Population Pharmacokinetics of Alemtuzumab (Campath) in Pediatric Hematopoietic Cell Transplantation: Towards Individualized Dosing to Improve Outcome

Rick Admiraal; Cornelia M Jol-van der Zijde; Juliana M Furtado Silva; Catherijne A J Knibbe; Arjan C Lankester; Jaap Jan Boelens; Goeff Hale; Aniekan Etuk; Melanie Wilson; Stuart Adams; Paul Veys; Charlotte van Kesteren; Robbert G M Bredius

doi:10.1007/s40262-019-00782-0

Population Pharmacokinetics of Alemtuzumab (Campath) in Pediatric Hematopoietic Cell Transplantation: Towards Individualized Dosing to Improve Outcome

Rick Admiraal, Cornelia M Jol-van der Zijde, Juliana M Furtado Silva, Catherijne A J Knibbe, Arjan C Lankester, Jaap Jan Boelens, Goeff Hale, Aniekan Etuk, Melanie Wilson, Stuart Adams, Paul Veys, Charlotte van Kesteren, Robbert G M Bredius

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND AND OBJECTIVE: Alemtuzumab (Campath®) is used to prevent graft-versus-host disease and graft failure following pediatric allogeneic hematopoietic cell transplantation. The main toxicity includes delayed immune reconstitution, subsequent viral reactivations, and leukemia relapse. Exposure to alemtuzumab is highly variable upon empirical milligram/kilogram dosing.

METHODS: A population pharmacokinetic (PK) model for alemtuzumab was developed based on a total of 1146 concentration samples from 206 patients, aged 0.2-19 years, receiving a cumulative intravenous dose of 0.2-1.5 mg/kg, and treated between 2003 and 2015 in two centers.

RESULTS: Alemtuzumab PK were best described using a two-compartment model with a parallel saturable and linear elimination pathway. The linear clearance pathway, central volume of distribution, and intercompartmental distribution increased with body weight. Blood lymphocyte counts, a potential substrate for alemtuzumab, did not impact clearance.

CONCLUSION: The current practice with uniform milligram/kilogram doses leads to highly variable exposures in children due to the non-linear relationship between body weight and alemtuzumab PK. This model may be used for individualized dosing of alemtuzumab.

Original language	English
Pages (from-to)	1609-1620
Number of pages	12
Journal	Clinical Pharmacokinetics
Volume	58
Issue number	12
DOIs	https://doi.org/10.1007/s40262-019-00782-0
Publication status	Published - Dec 2019
Externally published	Yes

Keywords

Adolescent
Alemtuzumab/administration & dosage
Antineoplastic Agents, Immunological/administration & dosage
Body Weight
Child
Child, Preschool
Dose-Response Relationship, Drug
Female
Graft vs Host Disease/prevention & control
Hematopoietic Stem Cell Transplantation/methods
Humans
Infant
Male
Models, Biological
Precision Medicine
Prospective Studies
Tissue Distribution
Young Adult

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10.1007/s40262-019-00782-0

Cite this

Admiraal, R., Jol-van der Zijde, C. M., Furtado Silva, J. M., Knibbe, C. A. J., Lankester, A. C., Boelens, J. J., Hale, G., Etuk, A., Wilson, M., Adams, S., Veys, P., van Kesteren, C., & Bredius, R. G. M. (2019). Population Pharmacokinetics of Alemtuzumab (Campath) in Pediatric Hematopoietic Cell Transplantation: Towards Individualized Dosing to Improve Outcome. Clinical Pharmacokinetics, 58(12), 1609-1620. https://doi.org/10.1007/s40262-019-00782-0

@article{e1a5605ae01e4e47b08605a3fc916b29,

title = "Population Pharmacokinetics of Alemtuzumab (Campath) in Pediatric Hematopoietic Cell Transplantation: Towards Individualized Dosing to Improve Outcome",

abstract = "BACKGROUND AND OBJECTIVE: Alemtuzumab (Campath{\textregistered}) is used to prevent graft-versus-host disease and graft failure following pediatric allogeneic hematopoietic cell transplantation. The main toxicity includes delayed immune reconstitution, subsequent viral reactivations, and leukemia relapse. Exposure to alemtuzumab is highly variable upon empirical milligram/kilogram dosing.METHODS: A population pharmacokinetic (PK) model for alemtuzumab was developed based on a total of 1146 concentration samples from 206 patients, aged 0.2-19 years, receiving a cumulative intravenous dose of 0.2-1.5 mg/kg, and treated between 2003 and 2015 in two centers.RESULTS: Alemtuzumab PK were best described using a two-compartment model with a parallel saturable and linear elimination pathway. The linear clearance pathway, central volume of distribution, and intercompartmental distribution increased with body weight. Blood lymphocyte counts, a potential substrate for alemtuzumab, did not impact clearance.CONCLUSION: The current practice with uniform milligram/kilogram doses leads to highly variable exposures in children due to the non-linear relationship between body weight and alemtuzumab PK. This model may be used for individualized dosing of alemtuzumab.",

keywords = "Adolescent, Alemtuzumab/administration & dosage, Antineoplastic Agents, Immunological/administration & dosage, Body Weight, Child, Child, Preschool, Dose-Response Relationship, Drug, Female, Graft vs Host Disease/prevention & control, Hematopoietic Stem Cell Transplantation/methods, Humans, Infant, Male, Models, Biological, Precision Medicine, Prospective Studies, Tissue Distribution, Young Adult",

author = "Rick Admiraal and {Jol-van der Zijde}, {Cornelia M} and {Furtado Silva}, {Juliana M} and Knibbe, {Catherijne A J} and Lankester, {Arjan C} and Boelens, {Jaap Jan} and Goeff Hale and Aniekan Etuk and Melanie Wilson and Stuart Adams and Paul Veys and {van Kesteren}, Charlotte and Bredius, {Robbert G M}",

year = "2019",

month = dec,

doi = "10.1007/s40262-019-00782-0",

language = "English",

volume = "58",

pages = "1609--1620",

journal = "Clinical Pharmacokinetics",

issn = "0312-5963",

publisher = "Adis",

number = "12",

}

Admiraal, R, Jol-van der Zijde, CM, Furtado Silva, JM, Knibbe, CAJ, Lankester, AC, Boelens, JJ, Hale, G, Etuk, A, Wilson, M, Adams, S, Veys, P, van Kesteren, C & Bredius, RGM 2019, 'Population Pharmacokinetics of Alemtuzumab (Campath) in Pediatric Hematopoietic Cell Transplantation: Towards Individualized Dosing to Improve Outcome', Clinical Pharmacokinetics, vol. 58, no. 12, pp. 1609-1620. https://doi.org/10.1007/s40262-019-00782-0

Population Pharmacokinetics of Alemtuzumab (Campath) in Pediatric Hematopoietic Cell Transplantation: Towards Individualized Dosing to Improve Outcome. / Admiraal, Rick; Jol-van der Zijde, Cornelia M; Furtado Silva, Juliana M et al.
In: Clinical Pharmacokinetics, Vol. 58, No. 12, 12.2019, p. 1609-1620.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Population Pharmacokinetics of Alemtuzumab (Campath) in Pediatric Hematopoietic Cell Transplantation

T2 - Towards Individualized Dosing to Improve Outcome

AU - Admiraal, Rick

AU - Jol-van der Zijde, Cornelia M

AU - Furtado Silva, Juliana M

AU - Knibbe, Catherijne A J

AU - Lankester, Arjan C

AU - Boelens, Jaap Jan

AU - Hale, Goeff

AU - Etuk, Aniekan

AU - Wilson, Melanie

AU - Adams, Stuart

AU - Veys, Paul

AU - van Kesteren, Charlotte

AU - Bredius, Robbert G M

PY - 2019/12

Y1 - 2019/12

N2 - BACKGROUND AND OBJECTIVE: Alemtuzumab (Campath®) is used to prevent graft-versus-host disease and graft failure following pediatric allogeneic hematopoietic cell transplantation. The main toxicity includes delayed immune reconstitution, subsequent viral reactivations, and leukemia relapse. Exposure to alemtuzumab is highly variable upon empirical milligram/kilogram dosing.METHODS: A population pharmacokinetic (PK) model for alemtuzumab was developed based on a total of 1146 concentration samples from 206 patients, aged 0.2-19 years, receiving a cumulative intravenous dose of 0.2-1.5 mg/kg, and treated between 2003 and 2015 in two centers.RESULTS: Alemtuzumab PK were best described using a two-compartment model with a parallel saturable and linear elimination pathway. The linear clearance pathway, central volume of distribution, and intercompartmental distribution increased with body weight. Blood lymphocyte counts, a potential substrate for alemtuzumab, did not impact clearance.CONCLUSION: The current practice with uniform milligram/kilogram doses leads to highly variable exposures in children due to the non-linear relationship between body weight and alemtuzumab PK. This model may be used for individualized dosing of alemtuzumab.

AB - BACKGROUND AND OBJECTIVE: Alemtuzumab (Campath®) is used to prevent graft-versus-host disease and graft failure following pediatric allogeneic hematopoietic cell transplantation. The main toxicity includes delayed immune reconstitution, subsequent viral reactivations, and leukemia relapse. Exposure to alemtuzumab is highly variable upon empirical milligram/kilogram dosing.METHODS: A population pharmacokinetic (PK) model for alemtuzumab was developed based on a total of 1146 concentration samples from 206 patients, aged 0.2-19 years, receiving a cumulative intravenous dose of 0.2-1.5 mg/kg, and treated between 2003 and 2015 in two centers.RESULTS: Alemtuzumab PK were best described using a two-compartment model with a parallel saturable and linear elimination pathway. The linear clearance pathway, central volume of distribution, and intercompartmental distribution increased with body weight. Blood lymphocyte counts, a potential substrate for alemtuzumab, did not impact clearance.CONCLUSION: The current practice with uniform milligram/kilogram doses leads to highly variable exposures in children due to the non-linear relationship between body weight and alemtuzumab PK. This model may be used for individualized dosing of alemtuzumab.

KW - Adolescent

KW - Alemtuzumab/administration & dosage

KW - Antineoplastic Agents, Immunological/administration & dosage

KW - Body Weight

KW - Child

KW - Child, Preschool

KW - Dose-Response Relationship, Drug

KW - Female

KW - Graft vs Host Disease/prevention & control

KW - Hematopoietic Stem Cell Transplantation/methods

KW - Humans

KW - Infant

KW - Male

KW - Models, Biological

KW - Precision Medicine

KW - Prospective Studies

KW - Tissue Distribution

KW - Young Adult

U2 - 10.1007/s40262-019-00782-0

DO - 10.1007/s40262-019-00782-0

M3 - Article

C2 - 31131436

SN - 0312-5963

VL - 58

SP - 1609

EP - 1620

JO - Clinical Pharmacokinetics

JF - Clinical Pharmacokinetics

IS - 12

ER -

Population Pharmacokinetics of Alemtuzumab (Campath) in Pediatric Hematopoietic Cell Transplantation: Towards Individualized Dosing to Improve Outcome

Abstract

Keywords

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