Population Pharmacokinetic-Pharmacodynamic Modeling and Covariate Analyses of Neutropenia and Thrombocytopenia in Patients With Solid Tumors Treated With Lurbinectedin.
2021
Lurbinectedin is a selective inhibitor of oncogenic transcription. Reversible myelosuppression is its most relevant toxicity. Pharmacokinetic-pharmacodynamic analyses were conducted to characterize the time course of absolute neutrophil count and platelet count recovery and to detect and quantify the effect of relevant covariates in patients with advanced solid tumors treated with lurbinectedin. Absolute neutrophil counts, platelet counts, and lurbinectedin total plasma concentrations were assessed in 244 patients treated with lurbinectedin with varied dosing schedules and dose levels. A reference extended semi-mechanistic pharmacokinetic-pharmacodynamic model of myelosuppression was used, granulocyte colony-stimulating factor (G-CSF) administration was modeled as a dichotomous covariate; platelet transfusions were included as a bolus dose into the last compartment of the model, representing the central circulation. Final models were suitable to describe the time course of absolute neutrophil count and platelet count recovery. A lurbinectedin dose of 3.2 mg/m² every 3 weeks (q3wk) can be administered without primary prophylaxis with G-CSF. G-CSF followed by ≤2 dose reductions of 20%, if needed, gradually reduced grade 4 neutropenia from Cycle 3 onward. BSA-based dosing reduced the incidence of grade ≥3 thrombocytopenia. One-week dose delays due to low absolute neutrophil count occurred in 3.5 of patients, thus supporting q3wk administration. CYP3A inhibitors produced an absolute 11.0% and 6.2% increase of grade ≥3 neutropenia and thrombocytopenia, respectively. Neutropenia and thrombocytopenia after lurbinectedin administration to cancer patients are noncumulative, reversible, short lasting, and clinically manageable with secondary prophylaxis of G-CSF or platelet transfusion and, if needed, dose reductions. This article is protected by copyright. All rights reserved.
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