Population pharmacokinetics of busulfan in pediatric and young adult patients undergoing hematopoietic cell transplant: a model-based dosing algorithm for personalized therapy and implementation into routine clinical use

Population pharmacokinetic (PK) studies of busulfan in children have shown that individualized model-based algorithms provide improved targeted busulfan therapy when compared with conventional dose guidelines. The adoption of population PK models into routine clinical practice has been hampered by t...

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Vydané v:Therapeutic drug monitoring Ročník 37; číslo 2; s. 236
Hlavní autori: Long-Boyle, Janel R, Savic, Rada, Yan, Shirley, Bartelink, Imke, Musick, Lisa, French, Deborah, Law, Jason, Horn, Biljana, Cowan, Morton J, Dvorak, Christopher C
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States 01.04.2015
Predmet:
Adolescent
Age Factors
Algorithms
Busulfan - administration & dosage
Busulfan - pharmacokinetics
Child
Child, Preschool
Female
Hematopoietic Stem Cell Transplantation
Humans
Immunosuppressive Agents - administration & dosage
Immunosuppressive Agents - pharmacokinetics
Infant
Male
Models, Biological
Nonlinear Dynamics
Precision Medicine
Retrospective Studies
Young Adult
ISSN:1536-3694, 1536-3694
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Shrnutí:Population pharmacokinetic (PK) studies of busulfan in children have shown that individualized model-based algorithms provide improved targeted busulfan therapy when compared with conventional dose guidelines. The adoption of population PK models into routine clinical practice has been hampered by the tendency of pharmacologists to develop complex models too impractical for clinicians to use. The authors aimed to develop a population PK model for busulfan in children that can reliably achieve therapeutic exposure (concentration at steady state) and implement a simple model-based tool for the initial dosing of busulfan in children undergoing hematopoietic cell transplantation. Model development was conducted using retrospective data available in 90 pediatric and young adult patients who had undergone hematopoietic cell transplantation with busulfan conditioning. Busulfan drug levels and potential covariates influencing drug exposure were analyzed using the nonlinear mixed effects modeling software, NONMEM. The final population PK model was implemented into a clinician-friendly Microsoft Excel-based tool and used to recommend initial doses of busulfan in a group of 21 pediatric patients prospectively dosed based on the population PK model. Modeling of busulfan time-concentration data indicates that busulfan clearance displays nonlinearity in children, decreasing up to approximately 20% between the concentrations of 250-2000 ng/mL. Important patient-specific covariates found to significantly impact busulfan clearance were actual body weight and age. The percentage of individuals achieving a therapeutic concentration at steady state was significantly higher in subjects receiving initial doses based on the population PK model (81%) than in historical controls dosed on conventional guidelines (52%) (P = 0.02). When compared with the conventional dosing guidelines, the model-based algorithm demonstrates significant improvement for providing targeted busulfan therapy in children and young adults.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1536-3694
1536-3694
DOI:10.1097/FTD.0000000000000131