Chemical formula: C₂₂H₁₈FN₇O Molecular mass: 415.432 g/mol PubChem compound: 11625818
Idelalisib inhibits phosphatidylinositol 3-kinase p110δ (PI3Kδ), which is hyperactive in B-cell malignancies and is central to multiple signalling pathways that drive proliferation, survival, homing, and retention of malignant cells in lymphoid tissues and bone marrow. Idelalisib is a selective inhibitor of adenosine-5'-triphosphate (ATP) binding to the catalytic domain of PI3Kδ, resulting in inhibition of the phosphorylation of the key lipid second messenger phosphatidylinositol and prevention of Akt (protein kinase B) phosphorylation.
Idelalisib induces apoptosis and inhibits proliferation in cell lines derived from malignant B-cells and in primary tumour cells. Through inhibition of chemokine receptors CXCR4 and CXCR5 signalling induced by the chemokines CXCL12 and CXCL13, respectively, idelalisib inhibits homing and retention of malignant B-cells in the tumour microenvironment including lymphoid tissues and the bone marrow.
No mechanistic explanations for the development of resistance to treatment with idelalisib have been identified from clinical studies. Further investigation of this topic in current B-cell malignancy studies is not planned.
The effect of idelalisib (150 mg and 400 mg) on the QT/QTc interval was evaluated in a placebo- and positive-controlled (moxifloxacin 400 mg) crossover study in 40 healthy subjects. At a dose 2.7 times the maximum recommended dose, idelalisib did not prolong the QT/QTc interval (i.e., <10 ms).
Upon initiation of idelalisib, a temporary increase in lymphocyte counts (i.e., ≥50% increase from baseline and above absolute lymphocyte count of 5,000/mcL) has been observed. This occurs in approximately two-thirds of patients with CLL treated with idelalisib monotherapy and one-fourth of patients with CLL treated with idelalisib combination therapy. The onset of isolated lymphocytosis typically occurs during the first 2 weeks of idelalisib therapy and is often associated with reduction of lymphadenopathy. This observed lymphocytosis is a pharmacodynamic effect and should not be considered progressive disease in the absence of other clinical findings.
Following oral administration of a single dose of idelalisib, peak plasma concentrations were observed 2 to 4 hours post-dose under fed conditions and after 0.5 to 1.5 hours under fasted conditions.
Following 150 mg twice daily administration of idelalisib, average (range) Cmax and AUC at steady-state were 1,953 (272; 3,905) ng/mL and 10,439 (2,349; 29,315) ng•h/mL for idelalisib and 4,039 (669; 10,897) ng/mL and 39,744 (6,002; 119,770) ng•h/mL for GS-563117, respectively. The plasma exposures (Cmax and AUC) of idelalisib are approximately dose proportional between 50 mg and 100 mg and less than dose proportional above 100 mg.
Relative to fasting conditions, administration of an early capsule formulation of idelalisib with a high-fat meal resulted in no change in Cmax and a 36% increase in mean AUCinf. Idelalisib can be administered without regard to food.
Idelalisib is 93% to 94% bound to human plasma proteins at concentrations observed clinically. The mean blood-to-plasma concentration ratio was approximately 0.5. The apparent volume of distribution for idelalisib (mean) was approximately 96 L.
Idelalisib is metabolised primarily via aldehyde oxidase, and to a lesser extent via CYP3A and UGT1A4. The primary and only circulating metabolite, GS-563117, is inactive against PI3Kδ.
The terminal elimination half-life of idelalisib was 8.2 (range: 1.9; 37.2) hours and the apparent clearance of idelalisib was 14.9 (range: 5.1; 63.8) L/h following idelalisib 150 mg twice daily oral administration. Following a single 150 mg oral dose of [14C]-labelled idelalisib, approximately 78% and 15% was excreted in faeces and urine, respectively. Unchanged idelalisib accounted for 23% of total radioactivity recovered in urine over 48 hours and 12% of total radioactivity recovered in faeces over 144 hours.
In vitro data indicated that idelalisib is not an inhibitor of the metabolising enzymes CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A, or UGT1A1, or of the transporters OAT1, OAT3, or OCT2.
GS-563117 is not an inhibitor of the metabolising enzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or UGT1A1, or of the transporters P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, or OCT2.
Population pharmacokinetic analyses indicated that gender and race had no clinically relevant effect on the exposures to idelalisib or GS-563117.
Population pharmacokinetic analyses indicated that age had no clinically relevant effect on the exposures to idelalisib or GS-563117, including elderly subjects (65 years of age and older), compared to younger subjects.
A study of pharmacokinetics and safety of idelalisib was performed in healthy subjects and subjects with severe renal impairment (estimated CrCl 15 to 29 mL/min). Following a single 150 mg dose, no clinically relevant changes in exposures to idelalisib or GS-563117 were observed in subjects with severe renal impairment compared to healthy subjects.
A study of pharmacokinetics and safety of idelalisib was performed in healthy subjects and subjects with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment. Following a single 150 mg dose, idelalisib AUC (total, i.e., bound plus unbound) was ~60% higher in moderate and severe impairment compared to matched controls. The idelalisib AUC (unbound), after accounting for differences in protein binding, was ~80% (1.8-fold) higher in moderate and ~152% (2.5-fold) higher in severe impairment compared to matched controls.
The pharmacokinetics of idelalisib in paediatric subjects has not been established.
Idelalisib induced lymphoid depletion in spleen, thymus, lymph nodes and gut-associated lymphoid tissue. In general, B-lymphocyte dependent areas were more affected than T-lymphocyte dependent areas. In rats, idelalisib has the potential to inhibit T-dependent antibody responses. However, idelalisib did not inhibit the normal host response to Staphylococcus aureus and did not exacerbate the myelosuppressive effect of cyclophosphamide. Idelalisib is not considered to have broad immunosuppressive activity.
Idelalisib induced inflammatory changes in both rats and dogs. In studies up to 4 weeks in rats and dogs, hepatic necrosis was observed at 7 and 5 times the human exposure based on AUC, respectively. Serum transaminase elevations correlated with hepatic necrosis in dogs, but were not observed in rats. No hepatic impairment or chronic transaminase elevations were observed in rats or dogs in studies of 13 weeks and longer duration.
Idelalisib did not induce mutations in the microbial mutagenesis (Ames) assay, was not clastogenic in the in vitro chromosome aberration assay using human peripheral blood lymphocytes, and was not genotoxic in the in vivo rat micronucleus study.
The carcinogenicity potential of idelalisib was evaluated in a 26-week transgenic RasH2 mouse study and a 2-year rat study. Idelalisib was not carcinogenic at exposures up to 1.4/7.9-fold (male/female) in mice compared to the exposure in patients with haematologic malignancies administered the recommended dose of 150 mg twice daily. A dose-related increase in pancreatic islet cell tumors was observed at low incidence in male rats at exposures up to 0.4-fold compared to the human exposure at the recommended dose; a similar finding was not observed in female rats at 0.62-fold exposure margin.
In an embryo-foetal development study in rats, increased post-implantation loss, malformations (absence of caudal vertebrae and in some cases also of sacral vertebrae), skeletal variations and lower foetal body weights were observed. Malformations were observed at exposures from 12 times the human exposure based on AUC. Effects on embryo-foetal development were not investigated in a second species.
Degeneration of the seminiferous tubules in the testes was observed in 2- to 13-week repeated dose studies in dogs and rats, but not in studies of 26 weeks and longer duration. In a rat male fertility study, decreases in epididymides and testes weight were observed but no adverse effects on mating or fertility parameters, and no degeneration or loss in spermatogenesis were observed. Female fertility was not affected in rats.
Evaluation of the potential for phototoxicity in the embryonic murine fibroblast cell line BALB/c 3T3 was inconclusive for idelalisib due to cytotoxicity in the in vitro assay. The major metabolite, GS-563117, may enhance phototoxicity when cells are simultaneously exposed to UVA light. There is a potential risk that idelalisib, via its major metabolite, GS-563117, may cause photosensitivity in treated patients.
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