Pharmacokinetics and Pharmacodynamics of IPI-145, a Potent Inhibitor of Phosphoinositide-3-Kinase-δ,γ, Following Single- and Multiple-Dose Administration in Healthy Subjects and Patients with Advanced Hematologic Malignancies

• Published in: Blood 2012-11, Vol.120 (21), p.4853-4853
• Main Authors: Dunbar, Joi, Nevejans, Jylle, McKee, Charlotte, Faia, Kerrie, van Lier, Jan Jaap, Pruim, Peter, Stegehuis, Janet, Zhao, Sue, Kahl, Brad S., Horwitz, Steven M., Patel, Manish, Younes, Anas, Flinn, Ian W.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V120.21.4853.4853

Abstract 4853 Phosphoinositide-3-kinases (PI3Ks) play pivotal roles in cell signaling and regulate a variety of cellular functions. PI3K-δ and PI3K-γ isoforms are necessary for adaptive and innate immunity and contribute to the development and maintenance of inflammatory and autoimmune diseases and hematologic malignancies. IPI-145 is a potent inhibitor of PI3K- δ,γ isoforms (Ki = 23 pM and 243 pM, respectively) in clinical development for patients with advanced hematologic malignancies and inflammatory/autoimmune disorders. The pharmacokinetics (PK) and pharmacodynamics (PD) of IPI-145 were evaluated in a Phase 1 clinical study in healthy subjects and are being characterized in patients with advanced hematologic malignancies. In a healthy subject study, IPI-145 was administered orally as a single dose and as multiple doses once daily (QD) or twice daily (BID) for 14 days. In a Phase 1 oncology study, IPI-145 was administered orally starting at a dose of 8 mg BID. PK and PD markers were evaluated after the first dose and at steady state. PD activity (PI3K inhibition) in whole blood was evaluated using a basophil activation assay which measured reduction in CD63 expression on the surface of basophils following ex vivo stimulation. IPI-145 was well tolerated in healthy subjects at single doses up to 30 mg (highest dose tested) and up to 10 mg total daily dose (highest dose tested; 5 mg BID or 10 mg QD) for 14 days. In healthy subjects, the PK profile of IPI-145 is characterized by rapid absorption (peak plasma concentrations reached within 0.5–1 hour), moderately rapid elimination (half-life 3.5 to 9.5 hours following a single dose and 6.5 to 11.7 hours following repeat dosing) and dose proportional increases in systemic exposure (Cmax and AUC). Minimal accumulation was observed after multiple dose administration (accumulation ratio 1.65–1.83 for BID dosing and 1.54 for QD dosing). Following single oral dose administration, clearance ranged from 6.7 L/h to 11.1 L/h and the volume of distribution ranged from 38.8 L to 147 L. Excretion of unchanged IPI-145 in urine was