Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2           Pharmacodynamics
Lurbinectedin exposure-response relationships and the pharmacodynamic time-course for efficacy have not been fully characterized.
Increased incidence of Grade 4 neutropenia and Grade ≥ 3 thrombocytopenia were observed with increased lurbinectedin exposure.
Cardiac Electrophysiology
No large mean increase in QTc (i.e. > 20 ms) was detected following treatment with ZEPZELCA at the recommended dose of 3.2 mg/m2.

Pharmacokinetic Properties

12.3           Pharmacokinetics
Following the approved recommended dosage, geometric means (%CV) of plasma C max and AUC0-inf, were 107 µg/L (79%) and 551 µg•h/L (94%), respectively. No accumulation of lurbinectedin in plasma is observed upon repeated administrations every 3 weeks.
Distribution
The volume of distribution of lurbinectedin at steady state is 504 L (39%). Plasma protein binding is approximately 99%, to both albumin and α-1-acid glycoprotein.
Elimination
The terminal half-life of lurbinectedin is 51 hours. Total plasma clearance of lurbinectedin is 11 L/h (50%).
Metabolism
Lurbinectedin is metabolized by CYP3A4, in vitro.
Excretion
After a single dose of radiolabeled lurbinectedin administration, 89% of the radioactivity was recovered in feces (< 0.2% unchanged) and 6% in urine (1% unchanged).
Specific Populations
No clinically significant differences in the pharmacokinetics of lurbinectedin were identified based on age (18-85 years), sex, body weight (39-154 kg), mild to moderate renal impairment (CLcr 30 to 89 mL/min) or mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin between 1.0 – 1.5 × ULN and any AST). The effects of severe renal impairment (CLcr < 30 mL/min) and moderate or severe hepatic impairment (total bilirubin > 1.5 × ULN and any AST) on the pharmacokinetics of lurbinectedin have not been studied.
Drug Interactions Studies
Dedicated clinical drug-drug interaction studies with CYP3A modulators have not been conducted with lurbinectedin.
In vitro Studies
Cytochrome P450 (CYP) Enzymes: Lurbinectedin is metabolized by CYP3A4. Lurbinectedin is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4. Lurbinectedin is not an inducer of CYP1A2 or CYP3A4.
Transporter Systems: Lurbinectedin is a substrate of MDR1, but is not a substrate of OATB1P1, OATP1B3, OCT1, or MATE1.
Lurbinectedin inhibits MDR1, OATP1B1, OATP1B3, and OCT1 but not BCRP, BSEP, MATE1, OAT1, OAT3, or OCT2.