Abstract
Pharmacokinetics and Bronchopulmonary Disposition of PI3KDelta Inhibitor IC87114 after Intratracheal Administration in a Severe Asthma Model
Division of Hematology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, 45229, College of Pharmacy, Kyungsung University, Suyeong-ro 309, Nam-gu, Busan 608-736, Republic of Korea, Department of Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, 45229, Department of Pharmacology, New Drug Development Institute, Chonbuk National University Medical School, Jeonju 560-182, Graduate School of Clinical Pharmacy, Sookmyung Women’s University, Seoul, 140-742, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, 660-701, College of Pharmacy, Dong-Duk University, Seoul, 136-742, Department of Anatomy, Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, 560-182, Republic of Korea
Correspondence Address:
Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, 560-182, Republic of Korea, E-mail: leeyc@jbnu.ac.kr
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. Modeling 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.
