TY - JOUR
T1 - Population Pharmacokinetics of Inotuzumab Ozogamicin in Pediatric Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia
T2 - Results of Study ITCC-059
AU - Wu, Jen Hao
AU - Pennesi, Edoardo
AU - Bautista, Francisco
AU - Garrett, May
AU - Fukuhara, Kei
AU - Brivio, Erica
AU - Ammerlaan, Anneke C.J.
AU - Locatelli, Franco
AU - van der Sluis, Inge M.
AU - Rossig, Claudia
AU - Chen-Santel, Christiane
AU - Bielorai, Bella
AU - Petit, Arnaud
AU - Starý, Jan
AU - Díaz-de-Heredia, Cristina
AU - Rives, Susana
AU - O’Marcaigh, Aengus
AU - Rizzari, Carmelo
AU - Engstler, Gernot
AU - Nysom, Karsten
AU - Rubio-San-Simón, Alba
AU - Bruno, Benedicte
AU - Bertrand, Yves
AU - Brethon, Benoît
AU - Rialland, Fanny
AU - Plat, Geneviève
AU - Dirksen, Uta
AU - Sramkova, Lucie
AU - Zwaan, C. Michel
AU - Huitema, Alwin D.R.
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/7
Y1 - 2024/7
N2 - Background and Objective: Inotuzumab ozogamicin is an antibody-drug conjugate approved for treating relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults. Pediatric pharmacokinetic data of inotuzumab ozogamicin are lacking. This study is the first to examine the population pharmacokinetics of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL. Methods: From 531 adult patients with B-cell non-Hodgkin’s lymphoma, 234 adult patients with BCP-ALL, and 53 pediatric patients with BCP-ALL, 8924 inotuzumab ozogamicin serum concentrations were analyzed using non-linear mixed-effects modeling. A published adult inotuzumab ozogamicin population-pharmacokinetic model, a two-compartment model with linear and time-dependent clearance, was adapted to describe the pediatric data. Results: Modifications in this analysis, compared to the published adult model, included: (i) re-estimating pharmacokinetic parameters and covariate effects; (ii) modifying covariate representation; and (iii) introducing relevant pediatric covariate effects (age on the decay coefficient of time-dependent clearance and ALL effect (disease type and/or different bioanalytical analysis methods) on initial values of time-dependent clearance). For patients with relapsed/refractory BCP-ALL, increasing age was associated with a decreasing decay coefficient of time-dependent clearance, reflecting that the target-mediated drug clearance declines more rapidly in children. In pediatric BCP-ALL, the median [interquartile range] cumulative area under the concentration–time curve was significantly higher among responders (n = 42) versus non-responders (n = 10) at the end of the first cycle (26.1 [18.9–35.0] vs 10.1 [9.19–16.1], × 103 ng*h/mL, p < 0.001). From simulations performed at the recommended pediatric phase II dose, inotuzumab ozogamicin exposure reached a similar level as observed in responding pediatric trial participants. Conclusions: The pharmacokinetic profile of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL was well described in this study. No dose adjustment is required clinically for pediatric patients with BCP-ALL based on the simulated inotuzumab ozogamicin exposure at the recommended pediatric phase II dose, promising efficacy and acceptable tolerability.
AB - Background and Objective: Inotuzumab ozogamicin is an antibody-drug conjugate approved for treating relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults. Pediatric pharmacokinetic data of inotuzumab ozogamicin are lacking. This study is the first to examine the population pharmacokinetics of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL. Methods: From 531 adult patients with B-cell non-Hodgkin’s lymphoma, 234 adult patients with BCP-ALL, and 53 pediatric patients with BCP-ALL, 8924 inotuzumab ozogamicin serum concentrations were analyzed using non-linear mixed-effects modeling. A published adult inotuzumab ozogamicin population-pharmacokinetic model, a two-compartment model with linear and time-dependent clearance, was adapted to describe the pediatric data. Results: Modifications in this analysis, compared to the published adult model, included: (i) re-estimating pharmacokinetic parameters and covariate effects; (ii) modifying covariate representation; and (iii) introducing relevant pediatric covariate effects (age on the decay coefficient of time-dependent clearance and ALL effect (disease type and/or different bioanalytical analysis methods) on initial values of time-dependent clearance). For patients with relapsed/refractory BCP-ALL, increasing age was associated with a decreasing decay coefficient of time-dependent clearance, reflecting that the target-mediated drug clearance declines more rapidly in children. In pediatric BCP-ALL, the median [interquartile range] cumulative area under the concentration–time curve was significantly higher among responders (n = 42) versus non-responders (n = 10) at the end of the first cycle (26.1 [18.9–35.0] vs 10.1 [9.19–16.1], × 103 ng*h/mL, p < 0.001). From simulations performed at the recommended pediatric phase II dose, inotuzumab ozogamicin exposure reached a similar level as observed in responding pediatric trial participants. Conclusions: The pharmacokinetic profile of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL was well described in this study. No dose adjustment is required clinically for pediatric patients with BCP-ALL based on the simulated inotuzumab ozogamicin exposure at the recommended pediatric phase II dose, promising efficacy and acceptable tolerability.
UR - https://www.scopus.com/pages/publications/85196667879
U2 - 10.1007/s40262-024-01386-z
DO - 10.1007/s40262-024-01386-z
M3 - Article
C2 - 38907948
AN - SCOPUS:85196667879
SN - 0312-5963
VL - 63
SP - 981
EP - 997
JO - Clinical Pharmacokinetics
JF - Clinical Pharmacokinetics
IS - 7
ER -