Weize Huang, Pharm.D. Ph.D.: No financial relationships to disclose
Objectives: Brain metastases (BMs) pose a significant clinical challenge due to the high incidence in cancers such as non-small cell lung cancer (NSCLC) and breast cancer, poor prognosis, and limited therapeutic options [1]. Many anticancer drugs exhibit inadequate penetration across the blood–brain barrier (BBB), limiting their efficacy in the central nervous system (CNS). Although several brain-penetrant small molecule therapies have been approved, the quantitative relationship between intracranial drug exposure and clinical efficacy remains unestablished. The objective of this study was to characterize the relationship between intracranial exposure, in vitro potency, and intracranial clinical response across brain-penetrant tyrosine kinase inhibitors (TKIs), to inform dose selection strategies for brain penetrants.
Methods: In this study, fourteen tyrosine kinase inhibitors (TKIs) were included for analyses based on NCCN guideline-recommended therapies for BMs. For each drug, relevant data including the population PK model structure and parameters, dosing information, in vitro potency, plasma unbound fraction, and brain/CSF-to-plasma partitioning data were extracted. The plasma PK profiles were simulated using published population pharmacokinetics models at approved doses. The CSF exposures are extrapolated using unbound plasma fractions and CSF-to-plasma unbound concentration ratios (Kp,uu,CSF). Key intracranial exposure metrics including ratio of CSF steady-state trough concentration to IC₅₀ (Cmin,ss/IC₅₀), ratio of CSF steady-state average concentration to IC₅₀ (Cave,ss/IC₅₀), and percentage of the dosing interval at steady state during which CSF concentrations exceeded the IC₅₀ (T%>IC₅₀) were derived and correlated with intracranial efficacy from published clinical trials, to evaluate the intracranial exposure-response relationship for brain-penetrating TKIs.
Results: The analyses from the fourteen brain penetrants showed high variability in both extent and duration of steady state CSF exposure above IC50; some drugs maintain CSF exposure above IC50 during the entire dosing interval, while others provide only partial or no coverage. Among the nine NSCLC brain penetrants analyzed, an overall positive correlation was observed between intracranial exposure metrics and intracranial objective response rate (ORR). Higher exposure coverage above IC₅₀ was associated with improved intracranial efficacy.
Conclusions: This work demonstrates a positive intracranial exposure-response relationship across brain-penetrant TKIs. These findings highlight the importance of incorporating CNS PK and target coverage metrics into dose selection and optimization strategies, moving beyond the traditional plasma-based exposure metrics.
Citations: [1] Valiente M, Ahluwalia MS, Boire A, Brastianos PK, Goldberg SB, Lee EQ, et al. The Evolving Landscape of Brain Metastasis. Trends Cancer. 2018;4(3):176-96.
