Language

English

Publication Date

9-1-2026

Journal

Clinical Pharmacokinetics

DOI

10.1007/s40262-026-01672-y

PMID

42509527

PMCID

PMC13545124

PubMedCentral® Posted Date

7-27-2026

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Aniline Compounds, Nitriles, Quinolines, Child, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Male, Female, Protein Kinase Inhibitors, Adolescent, Child, Preschool, Models, Biological, Dose-Response Relationship, Drug, Infant, Adult, Antineoplastic Agents, Administration, Oral

Published Open-Access

yes

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