Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

11.2 Pharmacodynamics
Cardiac Electrophysiology
At doses of 14 mg/m2 as a 4-hour intravenous infusion, and at doses of 8 (0.57 times the recommended dose), 10 (0.71 times the recommended dose) or 12 (0.86 times the recommended dose) mg/m2 as a 1-hour infusion, no large changes in the mean QTc interval (>20 milliseconds) from baseline based on Fridericia correction method were detected. Small increase in mean QT interval (< 10 milliseconds) and mean QT interval increase between 10 to 20 milliseconds cannot be excluded.
Romidepsin was associated with a delayed concentration-dependent increase in heart rate in patients with advanced cancer with a maximum mean increase in heart rate of 20 beats per minute occurring at the 6-hour time point after start of romidepsin infusion for patients receiving 14 mg/m2 as a 4-hour infusion.

Pharmacokinetic Properties

11.3 Pharmacokinetics

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-∞) were 377 ng/mL and 1549 ng*hr/mL, respectively. Romidepsin exhibited linear pharmacokinetics across doses ranging from 1.0 (0.07 times the recommended dose) to 24.9 (1.76 times the recommended dose) mg/m2 when administered intravenously over 4 hours in patients with advanced cancers.

Distribution
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 is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1).
In vitro, romidepsin accumulates into human hepatocytes via an unknown active uptake process. Romidepsin is not a substrate of the following uptake transporters: BCRP, BSEP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2. In addition, romidepsin is not an inhibitor of BCRP, MRP2, MDR1 or OAT3. Although romidepsin did not inhibit OAT1, OCT2, and OATP1B3 at concentrations seen clinically (1 μmol/L), modest inhibition was observed at 10 μmol/L. Romidepsin was found to be an inhibitor of BSEP and OATP1B1.

Metabolism
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.
At therapeutic concentrations, romidepsin did not cause notable induction of CYP1A2, CYP2B6 and CYP3A4 in vitro. Therefore, pharmacokinetic drug-drug interactions are unlikely to occur due to CYP450 induction or inhibition by romidepsin when co-administered with CYP450 substrates.

Excretion
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.

Drug Interactions
Ketoconazole: Following co-administration of 8 mg/m2 ISTODAX (4-hour infusion) with ketoconazole, the overall romidepsin exposure was increased by approximately 25% and 10% for AUC0-∞ and Cmax, respectively, compared to romidepsin alone, and the difference in AUC0-∞ between the 2 treatments was statistically significant.
Rifampin: Following co-administration of 14 mg/m2 ISTODAX (4-hour infusion) with rifampin, the overall romidepsin exposure was increased by approximately 80% and 60% for AUC0-∞ and Cmax, respectively, compared to romidepsin alone, and the difference between the 2 treatments was statistically significant. Co-administration of rifampin decreased the romidepsin clearance and volume of distribution by 44% and 52%, respectively. The increase in exposure seen after co-administration with rifampin is likely due to rifampin’s inhibition of an undetermined hepatic uptake process that is predominant for the disposition of ISTODAX.


Drugs that inhibit P-glycoprotein: Drugs that inhibit p-glycoprotein may increase the concentration of romidepsin.
Specific Populations
Effect of Age, Gender, Race or Renal Impairment
The pharmacokinetics of romidepsin was not influenced by age (27 to 83 yrs), gender, race (white vs. black) or 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. The effect of end-stage renal disease (estimated creatine clearance less than 15 mL/min) on romidepsin pharmacokinetics has not been studied.

Hepatic Impairment
Romidepsin clearance decreased with increased severity of hepatic impairment. In patients with cancer, the geometric mean Cmax values after administration of 14, 7, and 5 mg/m2 romidepsin in patients with mild (B1: bilirubin ≤ULN and AST >ULN; B2: bilirubin >ULN but ≤1.5 x ULN and any AST), moderate (bilirubin >1.5 x ULN to ≤3 x ULN and any AST), and severe (bilirubin >3 x ULN and any AST) hepatic impairment were approximately 111%, 96%, and 86% of the corresponding value after administration of 14 mg/m2 romidepsin in patients with normal (bilirubin ≤upper limit of normal (ULN) and aspartate aminotransferase (AST) ≤ULN) hepatic function, respectively. The geometric mean AUCinf values in patients with mild, moderate, and severe hepatic impairment were approximately 144%, 114%, and 116% of the corresponding value in patients with normal hepatic function, respectively. Among these 4 cohorts, moderate interpatient variability was noted for the exposure parameters Cmax and AUCinf, as the coefficient of variation (CV) ranged from 30% to 54%.