Venetoclax pharmacokinetics in subjects with end-stage renal disease undergoing hemodialysis.

Abstract

e19042 Background: Venetoclax is a first-in-class Bcl-2 inhibitor approved for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia(AML) and is currently being investigated as a treatment for t(11;14)-positive relapsed/refractory multiple myeloma (MM). Renal insufficiency is a common comorbidity in patients with hematologic malignancies, and no clinical study has been conducted to assess how end stage renal disease might affect venetoclax pharmacokinetics. This study aimed to assess the pharmacokinetics of venetoclax after oral administration of a single 100 mg dose of venetoclax in subjects with normal renal function and end-stage renal disease, including those undergoing hemodialysis. Methods: Venetoclax was administered as a single 100 mg dose to 7 healthy female subjects with normal renal function (eGFR > 90 ml/min) and 6 female subjects with end-stage renal disease (ESRD) (eGFR < 15 ml/min) both prior to hemodialysis (Period 1) and between hemodialysis days (Period 2). Intensive PK and protein binding samples were collected from all subjects. Arterial and venous samples were collected from ESRD subjects during hemodialysis to assess the effect of hemodialysis on the pharmacokinetics of venetoclax. Pharmacokinetic parameters were estimated using non-compartmental methods. Results: There was no difference in plasma venetoclax concentrations between arterial and venous samples, suggesting that hemodialysis did not affect the PK of venetoclax. The fraction unbound (fu) of venetoclax increased approximately 2-fold for subjects with ESRD compared to subjects with normal renal function.The unbound Cmax and AUC0-48 of ESRD subjects, between dialysis days were comparable to unbound Cmax and AUC0-48 observed in the normal renal function subjects. The harmonic mean t1/2 between groups (normal renal function vs. ESRD) ranged from 11 and 12.2 hours, demonstrating that end-stage renal disease did not affect the half-life of venetoclax. Conclusions: End-stage renal disease does not alter unbound venetoclax plasma concentrations and no dose adjustment is neededfor patients with renal insufficiency based on pharmacokinetics. Clinical trial information: NCT04810598 .