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.

Children's Health Ireland at Crumlin Dublin Ireland

Department of Clinical Pharmacy University Medical Center Utrecht Utrecht The Netherlands

Department of Hematology Oncology and of Cell and Gene Therapy IRCCS Ospedale Pediatrico Bambino Gesú Catholic University of the Sacred Heart Rome Italy

Department of Paediatric Haematology and Oncology 2nd Faculty of Medicine Charles University Prague and Motol University Hospital Prague Czech Republic

Department of Paediatrics and Adolescent Medicine Copenhagen University Hospital Rigshospitalet Copenhagen Denmark

Department of Pediatric Hematology and Oncology Hopital Armand Trousseau APHP Sorbonne Université Paris France

Department of Pediatric Hematology and Oncology University Hospital Motol Prague Czech Republic

Department of Pediatric Hematology Hôpital Robert Debré Assistance Publique Hôpitaux de Paris Paris France

Department of Pediatric Oncology and Hematology Hospital Niño Jesús Madrid Spain

Department of Pediatric Oncology Erasmus MC Sophia Children's Hospital Rotterdam Wytemaweg 80 3015 CN Rotterdam The Netherlands

Department of Pediatrics Division of Oncology and Hematology Charité Universitätsmedizin Berlin German Cancer Consortium site Berlin Berlin Germany

Department of Pharmacy and Pharmacology Netherlands Cancer Institute Amsterdam The Netherlands

Division of Pediatric Hematology and Oncology Hospital Universitari Vall d'Hebron Barcelona Spain

Division of Pediatric Hematology and Oncology Sheba Medical Center Ramat Gan Israel

Institut de Recerca Sant Joan de Déu Barcelona Spain

Institute of Pediatric Hematology and Oncology Civil Hospital of Lyon Claude Bernard University Lyon France

Pediatric Hematology and Oncology University Children's Hospital Muenster Muenster Germany

Pediatric Hematology Hôpital Jeanne de Flandre CHRU de Lille Lille France

Pediatric Hematology Oncology Unit Department of Pediatrics IRCCS Foundation San Gerardo dei Tintori Monza and University of Milano Bicocca Monza Italy

Pediatric Oncology and Hematology Department Hospital Sant Joan de Déu de Barcelona Barcelona Spain

Pediatrics 3 University Hospital Essen German Cancer Consortium Site Essen Essen Germany

Pfizer Global Pharmacometrics San Diego CA USA

Pfizer R and D Japan Tokyo Japan

Princess Máxima Center for Pediatric Oncology Utrecht The Netherlands

Service d'Hématologie Immunologie Oncologie Hôpital des Enfants CHU Toulouse Toulouse France

Service Onco Hématologie Pédiatrique Hôpital Mère Enfant Nantes University Hospital Nantes France

St Anna Children's Hospital Medical University of Vienna Vienna Austria

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