Summary:We studied the pharmacokinetics of intravenous busulfan (Bu) in children in order to further optimize intravenous Bu dosing in relation to toxicity and survival. A total of 31 children undergoing Bu-based conditioning for allogeneic SCT were enrolled in a study. The starting dose was 1.0 mg/kg (age o4 years) and 0.8 mg/kg (age X4 years), four doses per day during 4 days. Dose adjustment was allowed up to a maximum dose of 1.0 mg/kg per dose if the target area under the serum concentration-time curve (AUC) was not reached. Pharmacokinetic studies were performed after the first dose. Donor engraftment was established in 28 out of 31 patients. The average AUC after the first dose was the same in children o4 years as in children X4 years. Mean clearance was higher in children o4 years than in children X4 years. In 35% of all patients, total AUC was within the target AUC. The other children's AUCs were below the target range. No relationships were found between systemic exposure to Bu and toxicity or clinical outcome. We concluded that, in accordance with previous data, within the observed AUCs no clear relationship was observed between Bu AUC and outcome with respect to toxicity, engraftment and relapse.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Ciclosporin is an immunosuppressant drug that is commonly used as prophylaxis against graft-versus-host disease (GVHD) after allogeneic haematopoietic stem cell transplantation (SCT) in children.• Therapeutic drug monitoring is necessary because of its unpredictable absorption and narrow therapeutic window.• Data on the pharmacokinetics of ciclosporin and the relation between its systemic exposure, as reflected by the AUC (area-under-the-curve), and the biological effect as GVHD prophylaxis are scarce in children after SCT. WHAT THIS STUDY ADDS• An adequate estimate of the systemic exposure of ciclosporin, following limiting sampling after intravenous and oral administration, can be obtained in children after SCT by determining the AUC using a two-compartment pharmacokinetic model with lag time in combination with a limited sampling strategy.• Large interindividual variability in ciclosporin clearance was found, which was independent of body weight; this finding justifies a dosing strategy distinct from that per kg body weight.• Limited sampling modelling may serve as a tool to study the relationship between systemic exposure (~AUC) and biological effects of ciclosporin, i.e. facilitation of engraftment, prevention of GVHD and avoidance of toxic effects of ciclosporin. AIMSTo develop a limited sampling strategy to determine ciclosporin systemic exposure [area-under-the-curve(AUC)]. This is meant to be the first step in a future study of the relationship between AUC and the biological effects of ciclosporin. METHODSThe pharmacokinetics of ciclosporin was investigated prospectively following stem cell transplantation (SCT) in 17 children, aged 1.8-16.1 years. Ciclosporin was given twice daily, intravenously over a short infusion of 2 h duration during the early post-SCT period, or orally later on, when oral medication was well tolerated. Parameter estimation was performed using nonlinear mixed effect modelling as implemented in the NONMEM program. Individual empirical Bayes estimates of clearance and distribution volume were correlated with the demographic variables. RESULTSPharmacokinetics was described adequately with a two-compartment model with lag time (population estimates: CL = 11.3 l h -1; Vc = 16.5 l; Vp = 59.9 l; t1/2 absorption = 0.78 h, tlag = 0.6 h). The AUCs, determined for the combination of trough level with one time point between 2 and 3 h after dosing, correlated very well with the reference AUC (r 2 = 0.97). No correlation was found between clearance and distribution volume, and the demographic patient variables length, body weight, age and glomerular filtration rate. CONCLUSIONA two-point limited sampling strategy, in combination with a Bayesian fitting procedure using the pharmacokinetic population model described, can adequately determine the AUC of ciclosporin. Since no correlation between clearance and body weight was found, dosing ciclosporin per kg bodyweight is not supported by the results of this study. We suggest starting with a fixed dose, fol...

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