Pharmacokinetics and bronchopulmonary disposition of PI3Kδ inhibitor IC87114 after intratracheal administration in a severe asthma model

Abstract

Type 2 helper T cell-predominant asthma is a refractory type of asthma that has motivated biomedical industries to develop novel drugs. The phosphoinositide 3-kinase pathway has been implicated in asthma and chronic obstructive pulmonary disease. IC87114 (2-[(6-aminopurin-9-yl)methyl]-5-methyl-3-[2-methylphenyl]quinazolin-4-one) was recently developed as a PI3Kδ inhibitor. In a neutrophil type 2 helper T cell dominant asthma model, pharmacokinetic analysis of IC87114 was performed. Following intratracheal administration of 1 mg/kg IC87114 to ovalbumin/lipopolysaccharide-sensitized/challenged mice, airway hyper-responsiveness and structural analysis was performed and the plasma concentration time course and bronchoalveolar lavage fluid concentration of IC87114 were described using a compartment model with a first-order elimination rate constant. Plasma had a three-fold higher Cmax compared to bronchoalveolar lavage fluid. The half-life of IC87114 in plasma and bronchoalveolar lavage fluid was 2.37 and 10.25 h, respectively. Enhanced airway hyper-responsiveness and increased peribroncholar and perivascular inflammatory cell infiltrates in the lungs were significantly reduced in the IC87114-administered group compared with the ovalbumin/lipopolysaccharide-exposed group. Modelling approaches sufficiently explained the relationship between systemic circulation and bronchoalveolar lavage fluid concentration of IC87114 with Kbronchoalveolar lavage/plasma (approximately 0.38 h-1) in ovalbumin/lipopolysaccharide-sensitized/challenged mice. Our results will be useful for understanding the relationship between the pharmacokinetics and pharmacodynamics of IC87114.