Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2 Pharmacodynamics
Based on the exposure response analyses for efficacy, a relationship between drug exposure and a greater likelihood of response was observed in clinical studies in patients with CLL/SLL, and in patients with AML. Based on the exposure response analyses for safety, a relationship between drug exposure and a greater likelihood of some safety events was observed in clinical studies in patients with AML. No exposure-safety relationship was observed in patients with CLL/SLL at doses up to 1200 mg given as monotherapy and up to 600 mg given in combination with rituximab.

Cardiac Electrophysiology
The effect of multiple doses of VENCLEXTA up to 1200 mg once daily (2 times the maximum approved recommended dosage) on the QTc interval was evaluated in an open-label, single- arm trial in 176 patients with previously treated hematologic malignancies. VENCLEXTA had no large effect on QTc interval (i.e., >20 ms) and there was no relationship between venetoclax exposure and change in QTc interval.

Pharmacokinetic Properties

12.3 Pharmacokinetics
Venetoclax mean (± standard deviation) steady state Cmax was 2.1 ± 1.1 mcg/mL and AUC0-24h was 32.8 ± 16.9 mcg•h/mL following administration of 400 mg once daily with a low-fat meal.
Venetoclax steady state AUC increased proportionally over the dose range of 150 to 800 mg (0.25 to 1.33 times the maximum approved recommended dosage). The pharmacokinetics of venetoclax does not change over time.
Absorption
Maximum plasma concentration of venetoclax was reached 5 to 8 hours following multiple oral administration under fed conditions.

Effect of Food
Administration with a low-fat meal (approximately 512 kilocalories, 25% fat calories, 60% carbohydrate calories, and 15% protein calories) increased venetoclax exposure by approximately 3.4-fold and administration with a high-fat meal (approximately 753 kilocalories, 55% fat calories, 28% carbohydrate calories, and 17% protein calories) increased venetoclax exposure by 5.1- to 5.3-fold compared with fasting conditions.
Distribution
Venetoclax is highly bound to human plasma protein with unbound fraction in plasma <0.01 across a concentration range of 1-30 micromolar (0.87-26 mcg/mL). The mean blood-to- plasma ratio was 0.57. The apparent volume of distribution (Vdss/F) of venetoclax ranged from 256-321 L in patients.
Elimination
The terminal elimination half-life of venetoclax was approximately 26 hours.
Metabolism
Venetoclax is predominantly metabolized by CYP3A in vitro. The major metabolite identified in plasma, M27, has an inhibitory activity against BCL-2 that is at least 58-fold lower than venetoclax in vitro and its AUC represented 80% of the parent AUC.
Excretion
After single oral dose of radiolabeled [14C]-venetoclax 200 mg to healthy subjects, >99.9% of the dose was recovered in feces (21% as unchanged) and <0.1% in urine within 9 days.

Specific Populations

No clinically significant differences in the pharmacokinetics of venetoclax were observed based on age (19 to 93 years), sex, weight, mild to severe renal impairment (CLcr 15 to 89 mL/min, calculated by Cockcroft-Gault), or mild to moderate hepatic impairment (normal total bilirubin and aspartate transaminase (AST) > upper limit of normal (ULN) or total bilirubin 1 to 3 times ULN). The effect of end-stage renal disease (CLcr < 15 mL/min) or dialysis on venetoclax pharmacokinetics is unknown.
Racial or Ethnic Groups
No clinically significant differences in the pharmacokinetics of venetoclax were observed in White, Black, and Asian patients enrolled in the United States. Of 771 patients with AML, Asian patients from Asian countries [China (5.6%), Japan (5.5%), South Korea (2.1%), and Taiwan (0.9%)] had 63% higher venetoclax exposure than non-Asian populations.

Patients with Hepatic Impairment

Following a single dose of VENCLEXTA 50 mg, venetoclax systemic exposure (AUC0-INF) was 2.7-fold higher in subjects with severe hepatic impairment (Child-Pugh C) compared to subjects with normal hepatic function [see Dosage and Administration (2.7) and Use in Specific Populations (8.7)]. No clinically relevant differences in venetoclax systemic exposure were observed between subjects with mild or moderate hepatic impairment and subjects with normal hepatic function.

Drug Interactions Studies
Clinical Studies
No clinically significant differences in venetoclax pharmacokinetics were observed when coadministered with azacitidine, azithromycin, cytarabine, decitabine, gastric acid reducing agents, obinutuzumab, or rituximab.
Ketoconazole
Concomitant use of ketoconazole (a strong CYP3A, P-gp and BCRP inhibitor) 400 mg once daily for 7 days increased venetoclax Cmax by 130% and AUC0-INF by 540% [see Drug Interactions (7.1)].
Ritonavir
Concomitant use of ritonavir (a strong CYP3A, P-gp and OATP1B1/B3 inhibitor) 50 mg once daily for 14 days increased venetoclax Cmax by 140% and AUC by 690% [see Drug Interactions (7.1)].
Posaconazole
Concomitant use of posaconazole (a strong CYP3A and P-gp inhibitor) 300 mg with VENCLEXTA 50 mg and 100 mg for 7 days resulted in 61% and 86% higher venetoclax Cmax, respectively, compared with VENCLEXTA 400 mg administered alone. The venetoclax AUC0- 24h was 90% and 144% higher, respectively [see Drug Interactions (7.1)].

Rifampin
Concomitant use of a single dose of rifampin (an OATP1B1/1B3 and P-gp inhibitor) 600 mg increased venetoclax Cmax by 106% and AUC0-INF by 78%. Concomitant use of multiple doses of rifampin (as a strong CYP3A inducer) 600 mg once daily for 13 days decreased venetoclax Cmax by 42% and AUC0-INF by 71% [see Drug Interactions (7.1)].
Warfarin
Concomitant use of a single 400 mg dose of VENCLEXTA with 5 mg of warfarin resulted in 18% to 28% increase in Cmax and AUC0-INF of R-warfarin and S-warfarin [see Drug Interactions (7.2)].
Digoxin
Concomitant use of a single dose of VENCLEXTA 100 mg with digoxin (a P-gp substrate) 0.5 mg increased digoxin Cmax by 35% and AUC0-INF by 9% [see Drug Interactions (7.2)].
In Vitro Studies
Venetoclax is not an inhibitor or inducer of CYP1A2, CYP2B6, CYP2C19, CYP2D6, or CYP3A4. Venetoclax is a weak inhibitor of CYP2C8, CYP2C9, and UGT1A1.
Venetoclax is not an inhibitor of UGT1A4, UGT1A6, UGT1A9, or UGT2B7.
Venetoclax is an inhibitor and substrate of P-gp and BCRP and weak inhibitor of OATP1B1.
Venetoclax is not an inhibitor of OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, or MATE2K.