Chemical formula: C₄₁H₄₄N₄O₁₀S Molecular mass: 784.88 g/mol PubChem compound: 57327016
Lurbinectedin inhibits the oncogenic transcription process through (i) its binding to CG-rich sequences of DNA, located within promoters of protein-coding genes; (ii) the eviction of oncogenic transcription factors from their binding sites; and (iii) the stalling of elongating RNA polymerase II and its specific degradation by the ubiquitin/proteasome machinery with all these processes leading to subsequent cell cycle arrest and tumour cell apoptosis.
Lurbinectedin suppresses the expression of inflammatory and motility-related genes at non-toxic nanomolar concentrations in vitro, while also inhibiting cell migration and adhesion. At higher concentrations, it induces apoptosis in monocytes and macrophages through caspase-8 activation. In vivo (murine models), antitumour dosing (0.18–0.20 mg/kg) restricts tumour growth, reduces specific immune cell populations, and decreases tumour vascularity.
The potential for QTc prolongation with lurbinectedin was evaluated in 39 patients with advanced cancer. Large effects (>10 ms) on the QTc interval were not detected with lurbinectedin dosed at 3.2 mg/m² every 21 days.
After a 3.2 mg/m² lurbinectedin dose administered as a 1-hour intravenous infusion, geometric means of total plasma Cmax and AUC∞, were 107 μg/L and 551 μg*h/L, respectively. No accumulation of lurbinectedin in plasma is observed upon repeated administrations every 21 days.
Typical volume of distribution of lurbinectedin at steady state is 504 L. Binding to plasma proteins is approximately 99%, to both albumin and α-1-acid glycoprotein, with a calculated blood-to-plasma partitioning ratio of 0.68.
In vitro studies with human liver microsomes and supersomes indicate that CYP3A4 is the main CYP enzyme responsible for the hepatic metabolism of lurbinectedin.
Cytochrome P450 (CYP) Enzymes: Lurbinectedin is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4. Lurbinectedin is not an inducer of CYP1A2 or CYP3A4. The potential of lurbinectedin to induce CYP2B6 is unknown.
Transporter Systems: Lurbinectedin is a substrate of MDR1 (P-gp), but is not a substrate of OATB1P1, OATP1B3, OCT1, or MATE1. In vitro, lurbinectedin showed inhibitory potential towards MDR1, OATP1B1, OATP1B3, and OCT1 however, these findings are not considered clinically relevant. Lurbinectedin is not an inhibitor of BCRP, BSEP, MATE1, OAT1, OAT3, or OCT2.
The terminal half-life of lurbinectedin is 51 hours. Total plasma clearance of lurbinectedin is 11 L/h.
The major route of lurbinectedin-related radioactivity excretion was via faeces (89% of dose), with only traces amounts of unchanged lurbinectedin detected in faeces (<0.2% of dose). Excretion in urine was the minor route (6% of dose), mainly as unchanged compound (1% of dose) and one metabolite (up to 1% of dose).
Lurbinectedin pharmacokinetics is linear at the dose range of 0.02-6.9 mg/m².
Population pharmacokinetics analyses showed that weight (range: 39-154 kg), age (range: 18-85 years), and gender do not have a clinically meaningful influence on the systemic exposure of lurbinectedin.
A dedicated study was conducted to evaluate the influence of varying degrees of hepatic impairment (HI) on lurbinectedin in patients with advanced solid tumours. Patients were classified according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) classification as having normal hepatic function or mild (total bilirubin ≤ ULN and AST > ULN, or total bilirubin >1 to ≤1.5 × ULN and AST = any), moderate (total bilirubin >1.5 to ≤3 × ULN and AST = any), or severe (total bilirubin >3 × ULN) HI. Patients with normal hepatic function and mild HI received lurbinectedin at 3.2 mg/m² and patients with moderate and severe HI received lurbinectedin at 1.6 mg/m². No statistically significant differences were observed on total lurbinectedin pharmacokinetics among cohorts. A statistically significant higher dose-normalised M1 AUC metabolite/parent ratio (MPR) was observed in patients with severe HI (ratio: 5.95, 90% CI: 2.54–13.98) and moderate HI (ratio: 8.65, 90% CI: 3.94–19.01) compared to patients with mild HI. No statistically significant differences were observed in M4 MPR according to HI groups.
Based on population pharmacokinetic analysis, no apparent pharmacokinetic difference was observed in 125 patients with mild who received lurbinectedin 3.2 mg/m² every 21 days as compared to 625 patients with normal hepatic function.
No dedicated studies of lurbinectedin have been conducted in patients with renal impairment. Based on population pharmacokinetic analyses, no apparent pharmacokinetic difference was observed in 165 patients with mild renal impairment (CrCL of 60-89 mL/min), 73 patients with moderate renal impairment (CrCL of 30-59 mL/min), and one patient with severe renal impairment (CrCL of 26 mL/min) who received lurbinectedin 3.2 mg/m² every 21 days as compared to 166 patients with normal renal function. The pharmacokinetic characteristics of lurbinectedin in patients with CrCL <30 mL/min or patients on dialysis are unknown.
The primary target for toxicity identified in nonclinical species (rat, dog and NHP) was characterised by severe, reversible and non-cumulative atrophy of bone marrow, which was associated with dose- related leukopenia, as well as thrombocytopenia and anaemia. In addition, lurbinectedin-treated animals experienced liver abnormalities (multiple dark areas or swollen liver, increased liver function markers, bile duct damage with necrosis and/or oedema, and hepatocellular degeneration/apoptosis and periportal hepatocytic hypertrophy). Additional findings were located in the gastro-intestinal tract (mucosal atrophy), kidneys (cortical tubular degeneration and vacuolation), heart (focal, slight to moderate myocardial degeneration and/or necrosis) and injection site (perivascular/vascular inflammatory reactions). A full recovery, after cessation of dosing, was noted for the majority of these alterations.
Positive genotoxicity results were obtained in vitro in mammalian cell lines showing dose related toxicity at all concentrations tested (range from 48 to 0.188 ng/mL). Positive genotoxicity findings are expected for lurbinectedin as a DNA-interacting antineoplastic agent.
Carcinogenicity testing of lurbinectedin has not been performed.
Lurbinectedin induced maternal toxicity at the single dose MTD level of 0.6 mg/m² administered on Day 10 post-coitum and severe embryo-toxicity, leading to 100% embryo lethality.
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