Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2       Pharmacodynamics

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EA06 

Exposure-Response Relationships
Over asciminib dosages of 10 mg to 200 mg twice daily (0.25 to 5 times the recommended 80 mg daily dosage), a lower exposure was associated with a smaller decrease in BCR-ABL1 level and a lower MMR rate at Week 24.
Over asciminib dosages of 10 mg to 280 mg twice daily (0.25 to 7 times the recommended 80 mg daily dosage), a higher exposure was associated with slightly higher incidence of some adverse reactions (e.g., Grade ≥ 3 lipase increase, Grade ≥ 3 hemoglobin decrease, Grade ≥ 2 ALT increase, Grade ≥ 2 AST increase, Grade ≥ 2 bilirubin increase, and any grade lipase increase).
Cardiac Electrophysiology
Asciminib does not cause a large mean increase in QTc interval (i.e., > 20 msec) at the maximum recommended clinical dosage (200 mg twice daily). Based on available clinical data, small mean QTc increase (< 10 msec) cannot be excluded.

Pharmacokinetic Properties

12.3       Pharmacokinetics
Asciminib steady-state exposure (AUC and Cmax) increase slightly more than dose proportional across the dose range of 10 to 200 mg (0.25 to 5 times the recommended 80 mg daily dosage) administered once or twice daily.
Pharmacokinetic parameters are presented as geometric mean (CV%) unless otherwise stated. The steady state Cmax and AUCtau of asciminib at recommended dosages are listed in Table 7.
Table 7: Steady Statea Asciminib Exposure at Recommended Dosages
Asciminib Dosage                 Cmax (ng/mL)                AUCtaub (ng*h/mL)            Accumulation Ratio 80 mg once daily                 1781 (23%)                     15112 (28%)                        1.30           40 mg twice daily                    793 (49%)                         5262 (48%)               1.65
200 mg twice daily                    5642 (40%)                       37547 (41%)               1.92 a
Steady state is achieved within 3 days.
b
AUCtau represents AUC0-12h for twice daily dosing and AUC0-24h for once daily dosing.


Absorption
The median (range) Tmax of asciminib is 2.5 hours (2 to 3 hours).
Effect of Food
The AUC and Cmax of asciminib decreased by 62% and 68%, respectively, with a high-fat meal (1000 calories, 50% fat) and by 30% and 35%, respectively, with a low-fat meal (400 calories, 25% fat) compared to the fasted state following administration of SCEMBLIX.
Distribution
The apparent volume of distribution of asciminib at steady state is 151 L (135%). Asciminib is the main circulating component in plasma (93% of the administered dose).
Asciminib is 97% bound to human plasma proteins in vitro.
Elimination
The total apparent clearance of asciminib is 6.7 L/hour (48%) at 40 mg twice daily and 80 mg once daily, and 4.1 L/hour (38%) at 200 mg twice daily. The terminal elimination half-life of asciminib is 5.5 hours (38%) at 40 mg twice daily and 80 mg once daily, and 9.0 hours (33%) at 200 mg twice daily.
Metabolism
Asciminib is metabolized by CYP3A4-mediated oxidation, UGT2B7- and UGT2B17-mediated glucuronidation.
Excretion
Eighty percent (57% as unchanged) and 11% (2.5% as unchanged) of the asciminib dose were recovered in the feces and in the urine of healthy subjects, respectively, following oral administration of a single 80 mg dose of radio-labeled asciminib.
Asciminib is eliminated by biliary secretion via breast cancer-resistant protein (BCRP).
Specific Populations
No clinically significant differences in the pharmacokinetics of asciminib were observed based on sex, age (20 to 88 years), race (Asian 20%, White 70%, Black/African American 4%), or body weight (42 - 184 kg), mild to moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2), or mild (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1 to 1.5 times ULN and any AST) to moderate (total bilirubin > 1.5 to 3 times ULN and any AST) hepatic impairment.
Patients with Renal Impairment
Asciminib AUCinf and Cmax are increased by 57% and 6%, respectively, in subjects with eGFR between 13 to < 30 mL/min/1.73 m2 and not requiring dialysis compared to subjects with normal renal function (eGFR ≥ 90 mL/min/1.73 m2) following oral administration of a single 40 mg dose of SCEMBLIX. The exposure changes in patients with severe renal impairment are not considered clinically meaningful.
Patients with Hepatic Impairment
Asciminib AUCinf and Cmax are increased by 33% and 4%, respectively, in subjects with severe hepatic impairment (total bilirubin > 3 times ULN and any AST), compared to subjects with normal hepatic function (total bilirubin ≤ ULN and AST ≤ ULN) following oral administration of a single 40 mg dose of SCEMBLIX. The exposure changes are not considered clinically meaningful.
Drug Interaction Studies
Clinical Studies and Model-Informed Approaches
Drugs That Affect Asciminib Plasma Concentration
Strong CYP3A Inhibitors: The asciminib AUCinf and Cmax increased by 36% and 19%, respectively, following coadministration of a single SCEMBLIX dose of 40 mg with a strong CYP3A4 inhibitor (clarithromycin). No clinically significant differences in the pharmacokinetics of asciminib were observed when coadministered with itraconazole, which is also a strong CYP3A4 inhibitor.
Strong CYP3A Inducers: Concomitant use of strong CYP3A inducers with SCEMBLIX has not been fully characterized.
Itraconazole Oral Solution: Coadministration of multiple doses of itraconazole oral solution containing hydroxypropyl-β- cyclodextrin with a single SCEMBLIX dose of 40 mg decreased asciminib AUCinf and Cmax by 40% and 50%, respectively. Concomitant use of oral products containing hydroxypropyl-β-cyclodextrin with SCEMBLIX other than itraconazole oral solution has not been fully characterized.
Imatinib: The asciminib AUCinf and Cmax increase by 108% and 59%, respectively following coadministration of a single SCEMBLIX dose of 40 mg with imatinib (an inhibitor of BCRP, CYP3A4, UGT2B17, and UGT1A3/4). The exposure changes are not considered clinically meaningful. Concomitant use of imatinib with SCEMBLIX at 200 mg twice daily has not been fully characterized.
Other Drugs: No clinically significant differences in the pharmacokinetics of asciminib were observed when coadministered with rabeprazole (acid-reducing agent) and quinidine (P-gp inhibitor).
Drugs That are Affected by Asciminib
CYP3A4 Substrates: The midazolam AUCinf and Cmax increased by 28% and 11%, respectively, following coadministration of a CYP3A4 substrate (midazolam) with SCEMBLIX 40 mg twice daily. The midazolam AUCinf and Cmax increased by 24% and 17%, respectively, following coadministration with SCEMBLIX at 80 mg once daily and 88% and 58%, respectively, at 200 mg twice daily.
CYP2C9 Substrates: The S-warfarin AUCinf and Cmax increased by 41% and 8%, respectively, following coadministration of CYP2C9 substrate (warfarin) with SCEMBLIX at 40 mg twice daily. The S-warfarin AUCinf and Cmax increased by 52% and 4%, respectively, following coadministration with SCEMBLIX at 80 mg once daily and 314% and 7%, respectively, at 200 mg twice daily.
CYP2C8 Substrates: The repaglinide (substrate of CYP2C8, CYP3A4, and OATP1B) AUCinf and Cmax increased by 8% and 14%, respectively, following coadministration of repaglinide with SCEMBLIX 40 mg twice daily. The repaglinide AUCinf and Cmax increased by 12% and 8%, respectively, following coadministration with SCEMBLIX at 80 mg once daily and 42% and 25%, respectively, at 200 mg twice daily. The rosiglitazone (substrate of CYP2C8 and CYP2C9) AUCinf and Cmax increased by 20% and 3%, respectively, following coadministration of rosiglitazone with SCEMBLIX 40 mg twice daily. The rosiglitazone AUCinf and Cmax increased by 24% and 2%, respectively, following coadministration with SCEMBLIX at 80 mg once daily and 66% and 8%, respectively, at 200 mg twice daily.
P-gp Substrates: Coadministration of SCEMBLIX with a drug that is a substrate of P-gp may result in a clinically relevant increase in the plasma concentrations of P-gp substrates, where minimal concentration changes may lead to serious toxicities.
In Vitro Studies
CYP450 and UGT Enzymes
Asciminib may reversibly inhibit UGT1A1 at plasma concentrations reached at a total daily dose of 80 mg and 200 mg twice daily. In addition, asciminib may reversibly inhibit CYP2C19 at concentrations reached at 200 mg twice daily dose.
Transporter Systems
Asciminib is a substrate of BCRP and P-gp. Asciminib inhibits BCRP, P-gp, OATP1B1, OATP1B3, and OCT1.
Asciminib may increase the exposure of OATP1B or BCRP substrates in a dose dependent manner.