Chemical formula: C₂₂H₁₇ClN₆O Molecular mass: 416.87 g/mol PubChem compound: 50905713
Duvelisib is a dual inhibitor of phosphatidylinositol 3-kinase p110δ (PI3K-δ) and PI3K-γ. PI3K-δ inhibition directly reduces proliferation and survival of malignant B-cell lines and primary CLL tumour cells, while PI3K-γ inhibition reduces the activity of CD4+ T cells and macrophages in the tumor microenvironment to support the malignant B cells. At 25 mg BID, the plasma levels of duvelisib may not be high enough to cause sustained inhibition of PI3K-γ, and the contribution of PI3K-γ inhibition to the efficacy may be limited.
The effect of multiple doses of duvelisib 25 and 75 mg BID on the corrected QT (QTc) interval was evaluated in patients with previously treated hematologic malignancies. Increases of >20 ms in the QTc interval were not observed.
Duvelisib exposure increased in a dose-proportional manner over a dose range of 8 mg to 75 mg (0.3 to 3 times the recommended dose) following a single dose. Dose proportionality was not estabilished after multiple doses.
At steady state following 25 mg BID administration of duvelisib in patients, the geometric mean (CV%) maximum concentration (Cmax) was 1.5 (64%) µg/mL and AUC was 7.9 (77%) µg•h/mL.
The absolute bioavailability of 25 mg duvelisib after a single oral dose in healthy volunteers was 42%. The median time to peak concentration (Tmax) was observed at 1 to 2 hours in patients.
Duvelisib may be administered without regard to food. The administration of a single dose of duvelisib with a high-fat meal (fat accounted for approximately 50% of the total caloric content of the meal) decreased Cmax by approximately 37% and decreased the AUC by approximately 6%, relative to fasting conditions.
Protein binding of duvelisib is greater than 95%. The mean blood-to-plasma ratio was 0.5. The geometric mean (CV%) apparent volume of distribution at steady state (Vss/F) is 28.5 L (62%).
Duvelisib is primarily metabolized by cytochrome P450 CYP3A4. The major metabolite is IPI-656, which is pharmacologically inactive at clinically observed exposure levels.
The geometric mean (CV%) apparent systemic clearance at steady-state is 4.2 L/hr (56%) in patients with lymphoma or leukaemia. The geometric mean (CV%) elimination half-life of duvelisib is 4.7 hours (57%) during 0-8 hours postdose.
Following a single 25 mg oral dose of radiolabeled duvelisib, 79% of the radioactivity was excreted in feces (11% unchanged) and 14% was excreted in the urine (1% unchanged). These data have been determined in healthy subjects.
Duvelisib is a substrate of P-glycoprotein (P-gp) and breast cancer-resistant protein (BCRP). Duvelisib is highly absorbed following an oral dose and therefore no clinically relevant effect of P-gp and BCRP inhibitors is expected.
In vitro studies combined with human in vivo Pharmacokinetic (PK) data suggested that clinically relevant drug-drug interactions of duvelisib and its main metabolite IPI-656 with substrates of OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BCRP, or P-gp are unlikely. Therefore, interaction studies with Pgp, BCRP and CYP2C8 are considered not necessary.
Both duvelisib and IPI-656 were determined as direct inhibitors of CYP2C8 and CYP3A4 as well as metabolism-dependent inhibitors of CYP3A4. Simulations indicated that at supratherapeutic doses duvelisib can be a mild inhibitor of CYP2C8, which is considered unlikely to result in clinically relevant interactions.
Age (18 to 90 years), sex, race, renal impairment (creatinine clearance 23 to 80 mL/min), hepatic impairment (Child Pugh Class A, B, and C) and body weight (40 to 154 kg) had no clinically significant effect on the exposure of duvelisib.
Duvelisib pharmacokinetics were highly variable in subjects with moderate and severe hepatic impairment.Geometric mean duvelisib AUC0-∞ in mild, moderate, and severely hepatically impaired subjects were lower (within 20%) compared to the exposure observed in healthy subjects and was 89%, 94%, and 81% of the exposure observed in healthy subjects and is not considered clinically significant. The exposures in moderately and severely impaired subjects were highly variable (CV% 46–67%) and these patients should be carefully monitored for adverse events. Exposures obtained in cancer patients were approximately 2-fold higher than the exposures observed in healthy subjects.
In repeat-dose toxicity studies in rat and cynomolgus monkey, adverse effects were mainly related to expected exaggarated pharmacology, including adverse effects on lymphoid tissues, bone marrow and haematology parameters at exposures of free duvelisib at 8 to 16 fold, corresponding to total duvelisib at 2 to 11 fold Maximum Recommended Human Dose (MRHD) of 25 mg BID in human.
Duvelisib did not cause genetic damage in in vitro or in vivo assays.
In dose range finding and pivotal embryo-fetal developmental toxicity studies in rat and rabbit, duvelisib (free fraction) induced embryo-fetal developmental toxicity only at free plasma exposures margins of >25 fold of 25 mg BID in human (MRHD), corresponding to 4 to 5 fold total plasma concentrations.
Fertility studies with duvelisib were not conducted. Histological findings in male and female rats were observed in the repeat dose toxicity studies and included testis (seminiferous epithelial atrophy, decreased weight, soft testes), and epididymis (small size, oligo/aspermia) in males and ovary (decreased weight) and uterus (atrophy) in females.
Carcinogenicity studies have not been conducted with duvelisib.
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