Population Pharmacokinetics of Inotuzumab Ozogamicin in Pediatric Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: Results of Study ITCC-059
Por:
Wu JH, Pennesi E, Bautista F, Garrett M, Fukuhara K, Brivio E, Ammerlaan ACJ, Locatelli F, van der Sluis IM, Rossig C, Chen-Santel C, Bielorai B, Petit A, Starý J, Díaz-de-Heredia C, Rives-Solà S, O'Marcaigh A, Rizzari C, Engstler G, Nysom K, Rubio-San-Simón A, Bruno B, Bertrand Y, Brethon B, Rialland F, Plat G, Dirksen U, Sramkova L, Zwaan CM and Huitema ADR
Publicada:
1 jul 2024
Ahead of Print:
1 jun 2024
Resumen:
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], x 10(3) 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.
Filiaciones:
Wu JH:
Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital Rotterdam, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Pennesi E:
Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital Rotterdam, Wytemaweg 80, 3015 CN, 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:
Pfizer Global Pharmacometrics, San Diego, CA, USA
Fukuhara K:
Pfizer R&D Japan, Tokyo, Japan
Brivio E:
Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital Rotterdam, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Ammerlaan ACJ:
Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital Rotterdam, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Locatelli F:
Department of Hematology, Oncology and of Cell and Gene Therapy, IRCCS Ospedale Pediatrico Bambino Gesú, Catholic University of the Sacred Heart, Rome, Italy
van der Sluis IM:
Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital Rotterdam, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Rossig C:
Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster, Germany
Chen-Santel C:
Department of Pediatrics, Division of Oncology and Hematology, Charité-Universitätsmedizin Berlin, German Cancer Consortium (DKTK) site Berlin, National Center for Tumor diseases (NCT) site Berlin, Berlin, Germany
Bielorai B:
Division of Pediatric Hematology and Oncology, Sheba Medical Center, Ramat-Gan, Israel
Petit A:
Department of Pediatric Hematology and Oncology, Hopital Armand Trousseau, APHP, Sorbonne Université, Paris, France
Starý J:
Department of Pediatric Hematology and Oncology, University Hospital Motol, Prague, Czech Republic
Díaz-de-Heredia C:
Division of Pediatric Hematology and Oncology. Hospital, Universitari Vall d'Hebron, Barcelona, Spain
Rives-Solà S:
Pediatric Oncology and Hematology Department, Hospital Sant Joan de Déu de Barcelona, Barcelona, Spain
Institut de Recerca Sant Joan de Déu, Barcelona, Spain
O'Marcaigh A:
Children's Health Ireland at Crumlin, Dublin, Ireland
Rizzari C:
Pediatric Hematology-Oncology Unit, Department of Pediatrics, IRCCS Foundation San Gerardo dei Tintori, Monza and University of Milano-Bicocca, Monza, Italy
Engstler G:
St Anna Children's Hospital, Medical University of Vienna, Vienna, Austria
Nysom K:
Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark
Rubio-San-Simón A:
Department of Pediatric Oncology and Hematology, Hospital Niño Jesús, Madrid, Spain
Bruno B:
Pediatric Hematology, Hôpital Jeanne de Flandre, , CHRU de Lille, Lille, France
Bertrand Y:
Institute of Pediatric Hematology and Oncology, Civil Hospital of Lyon, Claude Bernard University, Lyon, France
Brethon B:
Department of Pediatric Hematology, Hôpital Robert-Debré, Assistance Publique-Hôpitaux de Paris, Paris, France
Rialland F:
Service Onco-Hématologie Pédiatrique, Hôpital Mère-Enfant, Nantes University Hospital, Nantes, France
Plat G:
Service d'Hématologie-Immunologie-Oncologie, Hôpital des Enfants, CHU Toulouse, Toulouse, France
Dirksen U:
Pediatrics III, University Hospital Essen, German Cancer Consortium (DKTK) Site Essen, Essen, Germany
Sramkova L:
Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic
Zwaan CM:
Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital Rotterdam, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Huitema ADR:
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
Department of Pharmacy and Pharmacology, Netherlands Cancer Institute, Amsterdam, The Netherlands
Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands
Green Published, hybrid
|