Pharmacokinetics of Venetoclax, a Novel BCL‐2 Inhibitor, in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Non‐Hodgkin Lymphoma

Abstract

Venetoclax is a selective BCL-2 inhibitor that is approved in the United States for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least 1 prior therapy. The aim of this analysis was to characterize venetoclax pharmacokinetics in the plasma and urine of patients with hematological malignancies and evaluate the effect of dose proportionality, accumulation, weak and moderate CYP3A inhibitors, as well as low- and high-fat meals on venetoclax pharmacokinetics. Patients received a once-daily venetoclax dose of 20 to 1200 mg. Pharmacokinetic parameters were estimated using noncompartmental methods. Venetoclax peak exposures were achieved at 5 to 8 hours under low-fat conditions, and the mean terminal-phase elimination half-life ranged between 14.1 and 18.2 hours at different doses. Venetoclax steady-state exposures showed minimal accumulation and increased proportionally over the dose range of 300 to 900 mg. Low-fat and high-fat meals increased venetoclax exposures by approximately 4-fold relative to the fasting state. Moderate CYP3A inhibitors increased venetoclax exposures by 40% to 60%, whereas weak CYP3A inhibitors had no effect. A negligible amount of venetoclax was excreted in the urine. In summary, venetoclax exhibits a pharmacokinetic profile that is compatible with once-daily dosing with food regardless of fat content. Concomitant use of venetoclax with moderate CYP3A inhibitors should be avoided or venetoclax dose should be reduced during the venetoclax initiation and ramp-up phase in CLL patients. Renal excretion plays a minimal role in the elimination of venetoclax.

Venetoclax in Patients with Previously Treated Chronic Lymphocytic Leukemia

“…Venetoclax is orally bioavailable, highly plasma protein bound (>99%) and has a terminal half-life of 16 to 19 hours (42)(43)(44). In clinical trials, dosing has been daily, and steady state is typically reached within a week.…”

“…In clinical trials, dosing has been daily, and steady state is typically reached within a week. Accumulation over time is minor (44) and has not been an observed problem (43). At doses ranging between 300 and 900 mg/day, pharmacokinetic parameters are dose proportional (43).…”

“…Accumulation over time is minor (44) and has not been an observed problem (43). At doses ranging between 300 and 900 mg/day, pharmacokinetic parameters are dose proportional (43). Age and race have no effect on venetoclax pharmacokinetics (44).…”

“…No special dietary adjustment is thought necessary (45). At steady state, the peak concentration of venetoclax at the recommended dose of 400 mg/day is 2.1 AE 1.1 mg/mL when taken with a low-fat meal (42,43).…”

“…Venetoclax is metabolized by CYP3A4/5 and is a substrate for the P-glycoprotein efflux pump (43,46). Concomitant therapy with strong CYP3A inhibitors, such as some azole antifungals, should therefore be avoided, but if necessary, then should trigger a !75% venetoclax dose reduction (44).…”