To characterise the population pharmacokinetics of trabectedin (ET-743, Yondelis®) in cancer patients.
A total of 603 patients (945 cycles) receiving intravenous trabectedin as monotherapy at doses ranging from 0.024 to 1.8 mg/m2 and given as a 1-, 3- or 24-hour infusion every 21 days; a 1- or 3-hour infusion on days 1, 8 and 15 of a 28-day cycle; or a 1-hour infusion daily for 5 consecutive days every 21 days were included in the analysis. An open four-compartment pharmacokinetic model with linear elimination, linear and nonlinear distribution to the deep and shallow peripheral compartments, respectively, and a catenary compartment off the shallow compartment was developed to best describe the index dataset using NONMEM V software. The effect of selected patient covariates on trabectedin pharmacokinetics was investigated. Model evaluation was performed using good-ness-of-fit plots and relative error measurements for the test dataset. Simulations were undertaken to evaluate covariate effects on trabectedin pharmacokinetics.
The mean (SD) trabectedin elimination half-life was approximately 180 (61.4) hours. Plasma accumulation was limited when trabectedin was given every 3 weeks. Systemic clearance (31.5 L/h, coefficient of variation 51%) was 19.2% higher in patients receiving concomitant dexamethasone. The typical values of the volume of distribution at steady state for male and female patients were 6070L and 5240L, respectively. Within the range studied, age, body size variables, AST, ALT, alkaline Phosphatase, lactate dehydrogenase, total bilirubin, Creatinine clearance, albumin, total protein, Eastern Cooperative Oncology Group performance status and presence of liver metastases were not statistically related to trabectedin pharmacokinetic parameters. The pharmacokinetic parameters of trabectedin were consistent across the infusion durations and dose regimens evaluated.
The integration of trabectedin pharmacokinetic data demonstrated linear elimination, dose-proportionality up to 1.8 mg/m2 and time-independent pharmacokinetics. The pharmacokinetic impact of dexamethasone and sex covariates is probably limited given the moderate to large interindividual pharmacokinetic variability of trabectedin. The antiemetic and hepatoprotective effects are still a valid rationale to recommend dexamethasone as a supportive treatment for trabectedin.
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This study was presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, USA, June 2–6, 2006.
The authors would like to thank the hundreds of patients and the investigators and their medical, nursing, and laboratory staff who participated in the clinical studies included in the present study. The authors also thank Andrew Chow and Paul Soons for the comments and suggestions they provided during this analysis. During the conduct of the present work, Juan Jose Perez-Ruixo, Peter Zannikos and Kim Stuyckens were employees at Johnson & Johnson Pharmaceutical Research & Development, Arturo Soto-Matos and Luis Lopez-Lazaro were employees at PharmaMar, and Sarapee Hirankarn, Elizabeth Ludwig and Joel Owen were employees at Cognigen, who received consultation fees from Johnson & Johnson Pharmaceutical Research & Development. This study was supported by Johnson & Johnson Pharmaceutical Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium, and PharmaMar, Madrid, Spain. The authors have no other conflicts of interest to declare.
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Perez-Ruixo, J.J., Zannikos, P., Hirankam, S. et al. Population Pharmacokinetic Meta-Analysis of Trabectedin (ET-743, Yondelis®) in Cancer Patients. Clin Pharmacokinet 46, 867–884 (2007). https://doi.org/10.2165/00003088-200746100-00005
- Population Pharmacokinetic Model
- Linear Elimination