Development of a Population Pharmacokinetic Model of Busulfan in Children and Evaluation of Different Sampling Schedules for Precision Dosing
Efthymios Neroutsos,
Ricardo Nalda-Molina,
Anna Paisiou,
Kalliopi Zisaki,
Evgenios Goussetis,
Alexandros Spyridonidis,
Vasiliki Kitra,
Stelios Grafakos,
Georgia Valsami,
Aristides Dokoumetzidis
Affiliations
Efthymios Neroutsos
Laboratory of Biopharmaceutics & Pharmacokinetics, Department of Pharmacy, School of Health Sciences, National & Kapodistrian University of Athens, 15784 Athens, Greece
Ricardo Nalda-Molina
Department of Engineering, School of Pharmacy, Miguel Hernández University, 03550 San Juan de Alicante, Spain
Anna Paisiou
Bone Marrow Transplant Unit, “Agia Sophia” Children’s Hospital of Athens, 15127 Athens, Greece
Kalliopi Zisaki
Bone Marrow Transplant Unit, “Agia Sophia” Children’s Hospital of Athens, 15127 Athens, Greece
Evgenios Goussetis
Bone Marrow Transplant Unit, “Agia Sophia” Children’s Hospital of Athens, 15127 Athens, Greece
Alexandros Spyridonidis
Department of Internal Medicine, Bone Marrow Transplantation Unit, University Hospital of Patras, 26504 Patras, Greece
Vasiliki Kitra
Bone Marrow Transplant Unit, “Agia Sophia” Children’s Hospital of Athens, 15127 Athens, Greece
Stelios Grafakos
Bone Marrow Transplant Unit, “Agia Sophia” Children’s Hospital of Athens, 15127 Athens, Greece
Georgia Valsami
Laboratory of Biopharmaceutics & Pharmacokinetics, Department of Pharmacy, School of Health Sciences, National & Kapodistrian University of Athens, 15784 Athens, Greece
Aristides Dokoumetzidis
Laboratory of Biopharmaceutics & Pharmacokinetics, Department of Pharmacy, School of Health Sciences, National & Kapodistrian University of Athens, 15784 Athens, Greece
We develop a population pharmacokinetic model to describe Busulfan pharmacokinetics in paediatric patients and investigate by simulations the impact of various sampling schedules on the calculation of AUC. Seventy-six children had 2 h infusions every 6 h. A two-compartment linear model was found to adequately describe the data. A lag-time was introduced to account for the delay of the administration of the drug through the infusion pump. The mean values of clearance, central volume of distribution, intercompartmental clearance, and peripheral volume of distribution were 10.7 L/h, 39.5 L, 4.68 L/h and 17.5 L, respectively, normalized for a Body Weight (BW) of 70 kg. BW was found to explain a portion of variability with an allometric relationship and fixed exponents of 0.75 on clearance parameters and 1 on volumes. Interindividual variability for clearance and volume of distribution was found to be 28% and 41%, respectively, and interoccasion variability for clearance was found to be 11%. Three sampling schedules were assessed by simulations for bias and imprecision to calculate AUC by a non-compartmental and a model-based method. The latter was found to be superior in all cases, while the non-compartmental was unbiased only in sampling up to 12 h corresponding to a once-daily dosing regimen.
