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 -