokinetic blood samples were collected from jSLE treated by MMF and MPA plasma concentrations were determined using high-performance liquid chromatography system with ultraviolet detection (HPLC-UV). Individual AUC0-12 h at steady state was calculated using the trapezoid rule and compared with two LSS: (1) ISBA, a two-stage Bayesian approach developed for jSLE and (2) ADAPT, a non-linear mixed effects model with a parametric maximum likelihood approach developed with data from renal transplanted adults. RESULTS: We received 41 rich pediatric PK at steady state from jSLE and calculated individual AUC0-12 h. The external validation MPA AUC0-12 h was conducted by selecting the concentration-time points adapted to ISBA and ADAPT: (1) ISBA showed good accuracy (bias: - 0.8 mg h/L), (2) ADAPT resulted in a bias of 6.7 mg L/h. The corresponding relative root mean square prediction error (RSME) was 23% and 43% respectively. CONCLUSION: According to our external validation of two LSS of drug exposure, the ISBA model is recommended for Bayesian estimation of MPA AUC0-12 h in jSLE. In the literature focusing on MMF TDM, an efficacy cut-off for MPA AUC0-12 h between 30 and 45 mg h/L is proposed in jSLE but this requires additional validation.
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