Chemical formula: C₂₀H₁₈ClF₂N₅O₃ Molecular mass: 449.84 g/mol PubChem compound: 72165228
Asciminib is a potent inhibitor of ABL/BCR::ABL1 tyrosine kinase. Asciminib inhibits the ABL1 kinase activity of the BCR::ABL1 fusion protein by specifically targeting the ABL myristoyl pocket.
In vitro, asciminib inhibits the tyrosine kinase activity of ABL1 at mean IC50 values below 3 nanomolar. In patient-derived cancer cells, asciminib specifically inhibits the proliferation of cells harbouring BCR::ABL1 with IC50 values between 1 and 25 nanomolar. In cells engineered to express either the wild-type or the T315I mutant form of BCR::ABL1, asciminib inhibits cell growth with mean IC50 values of 0.61 ± 0.21 and 7.64 ± 3.22 nanomolar, respectively.
In mouse xenograft models of CML, asciminib dose-dependently inhibited the growth of tumours harbouring either the wild-type or the T315I mutant form of BCR::ABL1, with tumour regression being observed at doses above 7.5 mg/kg or 30 mg/kg twice daily, respectively.
Asciminib treatment is associated with an exposure-related prolongation of the QT interval.
The correlation between asciminib concentration and the estimated mean change from baseline of the QT interval with Fridericia’s correction (ΔQTcF) was evaluated in 239 patients with Ph+ CML or Ph+ acute lymphoblastic leukaemia (ALL) receiving asciminib at doses ranging from 10 to 280 mg twice daily and 80 to 200 mg once daily. The estimated mean ΔQTcF was 3.35 ms (upper bound of 90% CI: 4.43 ms) for the asciminib 40 mg twice-daily dose.
Asciminib is rapidly absorbed, with median maximum plasma level (Tmax) reached 2 to 3 hours after oral administration, independent of the dose. The geometric mean (geoCV%) of Cmax and AUCtau at steady state is 793 ng/ml (49%) and 5262 ng*h/ml (48%), respectively, following administration of asciminib at the 40 mg twice-daily dose. PBPK models predict that asciminib absorption is approximately 100%, while bioavailability is approximately 73%.
Asciminib bioavailability may be reduced by co-administration of oral medicinal products containing hydroxypropyl-β-cyclodextrin as an excipient. Co-administration of multiple doses of an itraconazole oral solution containing hydroxypropyl-β-cyclodextrin at a total of 8 g per dose with a 40 mg dose of asciminib decreased asciminib AUCinf by 40.2% in healthy subjects.
Food consumption decreases asciminib bioavailability, with a high-fat meal having a higher impact on asciminib pharmacokinetics than a low-fat meal. Asciminib AUC is decreased by 62.3% with a high-fat meal and by 30% with a low-fat meal compared to the fasted state.
Asciminib apparent volume of distribution at steady state is 111 litres based on population pharmacokinetic analysis. Asciminib is mainly distributed to plasma, with a mean blood-to-plasma ratio of 0.58, independent of the dose based on in vitro data. Asciminib is 97.3% bound to human plasma proteins, independent of the dose.
Asciminib is primarily metabolised via CYP3A4-mediated oxidation, and UGT2B7- and UGT2B17-mediated glucuronidation. Asciminib is the main circulating component in plasma (92.7% of the administered dose).
Asciminib is mainly eliminated via faecal excretion, with a minor contribution of the renal route. Eighty and 11% of the asciminib dose were recovered in the faeces and in the urine of healthy subjects, respectively, following oral administration of a single 80 mg dose of [14C]-labelled asciminib. Faecal elimination of unchanged asciminib accounts for 56.7% of the administered dose.
Asciminib is eliminated by biliary secretion via breast cancer-resistant protein (BCRP).
The oral total clearance (CL/F) of asciminib is 6.31 l/hour, based on population pharmacokinetic analysis. The elimination half-life of asciminib is 5.2 hours at 40 mg twice daily.
Asciminib exhibits a slight dose over-proportional increase in steady-state exposure (AUC and Cmax) across the dose range of 10 to 200 mg administered once or twice daily.
The geometric mean accumulation ratio is approximately 2-fold. Steady-state conditions are achieved within 3 days at the 40 mg twice-daily dose.
In vitro, asciminib reversibly inhibits CYP3A4/5, CYP2C9 and UGT1A1 at plasma concentrations reached at a 40 mg twice-daily dose.
Asciminib is a substrate of BCRP and P-gp.
Asciminib inhibits BCRP and P-gp with Ki values of 24.3 and 21.7 micromolar, respectively.
Asciminib is metabolised by several pathways, including the CYP3A4, UGT2B7 and UGT2B17 enzymes and biliary secreted by the transporter BCRP. Medicinal products inhibiting or inducing CYP3A4, UGT and BCRP pathways may alter asciminib exposure.
Asciminib systemic exposure is not affected by gender, race or body weight to any clinically relevant extent.
A dedicated renal impairment study including 6 subjects with normal renal function (absolute glomerular filtration rate [aGFR] ≥90 ml/min) and 8 subjects with severe renal impairment not requiring dialysis (aGFR 15 to <30 ml/min) has been conducted. Asciminib AUCinf and Cmax were increased by 56% and 8%, respectively, in subjects with severe renal impairment compared to subjects with normal renal function, following oral administration of a single 40 mg dose of asciminib. Population pharmacokinetic models indicate an increase in asciminib median steady-state AUC0-24h by 11.5% in subjects with mild to moderate renal impairment, compared to subjects with normal renal function.
A dedicated hepatic impairment study including 8 subjects each with normal hepatic function, mild hepatic impairment (Child-Pugh A score 5-6), moderate hepatic impairment (Child-Pugh B score 7-9) or severe hepatic impairment (Child-Pugh C score 10-15) was conducted. Asciminib AUCinf was increased by 22%, 3% and 66% in subjects with mild, moderate and severe hepatic impairment, respectively, compared to subjects with normal hepatic function, following oral administration of a single 40 mg dose of asciminib.
Moderate cardiovascular effects (increased heart rate, decreased systolic pressure, decreased mean arterial pressure, and decreased arterial pulse pressure) were observed in in vivo cardiac safety studies in dogs, likely at AUC exposures 12-fold higher than those achieved in patients at the recommended dose (RD) of 40 mg twice daily.
Pancreatic effects (serum amylase and lipase increases, acinar cell lesions) occurred in dogs at AUC exposures below those achieved in patients at the RD of 40 mg twice daily. A trend towards recovery was observed.
Elevations in liver enzymes and/or bilirubin were observed in rats, dogs and monkeys. Histopathological hepatic changes (centrilobular hepatocyte hypertrophy, slight bile duct hyperplasia, increased individual hepatocyte necrosis and diffuse hepatocellular hypertrophy) were seen in rats and monkeys. These changes occurred at AUC exposures either equivalent to (rats) or 12- to 18-fold (dogs and monkeys, respectively) higher than those achieved in patients at the RD of 40 mg twice daily. These changes were fully reversible.
Effects on the haematopoietic system (reduction in red blood cell mass, increased splenic or bone marrow pigment and increased reticulocytes) were consistent with a mild and regenerative, extravascular, haemolytic anaemia in all species. These changes occurred at AUC exposures either equivalent to (rats) or 12- to 14-fold (dogs and monkeys, respectively) higher than those achieved in patients at the RD of 40 mg twice daily. These changes were fully reversible.
Minimal mucosal hypertrophy/hyperplasia (increase in thickness of the mucosa with frequent elongation of villi) was present in the duodenum of rats at AUC exposures 30-fold higher than those achieved in patients at the RD of 40 mg twice daily. This change was fully reversible.
Minimal or slight hypertrophy of the adrenal gland and mild to moderate decreased vacuolation in the zona fasciculata occurred at AUC exposures either equivalent to (monkeys) or 19-fold (rats) higher than those achieved in patients at the RD of 40 mg twice daily. These changes were fully reversible.
Asciminib did not have mutagenic, clastogenic or aneugenic potential either in vitro nor in vivo. Carcinogenicity studies have not been conducted with asciminib.
Animal reproduction studies in pregnant rats and rabbits demonstrated that oral administration of asciminib during organogenesis induced embryotoxicity, foetotoxicity and teratogenicity.
In embryo-foetal development studies, a slight increase in foetal malformations (anasarca and cardiac malformations) and increased visceral and skeletal variants were observed in rats. Increased incidence of resorptions indicative of embryo-foetal mortality and a low incidence of cardiac malformations indicative of teratogenicity were observed in rabbits. In rats, at the foetal no observed adverse effect level (NOAEL) of 25 mg/kg/day, the AUC exposures were equivalent to those achieved in patients at the RD of 40 mg twice daily. In rabbits, at the foetal NOAEL of 15 mg/kg/day, the AUC exposures were equivalent to those achieved in patients at the RD of 40 mg twice daily.
In the rat fertility study, asciminib did not affect reproductive function in male and female rats. A slight effect on male sperm motility and sperm count was observed at doses of 200 mg/kg/day, likely at AUC exposures 19-fold higher than those achieved in patients at the RD of 40 mg twice daily.
A pre- and postnatal developmental toxicity study was not performed.
In mice, asciminib showed dose-dependent phototoxic effects starting at 200 mg/kg/day. At the NOAEL of 60 mg/kg/day, exposure based on Cmax in plasma was 15-fold higher than the exposure in patients at the RD of 40 mg twice daily
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