AUTHOR=Yang Fen , Wu Huali , Bo Yunhai , Lu Ye , Pan Hong , Li Su , Lu Qin , Xie Simin , Liao Harry , Wang Bing 

TITLE=Population Pharmacokinetic Modeling and Simulation of TQ-B3101 to Inform Dosing in Pediatric Patients With Solid Tumors

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.782518

DOI=10.3389/fphar.2021.782518

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> TQ-B3101 is a novel kinase inhibitor currently in development for the treatment of advanced malignant solid tumor and relapsed or refractory ALK-positive anaplastic large cell lymphoma.</p><p><bold>Methods:</bold> A population pharmacokinetic model was developed using data collected from a Phase 1 study and a Phase 2 study to characterize the pharmacokinetic of TQ-B3101 and its active metabolite (TQ-B3101M). The final model was used to optimize dosing of TQ-B3101 for pediatric patients (6-&lt;18 years) with anaplastic large cell lymphoma.</p><p><bold>Results:</bold> The pharmacokinetic of TQ-B3101 and TQ-B3101M was adequately described by a 1-compartment model with first-order absorption and elimination for parent drug coupled with a 2-compartment model with time-dependent clearance for the metabolite. The clearance of TQ-B3101M decreased over time with a maximum fractional reduction of 0.41. The estimated apparent clearance and apparent volume of distribution of TQ-B3101 were 2850 L/h and 4200 L, respectively. The elimination half-life of TQ-B3101 was 1.0 h. The distribution and elimination half-lives of TQ-B3101M at steady state were 4.9 and 39.4 h, respectively. The projected exposure of TQ-B3101M in virtual pediatric population following the body surface area tiered dosing regimen was similar to that in children pediatric patients after the recommended pediatric dose of crizotinib (280 mg/m2 twice daily), an analog of TQ-B3101M.</p><p><bold>Conclusion:</bold> A population pharmacokinetic model was developed to provide optimal dose of regimen for further development of TQ-B3101 in pediatric patients with anaplastic large cell lymphoma.</p>