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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Veröffentlicht in:	Therapeutic drug monitoring Jg. 37; H. 2; S. 236
Hauptverfasser:	Long-Boyle, Janel R, Savic, Rada, Yan, Shirley, Bartelink, Imke, Musick, Lisa, French, Deborah, Law, Jason, Horn, Biljana, Cowan, Morton J, Dvorak, Christopher C
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States 01.04.2015
Schlagworte:	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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Abstract	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.
AbstractList	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. 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.BACKGROUNDPopulation 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.PATIENTS AND METHODSModel 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).RESULTSModeling 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.CONCLUSIONSWhen compared with the conventional dosing guidelines, the model-based algorithm demonstrates significant improvement for providing targeted busulfan therapy in children and young adults.
Author	Long-Boyle, Janel R Law, Jason Bartelink, Imke Yan, Shirley Horn, Biljana Dvorak, Christopher C Cowan, Morton J Savic, Rada Musick, Lisa French, Deborah
Author_xml	– sequence: 1 givenname: Janel R surname: Long-Boyle fullname: Long-Boyle, Janel R organization: Departments of Clinical Pharmacy, and †Bioengineering and Therapeutics, University of California San Francisco; ‡Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York, NY; Departments of §Pharmacy, UCSF Benioff Children's Hospital, and ¶Laboratory Medicine, UCSF Medical Center, University of California San Francisco; ‖Department of Pediatrics, Floating Hospital for Children, Tufts University, Boston, MA; and Department of Pediatrics, UCSF Benioff Children's Hospital, University of California San Francisco – sequence: 2 givenname: Rada surname: Savic fullname: Savic, Rada – sequence: 3 givenname: Shirley surname: Yan fullname: Yan, Shirley – sequence: 4 givenname: Imke surname: Bartelink fullname: Bartelink, Imke – sequence: 5 givenname: Lisa surname: Musick fullname: Musick, Lisa – sequence: 6 givenname: Deborah surname: French fullname: French, Deborah – sequence: 7 givenname: Jason surname: Law fullname: Law, Jason – sequence: 8 givenname: Biljana surname: Horn fullname: Horn, Biljana – sequence: 9 givenname: Morton J surname: Cowan fullname: Cowan, Morton J – sequence: 10 givenname: Christopher C surname: Dvorak fullname: Dvorak, Christopher C
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SubjectTerms	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
Title	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
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