Bénédicte Franck1,2,3, Jean-Baptiste Woillard1,2,3, Yves Théorêt4, Henrique Bittencourt5, Emile Demers6, Annabelle Briand7,8, Pierre Marquet1,2,3, Anne-Laure Lapeyraque5, Philippe Ovetchkine5, Julie Autmizguine4,5,7,9. 1. INSERM, IPPRITT, U1248, Limoges, France. 2. Univ. Limoges, IPPRITT, Limoges, France. 3. Department of Pharmacology and Toxicology, CHU Limoges, Limoges, France. 4. Clinical Pharmacology Unit, CHU Sainte-Justine, Montreal, Quebec, Canada. 5. Department of Pediatrics, CHU Sainte-Justine, Montreal, Quebec, Canada. 6. Department of Pharmacy, CHU Sainte-Justine, Montreal, Quebec, Canada. 7. Research Center, CHU Sainte-Justine, Quebec, Montreal, Canada. 8. Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada. 9. Department of Pharmacology and Physiology, Université de Montréal, Montreal, Quebec, Canada.
Abstract
AIMS: Ganciclovir (GCV) and its prodrug valganciclovir (VGCV) are first-line agents to prevent and treat cytomegalovirus in transplant recipients. There is high pharmacokinetic (PK) interindividual variability and PK data are scarce, especially in paediatric stem cell transplant (SCT) recipients. We sought to determine the optimal GCV and VGCV dosing in transplanted children. METHODS: We conducted a single-centre retrospective population PK (POPPK) study of IV GCV and enteral VGCV in paediatric solid organ transplant (SOT) and SCT recipients. We included children who were transplanted and had available plasma GCV concentrations, done per standard of care. POPPK analysis was performed using a nonlinear mixed effects modelling approach with NONMEM. Optimal dosing was determined based on the achievement of the surrogate efficacy target: GCV 24 h area under the concentration-time curve (AUC0-24h ) of 40-60 mg.h.L-1 . RESULTS: Fifty children with a median [range] age of 7.5 years [0.5-17.4] contributed 580 PK samples. A two-compartment model with first-order absorption with a lag time and first-order elimination fit the data well. Creatinine clearance and body weight (WT) were significant covariates for GCV clearance (CL); and WT for the volumes of distribution. IV GCV 15-20 mg.kg-1 .day-1 divided every 12 hours achieved the highest probability of target achievement (PTA) (33.0-33.8%). Enteral VGCV 30 and 40 mg.kg-1 .day-1 divided every 12 hours in children 0-<6 years, and 6-18 years, respectively, achieved the highest PTA (29.1-33.0%). CONCLUSION: This is the first POPPK model developed in children with either SOT or SCT. Concentration target achievement was low, suggesting a potential benefit for therapeutic drug monitoring to ensure optimal exposure.
AIMS: Ganciclovir (GCV) and its prodrug valganciclovir (VGCV) are first-line agents to prevent and treat cytomegalovirus in transplant recipients. There is high pharmacokinetic (PK) interindividual variability and PK data are scarce, especially in paediatric stem cell transplant (SCT) recipients. We sought to determine the optimal GCV and VGCV dosing in transplanted children. METHODS: We conducted a single-centre retrospective population PK (POPPK) study of IV GCV and enteral VGCV in paediatric solid organ transplant (SOT) and SCT recipients. We included children who were transplanted and had available plasma GCV concentrations, done per standard of care. POPPK analysis was performed using a nonlinear mixed effects modelling approach with NONMEM. Optimal dosing was determined based on the achievement of the surrogate efficacy target: GCV 24 h area under the concentration-time curve (AUC0-24h ) of 40-60 mg.h.L-1 . RESULTS: Fifty children with a median [range] age of 7.5 years [0.5-17.4] contributed 580 PK samples. A two-compartment model with first-order absorption with a lag time and first-order elimination fit the data well. Creatinine clearance and body weight (WT) were significant covariates for GCV clearance (CL); and WT for the volumes of distribution. IV GCV 15-20 mg.kg-1 .day-1 divided every 12 hours achieved the highest probability of target achievement (PTA) (33.0-33.8%). Enteral VGCV 30 and 40 mg.kg-1 .day-1 divided every 12 hours in children 0-<6 years, and 6-18 years, respectively, achieved the highest PTA (29.1-33.0%). CONCLUSION: This is the first POPPK model developed in children with either SOT or SCT. Concentration target achievement was low, suggesting a potential benefit for therapeutic drug monitoring to ensure optimal exposure.