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Published on: November 22, 2021
OB-001 Enhances Osimertinib Brain Penetration: Preclinical Pharmacokinetics and Translational Rationale for
Hitesh B Mistry1, Jim Millen1, Josh Fleet1
1OncoBayesAlpha Ltd., London, United Kingdom.
Abstract:
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.
Insights
OB-001, a novel formulation of elacridar, significantly enhances brain delivery of osimertinib, a drug for EGFR-mutant NSCLC. This strategy shows promise for improving central nervous system efficacy in patients with brain metastases.
Area of Science:
- Pharmacology
- Oncology
- Drug Delivery
Background:
- Osimertinib is effective for EGFR-mutant NSCLC, including CNS disease.
- Low CNS penetration of osimertinib is a challenge, attributed to ABCB1/ABCG2 efflux.
- Elacridar is an inhibitor of these efflux pumps, but its crystalline form has poor bioavailability.
Purpose of the Study:
- To evaluate OB-001, an amorphous solid dispersion of elacridar, as a strategy to enhance osimertinib brain delivery.
- To compare the pharmacokinetic profile of OB-001 with crystalline elacridar.
- To assess the impact of OB-001 on osimertinib brain distribution in a preclinical model.
Main Methods:
- CD-1 mice were used to compare oral bioavailability of OB-001 and crystalline elacridar.
- Osimertinib brain distribution was assessed after pretreatment with OB-001 or crystalline elacridar.
- Pharmacokinetic parameters (AUC) in plasma and brain were analyzed.
Main Results:
- OB-001 demonstrated superior systemic exposure compared to crystalline elacridar.
- Pretreatment with OB-001 significantly increased osimertinib brain exposure (4.0- to 9.3-fold) with minimal impact on plasma levels.
- OB-001 at 10 mg/kg achieved comparable brain enhancement to a 10-fold higher dose of crystalline elacridar.
Conclusions:
- OB-001 effectively enhances brain delivery of osimertinib by inhibiting efflux transporters.
- This formulation selectively boosts CNS exposure of osimertinib, sparing systemic pharmacokinetics.
- Preclinical data support OB-001 as a promising strategy to improve CNS efficacy in EGFR-mutant NSCLC.
