Development of a Population Pharmacokinetic Model of Busulfan in Children and Evaluation of Different Sampling Schedules for Precision Dosing
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...
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MDPI AG
2022-03-01
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| Online Access: | https://www.mdpi.com/1999-4923/14/3/647 |
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| author | Efthymios Neroutsos Ricardo Nalda-Molina Anna Paisiou Kalliopi Zisaki Evgenios Goussetis Alexandros Spyridonidis Vasiliki Kitra Stelios Grafakos Georgia Valsami Aristides Dokoumetzidis |
| author_facet | Efthymios Neroutsos Ricardo Nalda-Molina Anna Paisiou Kalliopi Zisaki Evgenios Goussetis Alexandros Spyridonidis Vasiliki Kitra Stelios Grafakos Georgia Valsami Aristides Dokoumetzidis |
| author_sort | Efthymios Neroutsos |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T12:58:11Z |
| format | Article |
| id | doaj.art-bdba15ffde1540cf8b859651813054a0 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T12:58:11Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-bdba15ffde1540cf8b859651813054a02023-11-30T21:57:55ZengMDPI AGPharmaceutics1999-49232022-03-0114364710.3390/pharmaceutics14030647Development of a Population Pharmacokinetic Model of Busulfan in Children and Evaluation of Different Sampling Schedules for Precision DosingEfthymios Neroutsos0Ricardo Nalda-Molina1Anna Paisiou2Kalliopi Zisaki3Evgenios Goussetis4Alexandros Spyridonidis5Vasiliki Kitra6Stelios Grafakos7Georgia Valsami8Aristides Dokoumetzidis9Laboratory of Biopharmaceutics & Pharmacokinetics, Department of Pharmacy, School of Health Sciences, National & Kapodistrian University of Athens, 15784 Athens, GreeceDepartment of Engineering, School of Pharmacy, Miguel Hernández University, 03550 San Juan de Alicante, SpainBone Marrow Transplant Unit, “Agia Sophia” Children’s Hospital of Athens, 15127 Athens, GreeceBone Marrow Transplant Unit, “Agia Sophia” Children’s Hospital of Athens, 15127 Athens, GreeceBone Marrow Transplant Unit, “Agia Sophia” Children’s Hospital of Athens, 15127 Athens, GreeceDepartment of Internal Medicine, Bone Marrow Transplantation Unit, University Hospital of Patras, 26504 Patras, GreeceBone Marrow Transplant Unit, “Agia Sophia” Children’s Hospital of Athens, 15127 Athens, GreeceBone Marrow Transplant Unit, “Agia Sophia” Children’s Hospital of Athens, 15127 Athens, GreeceLaboratory of Biopharmaceutics & Pharmacokinetics, Department of Pharmacy, School of Health Sciences, National & Kapodistrian University of Athens, 15784 Athens, GreeceLaboratory of Biopharmaceutics & Pharmacokinetics, Department of Pharmacy, School of Health Sciences, National & Kapodistrian University of Athens, 15784 Athens, GreeceWe 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.https://www.mdpi.com/1999-4923/14/3/647busulfanpaediatricacute myelogenous leukemiahematopoietic stem cell transplantationpharmacometricsmodel-informed precision dosing |
| spellingShingle | Efthymios Neroutsos Ricardo Nalda-Molina Anna Paisiou Kalliopi Zisaki Evgenios Goussetis Alexandros Spyridonidis Vasiliki Kitra Stelios Grafakos Georgia Valsami Aristides Dokoumetzidis Development of a Population Pharmacokinetic Model of Busulfan in Children and Evaluation of Different Sampling Schedules for Precision Dosing Pharmaceutics busulfan paediatric acute myelogenous leukemia hematopoietic stem cell transplantation pharmacometrics model-informed precision dosing |
| title | Development of a Population Pharmacokinetic Model of Busulfan in Children and Evaluation of Different Sampling Schedules for Precision Dosing |
| title_full | Development of a Population Pharmacokinetic Model of Busulfan in Children and Evaluation of Different Sampling Schedules for Precision Dosing |
| title_fullStr | Development of a Population Pharmacokinetic Model of Busulfan in Children and Evaluation of Different Sampling Schedules for Precision Dosing |
| title_full_unstemmed | Development of a Population Pharmacokinetic Model of Busulfan in Children and Evaluation of Different Sampling Schedules for Precision Dosing |
| title_short | Development of a Population Pharmacokinetic Model of Busulfan in Children and Evaluation of Different Sampling Schedules for Precision Dosing |
| title_sort | development of a population pharmacokinetic model of busulfan in children and evaluation of different sampling schedules for precision dosing |
| topic | busulfan paediatric acute myelogenous leukemia hematopoietic stem cell transplantation pharmacometrics model-informed precision dosing |
| url | https://www.mdpi.com/1999-4923/14/3/647 |
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