BACKGROUND AND OBJECTIVES: Lurbinectedin is an inhibitor of RNA polymerase II 
currently under clinical development for intravenous administration as a single 
agent and in combination with other anti-tumor agents for the treatment of 
several tumor types. The objective of this work was to develop a 
population-pharmacokinetic model in this patient setting and to elucidate the 
main predictors to guide the late stages of development.
METHODS: Data from 443 patients with solid and hematologic malignancies treated 
in six phase I and three phase II trials with lurbinectedin as a single agent or 
combined with other agents were included in the analysis. The potential 
influence of demographic, co-treatment, and laboratory characteristics on 
lurbinectedin pharmacokinetics was evaluated.
RESULTS: The final population-pharmacokinetic model was an open 
three-compartment model with linear distribution and linear elimination from the 
central compartment. Population estimates for total plasma clearance, and 
apparent volume at steady state were 11.2 L/h and 438 L, respectively. 
Inter-individual variability was moderate for all parameters, ranging from 20.9 
to 51.2%. High α-1-acid glycoprotein and C-reactive protein, and low albumin 
reduced clearance by 28, 20, and 20%, respectively. Co-administration of 
cytochrome P450 3A inhibitors reduced clearance by 30%. Combinations with other 
anti-tumor agents did not modify the pharmacokinetics of lurbinectedin 
significantly.
CONCLUSION: The population-pharmacokinetic model indicated neither a dose nor 
time dependency, and no clinically meaningful pharmacokinetic differences were 
found when co-administered with other anticancer agents. A chronic inflammation 
pattern characterized by decreased albumin and increased C-reactive protein and 
α-1-acid glycoprotein levels led to high lurbinectedin exposure. 
Co-administration of cytochrome P450 3A inhibitors increased lurbinectedin 
exposure.