Lurbinectedin

Lurbinectedin is an alkylating drug that binds guanine residues in the minor groove of DNA, forming adducts and resulting in a bending of the DNA helix towards the major groove. Adduct formation triggers a cascade of events that can affect the subsequent activity of DNA binding proteins, including some transcription factors, and DNA repair pathways, resulting in perturbation of the cell cycle and eventual cell death.

Lurbinectedin inhibited human monocyte activity in vitro and reduced macrophage infiltration in implanted tumors in mice.

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 lurbinectedin at the recommended dose of 3.2 mg/m².

Following the approved recommended dosage, geometric means (%CV) of plasma C_max and AUC_0-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.