TY - JOUR
T1 - Individualized dosing guidelines for PEGasparaginase and factors influencing the clearance
T2 - A population pharmacokinetic model
AU - Kloos, Robin Q.H.
AU - Mathôt, Ron
AU - Pieters, Rob
AU - van der Sluis, Inge M.
N1 - Funding Information: This work was supported by the KiKa foundation.
Publisher Copyright: © 2021 Ferrata Storti Foundation
PY - 2021/5
Y1 - 2021/5
N2 - Considerable inter- and intra-patient variability exist in serum activity levels of PEGasparaginase, essential for pediatric acute lymphoblastic leukemia (ALL) treatment. A population pharmacokinetic (popPK) model was developed, identifying patient characteristics that explain these variabilities. Patients (n=92) were treated according to the Dutch Childhood Oncology Group (DCOG) ALL-11 protocol, using therapeutic drug monitoring to individualize PEGasparaginase doses. Non-linear mixed effects modeling (NONMEM) was used to analyze popPK evaluating several covariates. The final model was validated using an independent database (n=28). Guidelines for starting doses and dose adjustments were developed. A one-compartment model with time-dependent clearance was adequately described in popPK. Normalization of clearance and volume of distribution by body surface area reduced inter-individual variability. Clearance was 0.084 L/day/m2 for 12.7 days, increasing by 0.082 L/day/m2/day thereafter. Clearance was 38% higher during an infection, and 11-19% higher during induction treatment than during intensification and maintenance (P<0.001). In order to target an asparaginase activity level of 100 IU/L, a loading dose of 800 IU/m2 (induction) and 600 IU/m2 (intensification) is advised. In conclusion, variability of PEGasparaginase activity levels can be explained by body surface area, the treatment phase and the occurrence of an infection. With this popPK model, PEGasparaginase treatment can be individualized further, taking into account the covariates and the dosing guidelines provided. (clinicaltrials gov. Identifier [CCMO register]: NL50250.078.14).
AB - Considerable inter- and intra-patient variability exist in serum activity levels of PEGasparaginase, essential for pediatric acute lymphoblastic leukemia (ALL) treatment. A population pharmacokinetic (popPK) model was developed, identifying patient characteristics that explain these variabilities. Patients (n=92) were treated according to the Dutch Childhood Oncology Group (DCOG) ALL-11 protocol, using therapeutic drug monitoring to individualize PEGasparaginase doses. Non-linear mixed effects modeling (NONMEM) was used to analyze popPK evaluating several covariates. The final model was validated using an independent database (n=28). Guidelines for starting doses and dose adjustments were developed. A one-compartment model with time-dependent clearance was adequately described in popPK. Normalization of clearance and volume of distribution by body surface area reduced inter-individual variability. Clearance was 0.084 L/day/m2 for 12.7 days, increasing by 0.082 L/day/m2/day thereafter. Clearance was 38% higher during an infection, and 11-19% higher during induction treatment than during intensification and maintenance (P<0.001). In order to target an asparaginase activity level of 100 IU/L, a loading dose of 800 IU/m2 (induction) and 600 IU/m2 (intensification) is advised. In conclusion, variability of PEGasparaginase activity levels can be explained by body surface area, the treatment phase and the occurrence of an infection. With this popPK model, PEGasparaginase treatment can be individualized further, taking into account the covariates and the dosing guidelines provided. (clinicaltrials gov. Identifier [CCMO register]: NL50250.078.14).
UR - http://www.scopus.com/inward/record.url?scp=85102318315&partnerID=8YFLogxK
U2 - 10.3324/haematol.2019.242289
DO - 10.3324/haematol.2019.242289
M3 - Article
C2 - 32327497
AN - SCOPUS:85102318315
SN - 0390-6078
VL - 106
SP - 1254
EP - 1261
JO - Haematologica
JF - Haematologica
IS - 5
ER -