Neroutsos E, Nalda-Molina R, Paisiou A, Zisaki K, Goussetis E, Spyridonidis A, Kitra M, Grafakos S, Valsami G, Dokoumetzidis A
Department of Pharmacy University of Athens
Objectives:
Pharmacokinetics of i.v busulfan vary significantly in pediatric population, while infusion lag-time occurring due to busulfan administration by i.v. “microinfusion” may affect the calculation of the AUC used for dose individualization recommended in the SPC of the drug. The aim of this study was to develop a population pharmacokinetic model for busulfan in pediatric patients incorporating the infusion lag-time during, the application of Bayesian individualization of dosage, and comparison with the conventional methodology.
Methods:
Therapeutic drug monitoring (TDM) and dose individualization of i.v. BU was performed in 76 pediatric patients with a mean age of 7.6 years (range 0.5-19 years) undergoing bone marrow transplantation. The dose given was 0.8-1.2 mg / kg depending on patient weight. Each infusion lasted about two to three hours and was administered to each patient every six hours for four consecutive days before chemotherapy or two consecutive days. Samples were taken at time 0 , 2-3 h (at the end of infusion), at 2.5 or 3.5 h, and at 4 and 6 hours of the first day and after the first dose and in several patients also after the fifth dose . The infusion time was recorded and the infusion lag time was calculated. A population PK (POPPK) model was developed using the nonlinear mixed effect models (NONEMEM 7.3). One and two compartment models, with and without lag time, as well as different error models were tested. Interindividual variability (IIV) was considered to be univariate log-normal for all the parameters. Various covariates such as Age and BW, CrCL were tested as covariates on the parameters of the final model. The model was evaluated using diagnostic plots, VPC and bootstrap methods which were carried out in PSN.
Results:
The model that best described the data was the two-compartment model with first order elimination kinetics. The estimated parameters were clearance, CL=5.1 L/h, volume of distribution of the central, Vc=14.4 L, and peripheral, Vp=1.49 L, compartments and intercompartmental clearance, Q=3.77 L/h. Inter-individual variability (IIV) was estimated for CL (26.4%) and Vc (32.6%) as well as Inter Occasion variability (IOV) for CL (11.2%) and Vc (19.2%), and a significant correlation was found between CL and Vc. The combined error model was used to describe residual variability. Inclusion of the infusion lag time improved the model. Weight as covariate on CL (exponent 0.75) and Vc (exponent 1) introduced in an allometric way improved the model. Age maturation introduced as Hill function, also improved the model marginally, with exponent 14.5 and TM50=64 weeks. The model was evaluated by goodness of fit plots, bootstrap analysis, and its predictive ability (VPC plot) and was considered suitable for describing BU’s PK in pediatric patients.
Conclusions:
A POPPK model was developed for paediatric patients that can be used for therapeutic drug monitoring of busulfan. The model includes the infusion lag time that is present due delay of the arrival of the drug to catheter which is significant in small patients where the capacity of the cable is comparable to the volume of the administered solution.
Reference: PAGE () Abstr 9575 [www.page-meeting.org/?abstract=9575]
Poster: Drug/Disease Modelling - Oncology