Population Pharmacokinetics of Inotuzumab Ozogamicin in Pediatric Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: Results of Study ITCC-059
Copyright policy )Population Pharmacokinetics of Inotuzumab Ozogamicin in Pediatric Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: Results of Study ITCC-059
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.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.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.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.
- Catholic University of the Sacred Heart Italy
- Sorbonne Paris Cité France
- Charles University Czech Republic
- Sorbonne University France
- University Hospital in Motol Czech Republic
DISEASES::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Recurrence, Male, Adult, Adolescent, Other subheadings::Other subheadings::/therapeutic use, NAMED GROUPS::Persons::Age Groups::Child, Medizin, Otros calificadores::Otros calificadores::/uso terapéutico, Adolescent [MeSH] ; Female [MeSH] ; Aged [MeSH] ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy [MeSH] ; Adult [MeSH] ; Humans [MeSH] ; Middle Aged [MeSH] ; Models, Biological [MeSH] ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/blood [MeSH] ; Recurrence [MeSH] ; Infant [MeSH] ; Male [MeSH] ; Antineoplastic Agents, Immunological/therapeutic use [MeSH] ; Young Adult [MeSH] ; Antineoplastic Agents, Immunological/administration ; Antineoplastic Agents, Immunological/pharmacokinetics [MeSH] ; Original Research Article ; Inotuzumab Ozogamicin/pharmacokinetics [MeSH] ; Child [MeSH] ; Child, Preschool [MeSH] ; Inotuzumab Ozogamicin/administration, Medicaments antineoplàstics - Ús terapèutic, DENOMINACIONES DE GRUPOS::personas::Grupos de Edad::niño, Models, Biological, Young Adult, Antineoplastic Agents, Immunological, Càncer - Recaiguda, COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos::inmunoterapia antineoplásica, Recurrence, DISEASES::Hemic and Lymphatic Diseases::Lymphatic Diseases::Lymphoproliferative Disorders::Leukemia, Lymphoid::Precursor Cell Lymphoblastic Leukemia-Lymphoma::Precursor B-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, Humans, Pharmacology (medical), Inotuzumab Ozogamicin, Original Research Article, Child, Leucèmia limfoblàstica - Tractament, Aged, Pharmacology, Infant, Middle Aged, ENFERMEDADES::afecciones patológicas, signos y síntomas::procesos patológicos::atributos de la enfermedad::recurrencia, Child, Preschool, Female, Infants, ENFERMEDADES::enfermedades hematológicas y linfáticas::enfermedades linfáticas::trastornos linfoproliferativos::leucemia linfoide::leucemia-linfoma linfoblástico de células precursoras::leucemia-linfoma linfoblástico de células B precursoras
DISEASES::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Recurrence, Male, Adult, Adolescent, Other subheadings::Other subheadings::/therapeutic use, NAMED GROUPS::Persons::Age Groups::Child, Medizin, Otros calificadores::Otros calificadores::/uso terapéutico, Adolescent [MeSH] ; Female [MeSH] ; Aged [MeSH] ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy [MeSH] ; Adult [MeSH] ; Humans [MeSH] ; Middle Aged [MeSH] ; Models, Biological [MeSH] ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/blood [MeSH] ; Recurrence [MeSH] ; Infant [MeSH] ; Male [MeSH] ; Antineoplastic Agents, Immunological/therapeutic use [MeSH] ; Young Adult [MeSH] ; Antineoplastic Agents, Immunological/administration ; Antineoplastic Agents, Immunological/pharmacokinetics [MeSH] ; Original Research Article ; Inotuzumab Ozogamicin/pharmacokinetics [MeSH] ; Child [MeSH] ; Child, Preschool [MeSH] ; Inotuzumab Ozogamicin/administration, Medicaments antineoplàstics - Ús terapèutic, DENOMINACIONES DE GRUPOS::personas::Grupos de Edad::niño, Models, Biological, Young Adult, Antineoplastic Agents, Immunological, Càncer - Recaiguda, COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos::inmunoterapia antineoplásica, Recurrence, DISEASES::Hemic and Lymphatic Diseases::Lymphatic Diseases::Lymphoproliferative Disorders::Leukemia, Lymphoid::Precursor Cell Lymphoblastic Leukemia-Lymphoma::Precursor B-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, Humans, Pharmacology (medical), Inotuzumab Ozogamicin, Original Research Article, Child, Leucèmia limfoblàstica - Tractament, Aged, Pharmacology, Infant, Middle Aged, ENFERMEDADES::afecciones patológicas, signos y síntomas::procesos patológicos::atributos de la enfermedad::recurrencia, Child, Preschool, Female, Infants, ENFERMEDADES::enfermedades hematológicas y linfáticas::enfermedades linfáticas::trastornos linfoproliferativos::leucemia linfoide::leucemia-linfoma linfoblástico de células precursoras::leucemia-linfoma linfoblástico de células B precursoras
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