Leniolisib

Absorption

The systemic drug exposure (AUC and Cmax) of leniolisib increases dose proportionally. During twice daily dosing approximately 12 hours apart, leniolisib accumulates approximately 1.4-fold (range of 1.0 to 2.2) in achieving steady-state. Steady-state drug concentrations can be expected to be reached after approximately two to three days. The Tmax is about one hour. Food has negligible effects on the systemic exposure of leniolisib.

Toxicity

No information on the LD50 of leniolisib is available. If overdosage occurs, monitor the patient for any signs or symptoms of adverse reactions. Treatment of overdose with leniolisib consists of general supportive measures, including monitoring of vital signs as well as observation of the clinical status of the patient.

Background

Leniolisib is a potent and selective inhibitor of phosphoinositide 3-kinase δ (PI3Kδ). The FDA approved leniolisib on March 24, 2023, making it the first treatment for activated phosphoinositide 3-kinase delta syndrome (APDS). APDS is a primary immunodeficiency caused by mutations in genes encoding the PI3Kδ, thereby increasing the activity of PI3Kδ, causing immune dysfunction, and elevating susceptibility to infections. Leniolisib works to inhibit hyperactive PI3Kδ. Investigations for using leniolisib in primary Sj?gren’s syndrome are ongoing.

Indications

Leniolisib is indicated for the treatment of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) in adult and pediatric patients 12 years of age and older.

Biological Activity

Leniolisib (CDZ 173) is a potent and selective PI3Kδ inhibitor with IC50s of 0.244, 0.424, 2.23 and 0.011 μM for PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ, respectively.

Pharmacokinetics

Leniolisib works to block aberrant PI3Kδ-dependent signalling pathways of immune cells, such as B and T cells, neutrophils, monocytes, basophils, plasmocytoid dendritic cells, and mast cells. In vitro, leniolisib dose-dependently suppresses the PI3Kδ pathway hyperactivation in cell lines overexpressing p110δ mutants and in primary immune cells from patients with APDS. Ex vivo pharmacodynamics of leniolisib in the proportion of phosphorylated Akt (pAkt)- positive B cells were assessed intra-individually at 10, 30, and 70 mg twice daily for four weeks at each dose level in patients with APDS. Within the explored dose range, higher leniolisib plasma concentrations were generally associated with a higher reduction of pAkt-positive B cells. Higher doses were associated with a slightly higher peak and more sustained reduction. Treatment with leniolisib 70 mg twice a day at a steady state is estimated to produce a time-averaged reduction of pAkt-positive B cells by approximately 80%.

Metabolism

About 60% of leniolisib is metabolized by the liver. Leniolisib undergoes oxidative metabolism, which is primarily mediated by CYP3A4 (94.5%), as well as CYP3A5 (3.5%), CYP1A2 (0.7%) and CYP2D6 (0.7%) to a minor extent. Few metabolites of leniolisib have been characterized in one study; however, no metabolites were abundant in plasma relative to the parent drug. Other metabolic pathways include dealkylation, demethylation, and hydroxylation.
Other suggested excretion routes include intestinal secretion by BCRP and CYP1A1-mediated extrahepatic metabolism.