Population Pharmacokinetics of Bosutinib in Children with Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia Based on a Phase I Dose-Finding Trial (ITCC-054/COG AAML1921) and Pediatric Recommended Phase II Dosage Evaluation

BACKGROUND AND OBJECTIVES: Bosutinib, an orally administered dual Src and Bcr-Abl tyrosine kinase inhibitor (TKI), is approved for the treatment of chronic phase Philadelphia chromosome-positive chronic myelogenous leukemia, newly diagnosed or resistant/intolerant to previous treatment of one or more TKIs in adults and children ≥ 1 years (by the US Food and Drug Administration) and ≥ 6 years (by the European Medicines Agency). Owing to the limitations of non-compartmental analysis in pharmacokinetic (PK) characterization, this study applies a prior population PK modeling approach to describe the pediatric PK of bosutinib on the basis of its phase I dose-finding trial and the available bosutinib adult PK knowledge. METHODS: From 26 pediatric patients in the phase I part of the ITCC-054/COG AAML1921 trial, 235 plasma bosutinib concentration samples were analyzed. A published adult bosutinib population PK (popPK) model was used as the reference model; the frequentist prior modeling approach was used during model development to integrate adult PK information, especially for parameters with poor identifiability. RESULTS: Bosutinib pediatric PK was well characterized by a two-compartment model with first-order absorption, an absorption lag time of 0.467 h, and allometric scaling with fixed exponents. The typical clearance was 74.9 L/h (normalized to 70 kg), higher than the reported adult value (56.3 L/h). Model-based simulations validated that the bosutinib recommended phase II dose (RP2D) could achieve the target exposure observed in adults and demonstrated the influence of higher clearance in pediatric patients. CONCLUSIONS: This study presents the first pediatric bosutinib popPK model, integrating prior adult PK knowledge to enable robust PK characterization using a small pediatric dataset from an early trial stage. In addition, the model confirms a higher clearance in children and supports the RP2D concluded in the phase I dose-finding part of the ITCC-054/COG AAML1921 trial.

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Journal
Clinical Pharmacokinetics
Published
2026-07-27
DOI
https://doi.org/10.1007/s40262-026-01672-y
Primary Topic
Chronic Myeloid Leukemia Treatments
Type
article
Field-Weighted Citation Impact
0.00

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article

Population Pharmacokinetics of Bosutinib in Children with Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia Based on a Phase I Dose-Finding Trial (ITCC-054/COG AAML1921) and Pediatric Recommended Phase II Dosage Evaluation

C. Michel Zwaan, Markus Metzler, Franco Locatelli, Karey Kowalski et al.
Clinical Pharmacokinetics
Chronic Myeloid Leukemia Treatments
article

Population Pharmacokinetics of Bosutinib in Children with Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia Based on a Phase I Dose-Finding Trial (ITCC-054/COG AAML1921) and Pediatric Recommended Phase II Dosage Evaluation

C. Michel Zwaan, Markus Metzler, Franco Locatelli, Karey Kowalski, Stacy Cooper, Carmelo Rizzari, Erica Brivio, Nobuko Hijiya, May Garrett, Jen-Hao Wu, Laura Murillo, Yves Bertrand, Franciso Bautista, Donna Lancaster, Matthew Kutny, Arnaud Petit, Julie Krystal, Marieke Willemse, Brian Jermain, Alwin D. R. Huitema, Inge M. van der Sluis, Sara Zarnegar-Lumley, Andrew Bukowinski, Jessica Pollard, Michele Redell, Jean-Pierre Bourquin, Michael E. Roth, Jayashree Motwani
article en

Abstract

BACKGROUND AND OBJECTIVES: Bosutinib, an orally administered dual Src and Bcr-Abl tyrosine kinase inhibitor (TKI), is approved for the treatment of chronic phase Philadelphia chromosome-positive chronic myelogenous leukemia, newly diagnosed or resistant/intolerant to previous treatment of one or more TKIs in adults and children ≥ 1 years (by the US Food and Drug Administration) and ≥ 6 years (by the European Medicines Agency). Owing to the limitations of non-compartmental analysis in pharmacokinetic (PK) characterization, this study applies a prior population PK modeling approach to describe the pediatric PK of bosutinib on the basis of its phase I dose-finding trial and the available bosutinib adult PK knowledge. METHODS: From 26 pediatric patients in the phase I part of the ITCC-054/COG AAML1921 trial, 235 plasma bosutinib concentration samples were analyzed. A published adult bosutinib population PK (popPK) model was used as the reference model; the frequentist prior modeling approach was used during model development to integrate adult PK information, especially for parameters with poor identifiability. RESULTS: Bosutinib pediatric PK was well characterized by a two-compartment model with first-order absorption, an absorption lag time of 0.467 h, and allometric scaling with fixed exponents. The typical clearance was 74.9 L/h (normalized to 70 kg), higher than the reported adult value (56.3 L/h). Model-based simulations validated that the bosutinib recommended phase II dose (RP2D) could achieve the target exposure observed in adults and demonstrated the influence of higher clearance in pediatric patients. CONCLUSIONS: This study presents the first pediatric bosutinib popPK model, integrating prior adult PK knowledge to enable robust PK characterization using a small pediatric dataset from an early trial stage. In addition, the model confirms a higher clearance in children and supports the RP2D concluded in the phase I dose-finding part of the ITCC-054/COG AAML1921 trial.

Clinical Pharmacokinetics
Università Cattolica del Sacro Cuore (IT), Northwestern University (US), Lurie Children's Hospital (US), Royal Marsden NHS Foundation Trust (GB), The University of Texas MD Anderson Cancer Center (US), Harvard University (US), Johns Hopkins University (US), Pfizer (United States) (US), Baylor College of Medicine (US), Utrecht University (NL), Columbia University Irving Medical Center (US), The Netherlands Cancer Institute (NL), University Medical Center Utrecht (NL), University of Alabama at Birmingham (US), Sorbonne Université (FR), Hôpital Armand-Trousseau (FR), Universitätsklinikum Erlangen (DE), Assistance Publique – Hôpitaux de Paris (FR), Birmingham Children's Hospital (GB), Hospices Civils de Lyon (FR), Sidney Kimmel Cancer Center (US), Azienda Ospedaliera San Gerardo (IT), Oncode Institute (NL), Cohen Children's Medical Center (US), Bambino Gesù Children's Hospital (IT), Princess Máxima Center (NL), Vall d'Hebron Hospital Universitari (ES), University Children's Hospital Zurich (CH), Children's Hospital of Pittsburgh (US), Erasmus MC - Sophia Children’s Hospital (NL), Children's Cancer Center (US), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Sidney Kimmel Comprehensive Cancer Center (US), Dana-Farber/Boston Children's Cancer and Blood Disorders Center (US), Dan L Duncan Comprehensive Cancer Center
Pfizer
Good health and well-being
Openalex Percentile: Top 9%
Chronic Myeloid Leukemia Treatments
DOIOpen Access PDFOpenAlex
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