Laure Ponthier1,2, Pauline Ensuque2, Alexandre Destere1,3, Pierre Marquet1,4, Marc Labriffe1,4, Evelyne Jacqz-Aigrain5, Jean-Baptiste Woillard6,7. 1. Pharmacology & Transplantation, University Limoges, INSERM U1248 P&T, 2 rue du Pr Descottes, F-87000, Limoges, France. 2. Department of Pediatrics, University Hospital of Limoges, Limoges, France. 3. Department of Pharmacology and Toxicology, University Hospital of Nice, Nice, France. 4. Department of Pharmacology, Toxicology and Pharmacovigilance, University Hospital of Limoges, Limoges, France. 5. Pediatric Pharmacology, Department of Biological Pharmacology, Saint-Louis University Hospital, Assistance Publique - Hôpitaux de Paris, Saint-Louis, France. 6. Pharmacology & Transplantation, University Limoges, INSERM U1248 P&T, 2 rue du Pr Descottes, F-87000, Limoges, France. jean-baptiste.woillard@unilim.fr. 7. Department of Pharmacology, Toxicology and Pharmacovigilance, University Hospital of Limoges, Limoges, France. jean-baptiste.woillard@unilim.fr.
Abstract
INTRODUCTION: Vancomycin is one of the antibiotics most used in neonates. Continuous infusion has many advantages over intermittent infusions, but no consensus has been achieved regarding the optimal initial dose. The objectives of this study were: to develop a Machine learning (ML) algorithm based on pharmacokinetic profiles obtained by Monte Carlo simulations using a population pharmacokinetic model (POPPK) from the literature, in order to derive the best vancomycin initial dose in preterm and term neonates, and to compare ML performances with those of an literature equation (LE) derived from a POPPK previously published. MATERIALS AND METHODS: The parameters of a previously published POPPK model of vancomycin in children and neonates were used in the mrgsolve R package to simulate 1900 PK profiles. ML algorithms were developed from these simulations using Xgboost, GLMNET and MARS in parallel, benchmarked and used to calculate the ML first dose. Performances were evaluated in a second simulation set and in an external set of 82 real patients and compared to those of a LE. RESULTS: The Xgboost algorithm yielded numerically best performances and target attainment rates: 46.9% in the second simulation set of 400-600 AUC/MIC ratio vs. 41.4% for the LE model (p = 0.0018); and 35.3% vs. 28% in real patients (p = 0.401), respectively). The Xgboost model resulted in less AUC/MIC > 600, thus decreasing the risk of nephrotoxicity. CONCLUSION: The Xgboost algorithm developed to estimate the initial dose of vancomycin in term or preterm infants has better performances than a previous validated LE and should be evaluated prospectively.
INTRODUCTION: Vancomycin is one of the antibiotics most used in neonates. Continuous infusion has many advantages over intermittent infusions, but no consensus has been achieved regarding the optimal initial dose. The objectives of this study were: to develop a Machine learning (ML) algorithm based on pharmacokinetic profiles obtained by Monte Carlo simulations using a population pharmacokinetic model (POPPK) from the literature, in order to derive the best vancomycin initial dose in preterm and term neonates, and to compare ML performances with those of an literature equation (LE) derived from a POPPK previously published. MATERIALS AND METHODS: The parameters of a previously published POPPK model of vancomycin in children and neonates were used in the mrgsolve R package to simulate 1900 PK profiles. ML algorithms were developed from these simulations using Xgboost, GLMNET and MARS in parallel, benchmarked and used to calculate the ML first dose. Performances were evaluated in a second simulation set and in an external set of 82 real patients and compared to those of a LE. RESULTS: The Xgboost algorithm yielded numerically best performances and target attainment rates: 46.9% in the second simulation set of 400-600 AUC/MIC ratio vs. 41.4% for the LE model (p = 0.0018); and 35.3% vs. 28% in real patients (p = 0.401), respectively). The Xgboost model resulted in less AUC/MIC > 600, thus decreasing the risk of nephrotoxicity. CONCLUSION: The Xgboost algorithm developed to estimate the initial dose of vancomycin in term or preterm infants has better performances than a previous validated LE and should be evaluated prospectively.