Chemical formula: C₂₆H₂₃N₇O₂ Molecular mass: 465.517 g/mol PubChem compound: 71226662
Acalabrutinib is a selective inhibitor of Bruton tyrosine kinase (BTK). BTK is a signalling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signalling results in B-cell survival and proliferation, and is required for cellular adhesion, trafficking, and chemotaxis.
Acalabrutinib and its active metabolite, ACP-5862, form a covalent bond with a cysteine residue in the BTK active site, leading to irreversible inactivation of BTK with minimal off-target interactions.
In patients with B-cell malignancies dosed with acalabrutinib 100 mg twice daily, median steady-state BTK occupancy of ≥95% in peripheral blood was maintained over 12 hours, resulting in inactivation of BTK throughout the recommended dosing interval.
The effect of acalabrutinib on the QTc interval was evaluated in 46 healthy male and female subjects in a randomised, double-blind thorough QT study with placebo and positive controls. At a supratherapeutic dose, 4-times the maximum recommended dose, acalabrutinib did not prolong the QT/QTc interval to any clinically relevant extent (e.g., not greater than or equal to 10 ms).
The pharmacokinetics (PK) of acalabrutinib and its active metabolite, ACP-5862, were studied in healthy subjects and in patients with B-cell malignancies. Acalabrutinib exhibits dose-proportionality, and both acalabrutinib and ACP-5862 exhibit almost linear PK across a dose range of 75 to 250 mg. Population PK modelling suggests that the PK of acalabrutinib and ACP-5862 is similar across patients with different Bcell malignancies. At the recommended dose of 100 mg twice daily in patients with B-cell malignancies (including, CLL), the geometric mean steady state daily area under the plasma concentration over time curve (AUC24h) and maximum plasma concentration (Cmax) for acalabrutinib were 1679 ng•h/mL and 438 ng/mL, respectively, and for ACP-5862 were 4166 ng•h/mL and 446 ng/mL, respectively.
The time to peak plasma concentrations (Tmax) was 0.5-1.5 hours for acalabrutinib, and 1.0 hour for ACP5862. The absolute bioavailability of acalabrutinib was 25%.
In healthy subjects, administration of a single 75 mg dose of acalabrutinib with a high fat, high calorie meal (approximately 918 calories, 59 grams carbohydrate, 59 grams fat and 39 grams protein) did not affect the mean AUC as compared to dosing under fasted conditions. Resulting Cmax decreased by 69% and Tmax was delayed 1-2 hours.
Reversible binding to human plasma protein was 99.4% for acalabrutinib and 98.8% for ACP-5862. The in vitro mean blood-to-plasma ratio was 0.8 for acalabrutinib and 0.7 for ACP-5862. The mean steady state volume of distribution (Vss) was approximately 34 L for acalabrutinib.
In vitro, acalabrutinib is predominantly metabolised by CYP3A enzymes, and to a minor extent by glutathione conjugation and amide hydrolysis. ACP-5862 was identified as the major metabolite in plasma, that was further metabolized primarily by CYP3A-mediated oxidation, with a geometric mean exposure (AUC) that was approximately 2- to 3-fold higher than the exposure of acalabrutinib. ACP-5862 is approximately 50% less potent than acalabrutinib with regard to BTK inhibition.
In vitro studies indicate that acalabrutinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, UGT1A1 or UGT2B7 at clinically relevant concentrations and is unlikely to affect clearance of substrates of these CYPs.
In vitro studies indicate that ACP-5862 does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5, UGT1A1 or UGT2B7 at clinically relevant concentrations and is unlikely to affect clearance of substrates of these CYPs.
In vitro studies indicate that acalabrutinib and ACP-5862 are P-gp and BCRP substrates. Coadministration with BCRP inhibitors is however unlikely to result in clinically relevant drug interactions. Co-administration with an OATP1B1/1B3 inhibitor (600 mg rifampin, single dose) resulted in an increase in acalabrutinib Cmax and AUC by 1.2-fold and 1.4-fold (N=24, healthy subjects), respectively, which is not clinically relevant.
Acalabrutinib and ACP-5862 do not inhibit P-gp, OAT1, OAT3, OCT2, OATP1B1, OATP1B3 and MATE2-K at clinically relevant concentrations. Acalabrutinib may inhibit intestinal BCRP, while ACP5862 may inhibit MATE1 at clinically relevant concentrations. Acalabrutinib does not inhibit MATE1, while ACP-5862 does not inhibit BCRP at clinically relevant concentrations.
Following a single oral dose of 100 mg acalabrutinib, the terminal elimination half-life (t1/2) of acalabrutinib was 1 to 2 hours. The t1/2 of the active metabolite, ACP-5862, was approximately 7 hours.
The mean apparent oral clearance (CL/F) was 134 L/hr for acalabrutinib and 22 L/hr for ACP-5862 in patients with B-cell malignancies.
Following administration of a single 100 mg radiolabelled [14C]-acalabrutinib dose in healthy subjects, 84% of the dose was recovered in the faeces and 12% of the dose was recovered in the urine, with less than 2% of the dose excreted as unchanged acalabrutinib.
Based on population PK analysis, age (>18 years of age), sex, race (Caucasian, African American) and body weight did not have clinically meaningful effects on the PK of acalabrutinib and its active metabolite, ACP-5862.
No pharmacokinetic studies were performed with acalabrutinib in patients under 18 years of age.
Acalabrutinib undergoes minimal renal elimination. A pharmacokinetic study in patients with renal impairment has not been conducted.
Based on population PK analysis, no clinically relevant PK difference was observed in 408 subjects with mild renal impairment (eGFR between 60 and 89 mL/min/1.73m² as estimated by MDRD), 109 subjects with moderate renal impairment (eGFR between 30 and 59 mL/min/1.73m²) relative to 192 subjects with normal renal function (eGFR greater than or equal to 90 mL/min/1.73m²). The pharmacokinetics of acalabrutinib has not been characterised in patients with severe renal impairment (eGFR less than 29 mL/min/1.73m²) or renal impairment requiring dialysis. Patients with creatinine levels greater than 2.5 times the institutional ULN were not included in the clinical studies.
Acalabrutinib is metabolised in the liver. In dedicated hepatic impairment (HI) studies, compared to subjects with normal liver function (n=6), acalabrutinib exposure (AUC) was increased by 1.9-fold, 1.5-fold and 5.3-fold in subjects with mild (n=6) (Child-Pugh A), moderate (n=6) (Child-Pugh B) and severe (n=8) (Child-Pugh C) hepatic impairment, respectively. Subjects in the moderate HI group were however not significantly affected in markers relevant for the elimination capacity of drugs, so the effect of moderate hepatic impairment was likely underestimated in this study. Based on a population PK analysis, no clinically relevant difference was observed between subjects with mild (n=79) or moderate (n=6) hepatic impairment (total bilirubin between 1.5- to 3-times ULN and any AST) relative to subjects with normal (n=613) hepatic function (total bilirubin and AST within ULN).
Carcinogenicity studies have not been conducted with acalabrutinib.
Acalabrutinib was not mutagenic in a bacterial reverse mutation assay, in an in vitro chromosome aberration assay or in an in vivo mouse bone marrow micronucleus assay.
Based on phototoxicity assays using 3T3 cell line in vitro, acalabrutinib is considered to have a low risk for phototoxicity in humans.
In rats, microscopic findings of minimal to mild severity were observed in the pancreas (haemorrhage/pigment/inflammation/fibrosis in islets) at all dose levels. Non-adverse findings of minimal to mild severity in the kidneys (tubular basophilia, tubular regeneration, and inflammation) were observed in studies of up to 6-month duration with a No Observed Adverse Effect level (NOAEL) of 30 mg/kg/day in rats. The mean exposures (AUC) at the NOAEL in male and female rats correspond to 0.6x and 1x, respectively, the clinical exposure at the recommended dose of 100 mg twice daily, respectively. The Lowest Adverse Observed Effect Level (LOAEL) at which reversible renal (moderate tubular degeneration) and liver (individual hepatocyte necrosis) findings were observed in the chronic rat study was 100 mg/kg/day and provided an exposure margin 4.2-times greater than the clinical exposure at the recommended dose of 100 mg twice daily. In studies of 9 months duration in dogs, the NOAEL was 10 mg/kg/day corresponding to an exposure 3-times the clinical AUC at the recommended clinical dose. Minimal tubular degeneration in kidney, slight decreases in spleen weights and transient minimal to mild decreases in red cell mass and increases in ALT and ALP were observed at 30 mg/kg/day (9-times the clinical AUC) in dogs. Cardiac toxicities in rats (myocardial haemorrhage, inflammation, necrosis) and dogs (perivascular/vascular inflammation) were observed only in animals that died during studies at doses above the maximum tolerated dose (MTD). The exposures in rats and dogs with cardiac findings was at least 6.8-times and 25-times the clinical AUC, respectively. Reversibility for the heart findings could not be assessed as these findings were only observed at doses above the MTD.
No effects on fertility were observed in male or female rats at exposures 10- or 9-times the clinical AUC at the recommended dose, respectively.
No effects on embryofoetal development and survival were observed in pregnant rats, at exposures approximately 9-times the AUC in patients at the recommended dose of 100 mg twice daily. In two rat reproductive studies, dystocia (prolonged/difficult labour) was observed at exposures >2.3-times the clinical exposure at 100 mg twice daily. The presence of acalabrutinib and its active metabolite were confirmed in foetal rat plasma. Acalabrutinib and its active metabolite were present in the milk of lactating rats.
In an embryofoetal study in pregnant rabbits, decreased foetal body weight and delayed ossification were observed at exposure levels that produced maternal toxicity which were 2.4-times greater than the human AUC at the recommended dose.
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