OB-001 Enhances Osimertinib Brain Penetration: Preclinical Pharmacokinetics and Translational Rationale for EGFR-Mutant NSCLC with CNS Disease.

UNLABELLED: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor with proven efficacy in EGFR-mutant non-small cell lung cancer (NSCLC), including patients with central nervous system (CNS) disease. However, pharmacokinetic (PK) studies demonstrate low CNS penetration (CSF:plasma 0.8%-22%), largely due to ABCB1/ABCG2 efflux. OB-001, a KinetiSol amorphous solid dispersion formulation of elacridar, was developed to overcome the poor bioavailability of crystalline elacridar and evaluated as a strategy to enhance osimertinib brain delivery. In CD-1 mice, we compared the oral bioavailability of OB-001 (10, 30, 100 mg/kg) with crystalline elacridar (100 mg/kg) and assessed osimertinib (50 mg/kg orally) brain distribution after pretreatment with OB-001 (10 or 50 mg/kg) or crystalline elacridar (100 mg/kg). Plasma and perfused brain PK parameters were derived by noncompartmental analysis. AUClast values were compared using Bailer randomization test. OB-001 achieved greater systemic elacridar exposure than the crystalline methylcellulose suspension (P < 0.001). In vehicle-pretreated mice, osimertinib produced a brain:plasma AUC ratio of 7.1. OB-001 pretreatment increased brain AUClast 4-fold (10 mg/kg; P < 0.001) and 9.3-fold (50 mg/kg; P < 0.001) with minimal plasma change (1.1-1.4-fold). Crystalline elacridar at 100 mg/kg increased brain AUClast 5-fold (P < 0.001). Thus, OB-001 at 10 mg/kg achieved comparable brain enhancement with 10-fold higher dose of crystalline elacridar, whereas OB-001 at 50 mg/kg exceeded it. Translational benchmarking against in vitro potency suggested that raising estimated Kp,uu from ∼0.15 to ∼0.60 could improve efficacy. OB-001 selectively boosts osimertinib brain exposure while sparing systemic PK. These preclinical data support further evaluation of OB-001 as a strategy to enhance the CNS efficacy of osimertinib in EGFR-mutant NSCLC.

SIGNIFICANCE: Blood-brain barrier (BBB) efflux limits osimertinib brain exposure. Oral OB-001 pretreatment markedly increases brain concentrations with minimal plasma impact, supporting BBB transporter inhibition as a strategy to enhance CNS drug delivery.