生物活性

• 描述Leniolisib is a selective PI3Kδ inhibitor with IC50 values of 0.205, 0.087, 0.128, 0.064 and 0.05μM for PI3K wt, PI3K N334K, E525K, E1021K and C416R mutant, most commonly described in APDS (activated PI3Kδ syndrome). It led a selective PI3Kδ inhibitor, caused dose-dependent suppression of PI3Kδ pathway hyperactivation (measured as phosphorylation of AKT/S6) in cell lines ectopically expressing APDS-causative p110δ variants and in T-cell blasts derived from patients. Oral leniolisib led to a dose-dependent reduction in PI3K/AKT pathway activity assessed ex vivo and improved immune dysregulation. The elevated serum levels of CXCL13, CXCL10, IFNγ, and TNF in APDS patients were reduced by leniolisib treatment to levels measured in healthy volunteers. Also it improved lymphadenopathy, splenomegaly and cytopenias in APDS patients.

• 动物研究
  剂量	Rat: 10 mg/kg[2] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Rats[2] Dogs[2] Monkeys[2] Dose 1 mg/kg (i.v.) 30 mg/kg (p.o.) 0.1 mg/kg (i.v.) 0.3 mg/kg (p.o.) 0.1 mg/kg (i.v.) 0.3 mg/kg (p.o.) Administration i.v. p.o. i.v. p.o. i.v. p.o. Cmax, norm 334 nM (p.o.) 3410 nM (p.o.) T1/2 1.8 h (i.v.) 1.5 h (i.v.) 0.7 h (i.v.) Tmax <0.25 h (p.o.) 0.7 h (p.o.) <0.5 h (p.o.) CL 28 ml/min/kg (i.v.) 2 ml/min/kg (i.v.) 17 ml/min/kg (i.v.) Cmax 213 nM (p.o.) BAV >100% 58% (p.o.) 13% (p.o.) AUCnorm 20120 nM·h (i.v.) 11690 nM·h (p.o.) Vss 3.1 L/kg (i.v.) 0.3 L/kg (i.v.) 0.6 L/kg (i.v.) AUC(normalized to 1 mg/kg) 1355 nM·h (i.v.) 2107 nM·h (p.o.) 2250 nM·h (i.v.) 297 nM·h (p.o.)