Zepzelca
lurbinectedin
Species
MonkeyRatDog
Longest study
24 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat, dog and cynomolgus monkey
“The Sprague Dawley rat, Beagle dog and Cynomolgus monkey were the main species used for toxicological assessment of lurbinectedin.”
Why that species
Monkey chosen as non-rodent because its metabolism was more similar to human than other non-rodents
“Despite using dogs in the initial 4-week toxicology studies, the Applicant utilized the monkey in the 13-week non-rodent toxicology study due to metabolic data suggesting that monkey metabolism was more similar to human than other tested non-rodent species.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Intravenous administration of PM01183 at the dose of 0.125 mg/kg every 3 weeks for 8-cycles was not tolerated by Cynomolgus monkeys”
Study lengthopen answer page →
Longest pivotal study
24 (8-cycle q3w rat and monkey)
“Toxicology program for lurbinectedin was investigated in rats, dogs and NHPs for up to 24 weeks.”
Pivotal GLP studies
8-cycle (every 3 weeks) rat and monkey studies
“The highest doses used in the rat and monkey 8-cycle studies resulted in exposures approximately 8 times lower than the human exposure at the recommended dose of 3.2 mg/m2 once every 3 weeks.”
Route in tox
Intravenous bolus
“Route of administration: Bolus intravenous”
Skipped studiesopen answer page →
Genotoxicity
Ames negative; positive in mouse lymphoma TK assay; genotoxic
“Lurbinectedin was negative in the in vitro Ames assay but induced mutations in the mouse TK lymphoma assay, confirming that, as expected based on its mechanism of action, lurbinectedin is genotoxic.”
Carcinogenicity
Not conducted (advanced cancer patient population)
“The Applicant did not conduct carcinogenicity studies based on the proposed patient population.”
Reproductive & developmental
Preliminary single-dose rat EFD study only: no viable fetuses
“Six pregnant rats received a single lurbinectedin dose of 0.1 mg/kg (0.6 mg/m2 ) or vehicle control on Day 10. There were no viable fetuses in lurbinectedin-treated dams.”
Safety pharmacology
No clear acute cardiovascular, CNS or respiratory effects in any species
“There were no clear acute effects on cardiovascular, CNS, or respiratory parameters in any species.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Zepzelca don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oncology small molecules (ICH S9)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Injection-site lesions and bone marrow suppression (transient leukopenia, mild anemia) in all species (FDA multi-discipline review, p. 28)
NOAEL / key findings
Injection-site lesions and bone marrow suppression (transient leukopenia, mild anemia) in all species
“The major toxicological findings in all three tested species were injection site findings including hemorrhage, edema, inflammation, thrombosis, and necrosis and bone marrow effects leading to transient leukopenia and mild anemia with decreased cellularity in the bone marrow.”
Risksopen answer page →
Immune & cytokine safety
Lymphocyte and neutrophil decreases suggest a general decrease in immune responsiveness
“dose-dependent decreases in lymphocytes and neutrophils following repeated lurbinectedin administration suggest that there may have been a general decrease in immune responsiveness.”
Biodistribution & persistence
Highest tissue levels in spleen, lymph nodes, liver, thyroid, kidney, lung, skin; lowest in brain and testes
“The lowest radioactivity concentrations were detected in the brain (<5 and <2.3 ng-eq/g for male and female rats, respectively) and testes (<12 ng-eq/g). The highest values of total activity were in spleen, followed by lymph nodes, liver, thyroid glands, kidney, lung and skin.”
Modality-specific risk
Embryofetal lethality (no viable fetuses in rat EFD study)
“There were no viable fetuses in lurbinectedin-treated dams. A warning for embryo-fetal toxicity is included in the label”