Abstract Osimertinib is a third-generation EGFR TKI with proven efficacy in EGFR-mutant NSCLC, including patients with CNS disease. However, pharmacokinetic 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 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 PO) brain distribution after pretreatment with OB-001 (10 or 50 mg/kg) or crystalline elacridar (100 mg/kg). Plasma and perfused brain pharmacokinetic parameters derived by noncompartmental analysis. AUClast values were compared using Bailer’s randomization test. OB-001 achieved greater systemic elacridar exposure than the crystalline methylcellulose suspension (p0.001). In vehicle-pretreated mice, osimertinib produced a brain:plasma AUC ratio of 7.1. OB-001 pretreatment increased brain AUClast 4.0-fold (10 mg/kg; p0.001) and 9.3-fold (50 mg/kg; p0.001) with minimal plasma change (1.1–1.4-fold). Crystalline elacridar at 100 mg/kg increased brain AUClast 5.0-fold (p0.001). Thus, OB-001 at 10 mg/kg achieved comparable brain enhancement to 10-fold higher dose of crystalline elacridar, while 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 CNS efficacy of osimertinib in EGFR-mutant NSCLC.
Mistry et al. (Thu,) studied this question.