TY - JOUR
T1 - Pharmacokinetics of PEGasparaginase in Infants with Acute Lymphoblastic Leukemia
AU - Brigitha, Leiah J.
AU - Mondelaers, Veerle
AU - Liu, Yiwei
AU - Albertsen, Birgitte K.
AU - Zalewska-Szewczyk, Beata
AU - Rizzari, Carmelo
AU - Kotecha, Rishi S.
AU - Pieters, Rob
AU - Huitema, Alwin D.R.
AU - van der Sluis, Inge M.
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024.
PY - 2024/4
Y1 - 2024/4
N2 - Background: PEGasparaginase is known to be a critical drug for treating pediatric acute lymphoblastic leukemia (ALL), however, there is insufficient evidence to determine the optimal dose for infants who are less than one year of age at diagnosis. This international study was conducted to identify the pharmacokinetics of PEGasparaginase in infants with newly diagnosed ALL and gather insight into the clearance and dosing of this population. Methods: Infants with ALL who received treatment with PEGasparaginase were included in our population pharmacokinetic assessment employing non-linear mixed effects modelling (NONMEM). Results: 68 infants with ALL, with a total of 388 asparaginase activity samples, were included. PEGasparaginase doses ranging from 400 to 3,663 IU/m2 were administered either intravenously or intramuscularly. A one-compartment model with time-dependent clearance, modeled using a transit model, provided the best fit to the data. Body weight was significantly correlated with clearance and volume of distribution. The final model estimated a half-life of 11.7 days just after administration, which decreased to 1.8 days 14 days after administration. Clearance was 19.5% lower during the post-induction treatment phase compared to induction. Conclusion: The pharmacokinetics of PEGasparaginase in infants diagnosed under one year of age with ALL is comparable to that of older children (1–18 years). We recommend a PEGasparaginase dosing at 1,500 IU/m2 for infants without dose adaptations according to age, and implementing therapeutic drug monitoring as standard practice.
AB - Background: PEGasparaginase is known to be a critical drug for treating pediatric acute lymphoblastic leukemia (ALL), however, there is insufficient evidence to determine the optimal dose for infants who are less than one year of age at diagnosis. This international study was conducted to identify the pharmacokinetics of PEGasparaginase in infants with newly diagnosed ALL and gather insight into the clearance and dosing of this population. Methods: Infants with ALL who received treatment with PEGasparaginase were included in our population pharmacokinetic assessment employing non-linear mixed effects modelling (NONMEM). Results: 68 infants with ALL, with a total of 388 asparaginase activity samples, were included. PEGasparaginase doses ranging from 400 to 3,663 IU/m2 were administered either intravenously or intramuscularly. A one-compartment model with time-dependent clearance, modeled using a transit model, provided the best fit to the data. Body weight was significantly correlated with clearance and volume of distribution. The final model estimated a half-life of 11.7 days just after administration, which decreased to 1.8 days 14 days after administration. Clearance was 19.5% lower during the post-induction treatment phase compared to induction. Conclusion: The pharmacokinetics of PEGasparaginase in infants diagnosed under one year of age with ALL is comparable to that of older children (1–18 years). We recommend a PEGasparaginase dosing at 1,500 IU/m2 for infants without dose adaptations according to age, and implementing therapeutic drug monitoring as standard practice.
KW - acute lymphoblastic leukemia
KW - infant
KW - PEgasparaginase
KW - population pharmacokinetics
UR - http://www.scopus.com/inward/record.url?scp=85188690516&partnerID=8YFLogxK
U2 - 10.1007/s11095-024-03693-3
DO - 10.1007/s11095-024-03693-3
M3 - Article
C2 - 38538970
AN - SCOPUS:85188690516
SN - 0724-8741
VL - 41
SP - 711
EP - 720
JO - Pharmaceutical Research
JF - Pharmaceutical Research
IS - 4
ER -