Abstract

Lurbinectedin is a novel and potent selective inhibitor of active transcription of protein-coding genes, triggering apoptosis of cancerous cells, which has been approved for the treatment of patients with metastatic small-cell lung cancer with disease progression on or after platinum-based chemotherapy. Different studies aimed at exploring the disposition and metabolism of lurbinectedin were performed in vitro and in vivo (by intravenous administration of lurbinectedin). Low blood cell partitioning for lurbinectedin in rat, nonhuman primate (NHP) and human was determined as 23.4%, 29.8% and 9.8%, respectively. Protein binding was very high (>95%) in total plasma (rat, NHP, human), albumin and a-1-acid glycoprotein (both from human). In vitro, lurbinectedin underwent intense liver microsome-mediated metabolism (in 10 minutes, an 80% of the compound is metabolized in human), with CYP3A4 being the isoform involved in that metabolism; results also showed NHP being the nonclinical species which, metabolically, most closely resembles humans. Mass balance studies performed in rats (both genders), NHP (male only) and patients (both genders) demonstrated that the principal route of excretion of ¹⁴C-lurbinectedin-related radioactivity was through the feces (88.7{plus minus}10.1% in patients), with only a minor fraction recovered from the urine (5.6{plus minus}2.0% in patients). In plasma samples, the majority of lurbinectedin-related radioactivity was attributed to unchanged compound (95{plus minus}3.1% and 70.2{plus minus}10.9% in NHP and human, respectively); plasma metabolic profiling demonstrated the major (% compared to unchanged compound) circulating metabolites were N-Desmethyl-lurbinectedin (0.4{plus minus}0.2% and 10.4{plus minus}2.2% in NHP and patients, respectively) and 1',3'-Desmethylene-lurbinectedin (0.9{plus minus}0.7% and 14.3{plus minus}10.4% in NHP and patients, respectively).

Significance Statement Lurbinectedin is a novel and potent selective inhibitor of active transcription of protein-coding genes, triggering apoptosis of cancerous cells, recently approved for the treatment of patients with metastatic small-cell lung cancer with disease progression on or after platinum-based chemotherapy. The present study provides a complete set of information on the pharmacokinetics, biotransformation and elimination of ¹⁴C-lurbinectedin and its metabolites, following a single intravenous administration to nonclinical species (rats and NHP) and patients.