Purpose: To evaluate the best method for dosing busulfan in children, we retrospectively analyzed two different data sets from three different dosing regimens by means of population pharmacokinetics using NONMEM.Experimental Design: The development data set consisted of plasma samples from 94 children, in the age range of 0.4 to 18.8 years, receiving either oral or intravenous busulfan. The external model evaluation data set comprised 24 children, in the age range of 0.1 to 18.9 years, who belonged to the once-daily intravenous busulfan dosing regimen. A one-compartment model with first-order absorption using body surface area (BSA) or allometric body weight (BW) as covariate on clearance (CL) and BW as covariate on volume of distribution (V) were used to describe the results sufficiently. In addition to interindividual variability on all pharmacokinetic parameters, interoccasion variability was included for CL and V.Results: CL values in the present study did not reflect the shape of the CL versus weight curve reported in previous investigations. By external model evaluation, we were able to confirm these findings. Furthermore, bioavailability was calculated to be between 93% and 99% for the development data set. On the basis of the final models, we simulated two dosing schemes according to allometric BW and BSA showing that we estimated to include about 30% more patients into the proposed therapeutic area under the curve (AUC) range of 900 to 1,500 mM Ã min and could, furthermore, achieve a reduction in the AUC variability when dosed according to the labeled European Medicines Agency (EMA) dosing recommendation. Conclusion: We recommend a BSA or an allometric BW dosing regimen for individualizing busulfan therapy in children to reduce variability in busulfan exposure and to improve safety and efficacy of busulfan treatment. Clin Cancer Res; 17(21); 6867-77. Ó2011 AACR.

children and adolescents during secondary thromboembolic prophylaxis: a cohort study. J Thromb Haemost 2010; 8: 1950-8. Summary. Background: Enoxaparin has been extensively studied in adults on its safety and efficacy during prevention of symptomatic thromboembolism when acute anticoagulation or secondary prevention is required as a result of venous thrombosis or stroke. In children, it is still used off-label and little is known about the pharmacokinetics in children. Objectives: The aim of the present study was to evaluate whether a once-or twice-daily dosing regimen would be feasible in children to achieve appropriate plasma levels of enoxaparin. Patients/methods: A population pharmacokinetic model was developed using anti-factor (F)Xa activity data from 126 children (median age: 5.9 years) receiving enoxaparin either as a once-or twice-daily dosing regimen. Results: A two-compartment model was adequate for describing the enoxaparin kinetics. Body weight proved to be the most predictive covariate for clearance and central volume of distribution: clearance 15 mL h )1 kg . Interindividual variability was found to be 54% for clearance and 42% for volume of distribution. Conclusion: The model is capable of describing all age groups and dosing levels of our population and predicts 12 h and 24 h enoxaparin activities sufficiently. According to our results, a once-daily enoxaparin dosing regimen with frequent monitoring is feasible. In 53.2% of the patients the median 24 h trough level was above the desired range of 0.1 IU mL )1 anti-FXa activity for prophylaxis therapy.

Liposomal amphotericin B (LAMB) and caspofungin (CAS) are important antifungal agents in allogeneic hematopoieticInternal model validation showed predictability and robustness of both models. None of the covariates tested (LAMB or CAS comedication, gender, body weight, age, body surface area, serum bilirubin, and creatinine clearance) further improved the models. In summary, the disposition of LAMB and CAS was best described by two-compartment models. Drug exposures in aHSCT patients were comparable to those in other populations, and no PK interactions were observed between the two compounds.