Palbociclib (PBB) is an oral cyclin-dependent kinase 4/6 (CDK4/6) inhibitor approved for the treatment of HR+/HER2− breast cancer. However, poor adherence and limited tolerability of oral administration often compromise its therapeutic effectiveness, especially in palliative care for metastatic conditions. Dose reductions are frequently required to manage toxicity, but lower doses can still provide effective tumour control with reduced neutropenia risk, thereby improving quality of life and progression-free survival. Developing a long-acting injectable (LAI) formulation of PBB offers significant advantages for sustained therapy in advanced-stage cancer management.

This study focuses on dose selection, release profile optimisation, and the design of sterile PBB-loaded PLGA microsphere suspensions for intramuscular (IM) administration using physiologically based pharmacokinetic (PBPK) modelling and simulations. The PBPK model, developed and validated with data from oral and intravenous routes, enabled the prediction of IM pharmacokinetics. Clinical target product profiles were defined based on IC₅₀ and minimum steady-state concentration (Css, _min).

The dose optimisation study revealed that the rational selection of dose for both strengths, with an optimised sustained-release profile (Target 2, showing minimal initial burst and controlled release reaching ~55% by day 10.5 and ~90% by day 21), achieved the desired clinical quality target product profiles.

The developed model will further support polymer selection, specification setting, and drug-to-polymer ratio. Incorporating PBB’s physicochemical properties and host response helps guide rational formulation design.