Role of P-glycoprotein in the brain disposition of seletalisib: Evaluation of the potential for drug-drug interactions.

Seletalisib is an orally bioavailable selective inhibitor of phosphoinositide 3-kinase delta (PI3Kδ) in clinical development for the treatment of immune-mediated inflammatory diseases. The present study investigated the role of P-gp in seletalisib disposition, especially brain distribution, and the associated risks of interactions. Seletalisib was found to be actively transported by rodent and human P-gp in vitro (transfected LLC-PK1 cells; Km of ca. 20 µM), with minimal or no affinity for the other tested transporters. A distribution study in knockout rats (single oral dosing at 750 mg kg-1) showed that P-gp restricts the brain disposition of seletalisib while having minimal effect on its intestinal absorption. Restricted brain penetration was also observed in cynomolgus monkeys (single oral dosing at 30 mg kg-1) using brain microdialysis and cerebrospinal fluid sampling (Kp,uu of 0.09 and 0.24, respectively). These findings opened the question of potential pharmacokinetic interaction between seletalisib and P-gp inhibitors. In vitro, CsA inhibited the active transport of seletalisib with an IC50 of 0.13 µM. In rats, co-administration of high doses of CsA (bolus iv followed by continuous infusion) increased the brain distribution of seletalisib (single oral dosing at 5 mg kg-1). The observed data were found aligned with those predicted by in vitro-in vivo extrapolation. Based on the same extrapolation method combined with literature data, only very few P-gp inhibitors (i.e. CsA, quinine, quinidine) were predicted to increase the brain disposition of seletalisib in the clinical setting (maximal 3-fold changes).