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oai:recercat.cat:11351/118682025-10-24T10:37:13Zcom_2072_378070com_2072_378040col_2072_378092

Population Pharmacokinetics of Inotuzumab Ozogamicin in Pediatric Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: Results of Study ITCC-059 Wu, Jen-Hao Pennesi, Edoardo Bautista, F. Garrett, May Fukuhara, Kei Fukuhara Brivio, Erica Diaz de Heredia, Cristina Institut Català de la Salut [Wu JH, Pennesi E, Brivio E] Department of Pediatric Oncology, Erasmus MCSophia Children’s Hospital Rotterdam, Rotterdam, The Netherlands. Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands. [Bautista F] Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands. [Garrett M] Pfzer Global Pharmacometrics, San Diego, CA, USA. [ukuhara K] Pfzer R&D Japan, Tokyo, Japan. [Díaz de Heredia C] Servei d’Hematologia i Oncologia Pediàtriques, Vall d’Hebron Hospital Universitari, Barcelona, Spain Vall d'Hebron Barcelona Hospital Campus Infants Leucèmia limfoblàstica - Tractament Medicaments antineoplàstics - Ús terapèutic Càncer - Recaiguda DISEASES::Hemic and Lymphatic Diseases::Lymphatic Diseases::Lymphoproliferative Disorders::Leukemia, Lymphoid::Precursor Cell Lymphoblastic Leukemia-Lymphoma::Precursor B-Cell Lymphoblastic Leukemia-Lymphoma CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents::Antineoplastic Agents, Immunological Other subheadings::Other subheadings::/therapeutic use NAMED GROUPS::Persons::Age Groups::Child DISEASES::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Recurrence ENFERMEDADES::enfermedades hematológicas y linfáticas::enfermedades linfáticas::trastornos linfoproliferativos::leucemia linfoide::leucemia-linfoma linfoblástico de células precursoras::leucemia-linfoma linfoblástico de células B precursoras COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos::inmunoterapia antineoplásica Otros calificadores::Otros calificadores::/uso terapéutico DENOMINACIONES DE GRUPOS::personas::Grupos de Edad::niño ENFERMEDADES::afecciones patológicas, signos y síntomas::procesos patológicos::atributos de la enfermedad::recurrencia Population pharmacokinetics; Inotuzumab ozogamicin; Acute lymphoblastic leukemia Farmacocinètica poblacional; Inotuzumab ozogamicina; Leucèmia limfoblàstica aguda Farmacocinética poblacional; Inotuzumab ozogamicina; Leucemia linfoblástica aguda 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. ITCC-059 was sponsored by Erasmus MC and financed by Pfizer. 2024-08-26T07:04:20Z 2024-08-26T07:04:20Z 2024-07 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Wu JH, Pennesi E, Bautista F, Garrett M, Fukuhara K, Brivio E, et al. Population Pharmacokinetics of Inotuzumab Ozogamicin in Pediatric Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: Results of Study ITCC-059. Clin Pharmacokinet. 2024 Jul;63:981–997. 1179-1926 https://hdl.handle.net/11351/11868 10.1007/s40262-024-01386-z 38907948 001253108500001 http://hdl.handle.net/11351/11868 eng Clinical Pharmacokinetics;63 https://doi.org/10.1007/s40262-024-01386-z Attribution-NonCommercial 4.0 International http://creativecommons.org/licenses/by-nc/4.0/ info:eu-repo/semantics/openAccess application/pdf Scientia