OB-001 boost the brain penetration of multiple TKIs

Background: Osimertinib, Adagrasib, Tucatinib, Mobocertinib and Lorlatinib all demonstrate clinically meaningful CNS activity across numerous cancer types. However, all four agents show incomplete and variable CNS penetration, with reported CSF:plasma or Kp,uu values typically well below unity, largely due to ABCB1/ABCG2 efflux at the blood-brain barrier. OB-001 is a novel KinetiSol amorphous solid dispersion first-in-class efflux transporter inhibitor. We evaluated whether OB-001 can selectively enhance the brain distribution of kinase inhibitors. Methods: Male CD-1 mice received one of oral Osimertinib, Adagrasib, Tucatinib, Mobocertinib and Lorlatinib following 2-h pretreatment with vehicle or OB-001 (10 mg/kg). Plasma and perfused-brain concentrations were quantified to 24 h by LC-MS/MS. Pharmacokinetic parameters were derived by noncompartmental analysis, and fold-changes in area under the curve (AUC) between brain and plasma were compared. Results: OB-001 led to a 4, 33, 5, 11 and 4 -fold increase in Brain AUC for Osimertinib, Adagrasib, Tucatinib, Mobocertinib and Lorlatinib respectively. No change in plasma AUC was observed for Osimertinib and Adagrasib with less than 2-fold increase obserevd for Tucatinib, Mobocertinib and Lorlatinb. Conclusions: OB-001 selectively boosts brain exposure without substantially increasing systemic exposure. These data demonstrate that theoretically a pharmacokinetic window can be achevied with OB-001 whereby enhanced brain metatsases efficacy could be acheived for numerous kinase inhibitors without effecting systemic toxicity. These findings support OB-001 as a first-in-class CNS-targeted efflux modulating adjunct capable of elevating brain drug exposure beyond what is achievable by existing kinase inhibitors alone. OB-001 has strong translational rationale for combination development with Osimertinib, Adagrasib, Tucatinib, Mobocertinib and Lorlatinib-to further extend CNS disease control in numerous cancer types.