xposures 1.2-times those reported at clinical human doses (400 mg/day). No teratogenicity occurred in mice or rabbits.
Counsel patients about the reproductive risk and contraception requirements during venetoclax treatment. Pregnancy testing should be performed prior to starting venetoclax in female patients of reproductive potential. These patients should use effective contraception and avoid pregnancy during and for at least 30 days after venetoclax therapy. Women who become pregnant while receiving venetoclax should be apprised of the potential hazard to the fetus. Venetoclax may cause infertility in male patients based on animal findings; these patients should consider sperm banking.
MECHANISM OF ACTION
Venetoclax (ABT-199) is a selective inhibitor of B-cell lymphoma-2 (BCL-2) protein, an antiapoptotic protein that prevents chronic lymphocytic leukemia (CLL) cell death and is associated with chemotherapy resistance. Venetoclax mimics the BH3 domain on BCL-2 family proteins and binds with high affinity; this action antagonizes pro-apoptotic proteins like BIM and causes mitochondrial outer membrane permeabilization and the activation of caspases that kill cells.
PHARMACOKINETICS
Venetoclax is administered orally. It is highly bound to plasma proteins (> 99%) and has a mean blood-to-plasma ratio of 0.57. The apparent volume of distribution ranges from 256 to 321 liters and the terminal elimination half-life is about 26 hours. Venetoclax was metabolized via CYP3A4/5 to form the major metabolite, M27. This metabolite has activity that is at least 58-times lower than that of venetoclax in vitro. Venetoclax is eliminated primarily via feces; clearance from the systemic circulation is from hepatic elimination. In healthy subjects, greater than 99.9% and less than 0.1% of the radioactivity was excreted in the feces and urine, respectively, within 9 days of a radiolabeled [14C]-venetoclax 200-mg dose. Unchanged venetoclax accounted for 20.8% of the radiolabeled excretion product in feces.
Affected cytochrome P450 isoenzymes or transporters: CYP3A4/5 and P-gp
Venetoclax is a substrate of CYP3A4/5 and P-glycoprotein (P-gp). Co-administration with a strong CYP3A inhibitor at initiation or during the dose titration phase is contraindicated. Avoid concomitant use with moderate CYP3A inhibitors, strong or moderate CYP3A inducers, and P-glycoprotein (P-gp ) inhibitors. Significant drug interactions were observed when venetoclax was administered with a strong CYP3A inhibitor, a strong CYP3A inducer, or a P-glycoprotein (P-gp) inhibitor in healthy subjects or patients. In vitro, venetoclax inhibited P-gp substrates at therapeutic dose levels in the gut; therefore, administer P-gp substrates with a narrow therapeutic index at least 6 hours before venetoclax if concomitant use cannot be avoided. Additionally, venetoclax is a Breast Cancer Resistance Protein (BCRP) inhibitor and a weak OATP1B1 inhibitor in vitro.
Oral Route
The maximum plasma concentration (Cmax) was achieved at a Tmax of 5 to 8 hours following multiple venetoclax doses administered with food. The steady-state AUC value increased proportionally over the dose range of 150 mg to 800 mg. When venetoclax 400 mg/day was given with a low-fat meal, the mean steady state Cmax was 2.1 +/- 1.1 microgram (mcg)/mL and the mean AUC(0-24) was 32.8 +/- 16.9 mcg/mL X hour.
Effect of food: When venetoclax was administered with a low-fat and a high-fat meal, the AUC values were increased by 3. |
