Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

13.2 Pharmacodynamics
In patients with B-cell malignancies dosed with acalabrutinib 100 mg approximately every 12 hours, 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.

Cardiac Electrophysiology

At a dose 4 times the approved recommended dosage, CALQUENCE TABLETS does not prolong the QTc interval to any clinically relevant extent.

Pharmacokinetic Properties

13.3 Pharmacokinetics
Acalabrutinib and its active metabolite, ACP-5862, exposures increase proportionally with dose across a dose range of 75 to 250 mg (0.75 to 2.5 times the approved recommended single dosage) in patients with B-cell malignancies. At the recommended dose of 100 mg twice daily, the geometric mean (% coefficient of variation [CV]) daily area under the plasma drug concentration over time curve (AUC24h) and maximum plasma concentration (Cmax) for acalabrutinib were 1843 (38%) ng•h/mL and 563 (29%) ng/mL, respectively, and for ACP-5862 were 3947 (43%) ng•h/mL and 451 (52%) ng/mL, respectively.

Absorption

The geometric mean absolute bioavailability of acalabrutinib was 25%. Median (min, max) time to peak plasma concentration (Tmax) of acalabrutinib and its active metabolite, ACP-5862 were 0.5 (0.2, 3.0) hours and 0.75 (0.5, 4.0) hours, respectively.

Effect of Food

In healthy subjects, administration of a single 100 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 54% and Tmax was delayed 1-2 hours.

Distribution

The geometric mean (% CV) steady-state volume of distribution (Vss) of acalabrutinib and its active metabolite, ACP-5862 was approximately 101 (52%) L and 67 (32%) L, respectively. Human plasma protein of acalabrutinib and its active metabolite, ACP-5862, were 97.5% and 98.6%, respectively. The mean blood-to-plasma ratio of acalabrutinib and its active metabolite, ACP-5862, was 0.8 and 0.7, respectively.

Elimination

The geometric mean (% CV) terminal elimination half-life (t1/2) of acalabrutinib and its active metabolite, ACP-5862, were 1.4 (50%) hours and 6.4 (37%) hours, respectively. The geometric mean (%CV) apparent oral clearance (CL/F) of acalabrutinib and its active metabolite, ACP-5862, were 71 (35%) L/hr and 13 (42%) L/hr, respectively.

Metabolism

Acalabrutinib is predominantly metabolized by CYP3A enzymes, and to a minor extent, by glutathione conjugation and amide hydrolysis, based on in vitro studies. ACP-5862 was identified as the major active metabolite in plasma 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.

Excretion

Following administration of a single 100 mg radiolabeled acalabrutinib dose in healthy subjects, 84% of the dose was recovered in the feces (< 2% unchanged) and 12% of the dose was recovered in the urine (< 2% unchanged).

Specific Populations

There were no clinically significant differences in the pharmacokinetics of acalabrutinib and its active metabolite, ACP-5862, based on age (32 to 90 years), sex, race (Caucasian, African American), body weight (40 to 149 kg), or mild to moderate renal impairment (eGFR ≥ 30 mL/min/1.73m2 and eGFR < 89 mL/min/1.73m2, as estimated by MDRD (modification of diet in renal disease equation)). The effect of severe renal impairment (eGFR < 29 mL/min/1.73m2, MDRD) or renal impairment requiring dialysis on the pharmacokinetics of acalabrutinib is unknown.

Patients with Hepatic Impairment

The AUC of acalabrutinib increased 1.9-fold in subjects with mild hepatic impairment (Child-Pugh class A), 1.5-fold in subjects with moderate hepatic impairment (Child-Pugh class B) and 5.3-fold in subjects with severe hepatic impairment (Child-Pugh class C) compared to subjects with normal liver function. No clinically relevant PK difference in ACP-5862 was observed in subjects with severe hepatic impairment (Child-Pugh Class C) compared to subjects with normal liver function. No clinically relevant PK differences in acalabrutinib and ACP-5862 were observed in patients with mild or moderate hepatic impairment (total bilirubin less and equal to upper limit of normal [ULN] and AST greater than ULN, or total bilirubin greater than ULN and any AST) relative to patients with normal hepatic function (total bilirubin and AST within ULN).

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches
Strong CYP3A Inhibitors: Co-administration of acalabrutinib with itraconazole (strong CYP3A inhibitor) increase acalabrutinib Cmax by 3.9-fold and AUC by 5.1-fold in healthy subjects.

Moderate CYP3A Inhibitors: Co-administration of acalabrutinib with erythromycin (moderate CYP3A inhibitor), fluconazole (moderate CYP3A inhibitor), diltiazem (moderate CYP3A inhibitor) is predicted to increase acalabrutinib Cmax and AUC by approximately 2- to 3-fold.
Strong CYP3A Inducers: Co-administration of acalabrutinib with rifampin (strong CYP3A inducer) decreased acalabrutinib Cmax by 68% and AUC by 77% in healthy subjects.

Acid-Reducing Agents: No clinically significant differences in the pharmacokinetics of acalabrutinib were observed when co-administered with rabeprazole (proton pump inhibitor).

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Acalabrutinib is an inhibitor of CYP3A4/5, CYP2C8 and CYP2C9, but not CYP1A2, CYP2B6, CYP2C19, or CYP2D6. Acalabrutinib’s active metabolite, ACP-5862, is an inhibitor of CYP2C8, CYP2C9 and CYP2C19, but not CYP1A2, CYP2B6, CYP2D6, or CYP3A4/5.
Acalabrutinib is an inducer of CYP1A2, CYP2B6, and CYP3A4. Acalabrutinib’s active metabolite, ACP- 5862, is an inducer of CYP3A4.

Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes: Acalabrutinib and its active metabolite, ACP-5862, are not inhibitors of UGT1A1 or UGT2B7.

Transporter System: Acalabrutinib is an inhibitor of breast cancer resistance protein (BCRP), but not multidrug and toxin extrusion protein 1 (MATE1). Acalabrutinib’s active metabolite, ACP-5862, is an inhibitor of MATE1, but not BCRP. Acalabrutinib and its active metabolite, ACP-5862, are not inhibitors of P-glycoprotein (P-gp), organic anion transporter (OAT) 1, OAT3, organic cation transporter 2 (OCT2), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, or MATE2-K.

Acalabrutinib and its active metabolite, ACP-5862, are substrates of P-gp and BCRP. Acalabrutinib is not a substrate of OAT1, OAT3, OCT2, OATP1B1, or OATP1B3. Acalabrutinib’s active metabolite, ACP- 5862, is not a substrate of OATP1B1 or OATP1B3.