In this article, we will discuss Romidepsin (Mechanism of Action). So, let’s get started.
Mechanism of Action
Romidepsin is a histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from acetylated lysine residues in histones, resulting in the modulation of gene expression. HDACs also deacetylate non-histone proteins, such as transcription factors. In vitro, romidepsin causes the accumulation of acetylated histones, and induces cell cycle arrest and apoptosis of some cancer cell lines with IC50 values in the nanomolar range. The mechanism of the antineoplastic effect of romidepsin observed in nonclinical and clinical studies has not been fully characterized.
Romidepsin exhibited linear pharmacokinetics across doses ranging from 1.0 to 24.9 mg/m² when administered intravenously over 4 hours in patients with advanced cancers. In patients with T cell lymphomas who received 14 mg/m² of romidepsin intravenously over a 4-hour period on days 1, 8 and 15 of a 28-day cycle,
geometric mean values of the maximum plasma concentration (Cmax) and the
area under the plasma concentration versus time curve (AUC0-inf) were 377 ng/mL and 1549 ng*hr/mL, respectively.
Romidepsin is highly protein bound in plasma (92% to 94%) over the concentration range of 50 ng/mL to 1000 ng/mL with α1-acid-glycoprotein (AAG) being the principal binding protein.
Romidepsin undergoes extensive metabolism in vitro primarily by CYP3A4 with minor contribution from CYP3A5, CYP1A1, CYP2B6, and CYP2C19. At therapeutic concentrations, romidepsin did not competitively inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 in vitro.
Following 4-hour intravenous administration of romidepsin at 14 mg/m² on days 1, 8 and 15 of a 28-day cycle in patients with T cell lymphomas, the terminal half-life (t1/2) was approximately 3 hours. No accumulation of plasma concentration of romidepsin was observed after repeated dosing.
Effect of Age, Gender or Race
The population pharmacokinetic analysis of romidepsin showed that age, gender, or race (white vs black) did not appear to influence the pharmacokinetics of romidepsin.
Effect of Hepatic Impairment
No dedicated hepatic impairment study has been conducted for romidepsin. The population pharmacokinetic analysis indicates that mild hepatic impairment [total bilirubin (TB) ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN; or TB > 1.0x – 1.5x ULN and any AST] had no significant influence on romidepsin pharmacokinetics. As the effect of moderate (TB > 1.5x – 3x ULN and any AST) and severe (TB > 3x ULN and any AST) hepatic impairment on the pharmacokinetics of romidepsin is unknown, patients with moderate and severe hepatic impairment should be treated with caution.
Effect of Renal Impairment
No dedicated renal impairment study has been conducted for romidepsin. The
population pharmacokinetic analysis showed that romidepsin pharmacokinetics were not affected by mild (estimated creatinine clearance 50 – 80 mL/min), moderate (estimated creatinine clearance 30 – 50 mL/min), or severe (estimated creatinine clearance < 30 mL/min) renal impairment. Nonetheless, the effect of end-stage renal disease on romidepsin pharmacokinetics has not been studied. Thus, patients with end-stage renal disease should be treated with caution.