Population Pharmacokinetics of Dimethylacetamide in Children During Once-daily and Standard IV Busulfan Administration
M.N. Trame (1), I.H. Bartelink (2), J. Boos (3), J.J. Boelens (2), G. Hempel (1,3)
(1) Department of Pharmaceutical and Medical Chemistry – Clinical Pharmacy -, University of Muenster, Germany; (2) Departments of Hematology, Immunology and Clinical Pharmacy, University Medical Center Utrecht, The Netherlands; (3) Department of Pediatric Hematology and Oncology, University Children’s Hospital Muenster, Germany
Objectives: N,N-dimethylacetamide (DMA) is applied to children during high-dose chemotherapy as a solubilizer with the intravenous (IV) formulation of busulfan (Busilvex®). DMA has shown liver toxicity in rats, but relatively little is known of the behaviour of DMA in humans. This investigation was conducted because of concerns of altered pharmacokinetics after high doses of DMA in children. In a previous investigation (J Clin Oncol 25:1772-1778, 2007), we analysed the pharmacokinetic of DMA in 18 children. To confirm the results, we applied the model to a new dataset from children receiving a once-daily schedule of IV busulfan before combining the datasets from both schedules.
Methods: Out of fourty-three children receiving busulfan before bone marrow transplantation aged 0.1 to 18.9 years (median age 2.7), 18 children received IV busulfan as a 2 h infusion every 6 h in 15 doses of 0.7 to 1.0 mg/kg. Each dose contained between 5 mmol (437 mg) and 70.5 mmol (6142 mg) of DMA. The other 24 children received IV busulfan as 3 h infusion once daily for 4 consecutive days with a targeted AUC of busulfan of 4263 µM x min. The DMA concentration during this regimen devoted to be between 11 mmol (988 mg) and 105 mmol (9464 mg) per dose. All samples were analysed by LC-MS with a limit of quantification of 0.25 mg/L. By means of population pharmacokinetic modelling using nonlinear mixed-effects modelling (NONMEM) plasma concentration-time data were analysed. Several covariates such as age, body weight and body surface area were tested on their effects on the pharmacokinetic parameters.
Results: Peak plasma concentrations of DMA up to 3.09 mmol/L for the standard dosing and up to 8.77 mmol/L for the once-daily dosing were observed, respectively. Using a one-compartment model with clearance (Cl) increasing by 0.17% per hour the DMA kinetics was best described. By using body weight as a covariate for Cl and volume of distribution (V) the best results were obtained. The final population estimates for both dosing regimens of busulfan resulted in a Clinitial of DMA of 77.2 ml h-1 kg-1 ± 57.6% and a V of DMA of 493 ml kg-1 ± 26.5% (population mean ± interindividual variability). Interoccasion variability (IOV) for Clinitial (31.5%) was lower than interindividual variability.
Conclusion: Including the new dataset we were able to confirm the population pharmacokinetic model from our previous study without observing significant differences in Clinitial and V between the two cohorts.
