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.

Authors

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

Published in

Clinical pharmacokinetics. Jul 27, 2026. Epub Jul 27, 2026.

Abstract

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.
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.
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.
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.

PMID:
42509527
Bibliographic data and abstract were imported from PubMed on 28 Jul 2026.

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