Population Pharmacokinetics of Aplidin® (plitidepsin) in Subjects with Cancer
Ricardo Nalda-Molina1, Belén Valenzuela(1), Arturo Soto-Matos(2), Bernardo Miguel-Lillo(2), Miguel Angel Izquierdo(2)
(1) Pharmacy and Pharmaceutics Division, Department of Engineering, Faculty of Pharmacy, Miguel Hernández University, Spain. (2) 2 Clinical Pharmacology Department. Pharma Mar. Madrid, Spain.
Background and Objectives: Aplidin® (plitidepsin) is a cyclic depsipeptide compound isolated from Aplidium albicans that was shown to inhibit protein synthesis, induce apoptosis, G1 cell cycle arrest in cancer cells and to exert antiangiogenic properties. The objective of this study was to characterize the population pharmacokinetics of plitidepsin in cancer subjects.
Methods: A total of 283 subjects from 4 Phase I and 3 Phase II clinical trials receiving intravenous plitidepsin as monotherapy at doses ranging from 0.13 to 8.0 mg/m2 and given as 1- or 24-hr infusions every week; 3- or 24-hr biweekly; or 1-hr infusion daily for 5 consecutive days every 21 days were included in the analysis. An open three-compartment pharmacokinetic model with linear elimination and linear distribution to the peripheral compartments and blood was used to best describe the 2143 and 1759 blood and plasma concentrations, respectively (NONMEM V). The effect of selected covariates on plitidepsin pharmacokinetics was investigated. Pharmacokinetic model was evaluated using posterior predictive check and bootstrap. Computer simulations were undertaken to evaluate the effects of dosing regimen on plitidepsin pharmacokinetics.
Results: Typical value of plitidepsin terminal half-life was 12 days. Blood clearance (between subject variability) was 3.75 L/h (CV=66%), volume of distribution at steady-state was 1002 L and the blood to plasma ratio was 4. Age, sex, body size variables, AST, ALT, ALP, total bilirubin, creatinine clearance, albumin, total protein, haemoglobin and presence of liver metastases were not related to plitidepsin pharmacokinetics in blood or plasma. Bootstrap and posterior predictive check evidenced the model was deemed appropriate to describe the time course of plitidepsin blood and plasma concentrations in cancer patients.
Conclusions: The integration of phase I/II pharmacokinetic data demonstrated plitidepsin linear elimination and distribution to red blood cells, dose-proportionality up to 8.0 mg/m2, and time-independent pharmacokinetics. No clinically relevant covariates were identified as predictors of plitidepsin pharmacokinetics.