Lurbinectedin (Zepzelca™) received accelerated approval by the US FDA for the treatment of adults with metastatic small-cell lung cancer with disease progression on or after platinum-based chemotherapy. Its main toxicity is reversible myelosuppression. Semi-mechanistic pharmacokinetic/pharmacodynamic models were developed to characterize the time course of absolute neutrophil count (ANC) and platelet recovery following i.v. administration of single-agent lurbinectedin to explore the adequacy of dose regimens of lurbinectedin, such as 3.2 mg/m2 q3wk. The analysis included ANC and platelet data from 244 patients included in two phase 1 trials and three phase 2 trials with single-agent lurbinectedin using 2 different dosing schedules (Day 1 and Day 1 and 8, q3wk) at doses ranging from 0.02 to 6.9 mg/m2. The pharmacokinetic/pharmacodynamic models used to describe the ANC (see figure below) and platelet time course of recovery in patients treated with lurbinectedin were based on the model developed by Quartino et al. Covariates evaluated in the analyses included demographic factors, physical condition, blood chemistry, concomitant use of CYP3A inhibitors and/or inducers, and prior treatment. Additionally, the effect of G-CSF was assessed on several structural parameters of the ANC model. Lurbinectedin dosed at 3.2 mg/m2 administered q3wk as a 1-hour i.v. infusion is the highest dose that can be administered without primary prophylaxis with G-CSF treatment. Neutropenia after lurbinectedin treatment was non-cumulative, reversible, and short-lasting. The drop in ANC started at about Day 5 after lurbinectedin infusion, with a nadir at about Day 13 and recovery to baseline at Day 21. When administered as a q3wk regimen, depth and duration of neutropenia were dependent on lurbinectedin dose level and exposure. Apart from baseline ANC ≥2×109/L, other covariates explored did not have any clinically relevant effects on model pharmacokinetic/pharmacodynamic parameters and, therefore, adjustments of the 3.2 mg/m2 dose based on these covariates are not warranted. Platelet count started decreasing at about Day 5 after lurbinectedin administration, with a nadir 9-10 days after lurbinectedin administration and recovery to baseline at Day 15. Apart from body surface area and baseline platelets ≥250×109/L, other covariates did not have any clinically relevant effects on model pharmacokinetic/pharmacodynamic parameters and, therefore, dosage adjustments based on these covariates are not warranted. In cancer patients administered lurbinectedin, any neutropenia and thrombocytopenia observed were non-cumulative, reversible, short lasting, and clinically manageable with secondary prophylaxis with G-CSF or platelet transfusions and, depending on severity, dose reduction or discontinuation of lurbinectedin.