Population pharmacokinetics of trabectedin in adolescent patients with cancer
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To characterize the trabectedin population pharmacokinetics in children and adolescent patients with cancer and compare it with the trabectedin pharmacokinetics in adults.
Plasma concentrations from ten adolescent and three children with cancer (age range 4.0–17.0 years) treated with trabectedin at doses ranging from 1.1 to 1.7 mg/m2, administered as a 24-h continuous intravenous infusion every 3 weeks, were available for the analysis. An external model evaluation was performed to verify whether a previously developed adult population pharmacokinetic model was predictive of the pediatric plasma concentrations of trabectedin. The maximum a posteriori estimation of the individual pharmacokinetic parameters for pediatric patients was conducted, after successful completion of the external evaluation step. The relationships between pharmacokinetic parameters and body size were evaluated.
External evaluation methods showed no major differences between the adult population and children and adolescent patients of this study. The mean ± standard deviation (SD) of the individual estimated clearance and central volume of distribution in these children/adolescent patients was 36.4 ± 16.1 L/h and 13.2 ± 6.54 L, respectively. These values were similar to the typical values reported for adult patients—37.6 L/h and 13.9 L (for females) and 16.1 L (for males). The median area under the plasma concentration versus time curve (AUC) in children/adolescent patients was 55.1 µg h/L, while in the adult population the median AUC was 61.3 µg h/L, both administered a 1.5 mg/m2 dose regimen with mean (range) BSA for adults = 1.86 (0.90–2.80) vs children/adolescent patients = 1.49 (0.66–2.54).
The adult population pharmacokinetic model adequately described the trabectedin plasma concentrations and its variability in the pediatric population of patients involved in this assessment that mostly comprised adolescents. The trabectedin systemic exposure achieved in this population was comparable (within 12%) to the exposure obtained in adult population when the same dose, expressed in mg/m2, was administered.
KeywordsTrabectedin Cancer Pediatric Nonlinear mixed-effects modeling
The authors would like to thank all pediatric patients and their families, nurses, and physician who participated in the studies included in the analysis for their valuable contributions. The authors also thank Priya Ganpathy, MPharm, ISMPP CMPP™ (SIRO Clinpharm Pvt. Ltd, Thane, India) for writing assistance and Namit Ghildyal, Ph.D. (Janssen Global Services, LLC) for additional editorial assistance.
All authors met the ICMJE criteria and those who fulfilled the criteria are listed as authors. All authors provided substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; and drafted the work or revised it critically for important intellectual content; and made the final decision about where to publish these data. All authors agreed to be accountable for all aspects of the work.
The population PK modeling study was supported by funding from Janssen Research and Development, LLC. The sponsor also provided funding for development of this manuscript. Pediatric clinical trials of trabectedin were supported by the NCI intramural program or the Children’s Oncology Group, an NCI funded cooperative group.
Compliance with ethical standards
Conflict of interest
IP is an employee of Janssen-Cilag, Italy; JJPR and VH are employees of Janssen Pharmaceutica NV, Belgium; DO and MG are employees of Janssen Research and Development, LLC, USA (parent company Johnson and Johnson). BV received fees from Janssen as a consultant on this analysis. EF was a government employee at the time of the clinical trial and is currently a faculty member at the Perelman School of Medicine at the University of Pennsylvania, she received no funding from Janssen Pharmaceutica or Johnson and Johnson for conduct of the clinical trial or preparation of this manuscript.
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