Associate Director, Clinical Pharmacology Pfizer, Inc. San Diego, California, United States
Background: Bosutinib is an orally active TKI which inhibits the BCR-ABL kinase that promotes CML; it is also an inhibitor of Src family kinases including Src, Lyn, and Hck. Bosutinib received approval in the US for the treatment of adults with newly-diagnosed (ND) CP Ph+ CML and CP, AP, or BP Ph+ CML with resistance or intolerance to prior therapy (R/I).
The BCHILD study is an ongoing, Phase 1/2, multicenter, international, single-arm, open label study designed to identify a recommended dose of bosutinib administered orally QD in pediatric patients (ages 1 to < 18 years) with ND CP Ph+ CML or R/I CP, AP or BP Ph+ CML who have received at least 1 prior TKI therapy. The pediatric dose recommendations from the BCHILD study were refined using a dose banding approach supported by modeling and simulation for label simplification and ease of use. Methods: The dose banding approach was supported by PopPK simulations across BSA brackets. Due to the limited number of pediatric patients in the BCHILD study across BSA and age group categories by which the individual bosutinib plasma exposure metrics were available, a virtual population was developed based off demographics information across the intended age range sourced from the NHANES database. The individual bosutinib plasma exposure metrics (cAUC, AUCtau, Cavg, and Ctrough) were simulated for the NHANES-based virtual population using identical methods as the pediatric patients in the BCHILD study. Results: A fixed continuous dosing regimen of 400 mg/m2 was simulated with a maximum dose of 600 mg and compared to the recommended dose banding as shown in Figure 1.
The dose modification instructions for pediatric patients were similarly simplified for labeling to reflect the pediatric clinical study experience for dose reductions and escalations during study conduct. Conclusion: The projected exposures for the proposed dose banded starting dose recommendations for pediatric patients are in line with projections of the BSA-calculated dose conducted within the BCHILD study. In addition to label simplification for prescribers, patient benefits include potential to increase compliance by reducing pill burden, reduced medical error/drug waste by reducing unnecessary dose changes based on BSA changes at visits, and eliminating the need for a 25-mg capsule (only 50- and 100-mg capsule strengths would be required).
