Summary:In order to control busulfan pharmacokinetic variability and toxicity, a specific monitoring protocol was instituted in our bone marrow transplant BMT paediatric patients including a test dose, daily Bayesian forecasting of busulfan plasma levels, and Bayesian individualization of busulfan dosage regimens. Twenty-nine children received BMT after a busulfan-based conditioning regimen. Individual pharmacokinetic parameters were obtained following a 0.5 mg/kg test dose and were used for daily individualization of dosage regimens during the subsequent 4-day course of treatment. Doses were adjusted to reach a target mean AUC per 6 h between 4 and 6 g.h.ml
؉1. Plasma busulfan assays were performed by liquid chromatography. Pharmacokinetic analysis used the USC*PACK software. The performance of the test dose to predict AUC during the busulfan regimen was evaluated. Incidence of toxicity, chimerism and relapse, overall Kaplan-Meier survival, and VOD-free survival were compared after matching our patients (group A) with patients conditioned by using standard doses of busulfan (group B). Busulfan doses were decreased in 69% of patients compared to conventional doses. Expected AUC was significantly correlated with observed AUC and predictability of the test dose was 101.9 ؎ 17.9%. Incidence of VOD in group A was 3.4% vs 24.1% in group B, while the incidence of stomatitis was similar. Engraftment was successful in all patients in group A. The rate of full engraftment at 3 months post-BMT was higher in group A (P = 0.012). Long-term overall survival did not differ between the two groups, in contrast to the 90-day survival. VOD-free survival was higher in group A (P ؍ 0.026). Pharmacokinetic monitoring and individualization of busulfan dosage regimen are useful in improving clinical outcome and reducing early mortality in
The aim of this study was to identify the risk factors for acute graft-versus-host disease (aGVHD) in children transplanted from a matched-sibling donor (MSD) or an unrelated donor (UD). In all, 87 children consecutively underwent allogeneic bone marrow transplantation (BMT) from MSD (n=36), and UD (n=51). GVHD prophylaxis included CsA alone (n=33) or with MTX (n=51). ATG was added in UD-BMT and thalassemic recipients. CsA whole-blood concentrations were measured by EMIT and the dosing regimen was monitored by Bayesian pharmacokinetic modelling. Trough blood concentration (TBC) during the first 2 weeks post transplantation was lower in children who developed grade II-IV aGVHD than those developing no GVHD or only grade I (57+/-9 vs 94+/-8 ng/ml, P=0.007), whereas peak blood concentration and area under concentration curve vs time were similar in both groups. TBC <85 ng/ml and 'use of MTX' were associated with aGVHD in MSD-SCT (P=0.003 and 0.007, respectively) as well as in UD-SCT (P=0.006 and 0.003). Donor age >or=8 years was significant only in MSD-BMT. Our results have shown the significant decisive role of pharmacological factors such as CSA TBC or use of MTX in the occurrence of GVHD in MSD as well as in UD paediatric BMT.
Background
Busulfan dose adjustment is routinely guided by plasma concentration monitoring using 4–9 blood samples per dose adjustment, but a pharmacometric Bayesian approach could reduce this sample burden.
Methods
The authors developed a non-parametric population model with Pmetrics. They used it to simulate optimal initial busulfan dosages, and in a blinded fashion, they compared dosage adjustments using the model in the BestDose™ software to dosage adjustments calculated by non-compartmental estimation of AUC at a national reference laboratory in a cohort of patients not included in model building.
Results
Mean (range) age of the 53 model-building subjects was 7.8 (0.2 – 19.0) years and weight was 26.5 (5.6 – 78.0) kg, similar to nearly 120 validation subjects. There were 16.7 (6 – 26) samples per subject to build the model. The BestDose cohort was also diverse: 10.2 (0.25 – 18) years and 46.4 (5.2 – 110.9) kg. Mean bias and imprecision of the one-compartment model-predicted busulfan concentrations were 0.42% and 9.2%, and were similar in the validation cohorts. Initial dosages to achieve average concentrations of 600–900 ng/mL were 1.1 mg/kg (≤12kg, 67% in the target range and 1.0 mg/kg (>12 kg, 76% in the target range). Using all 9 concentrations after dose 1 in the Bayesian estimation of dose requirements, the mean (95% CI) bias of BestDose calculations for the third dose was 0.2% (−2.4% to 2.9%, P=0.85), compared with the standard non-compartmental method based on 9 concentrations. With one optimally timed concentration 15 minutes after the infusion (calculated with the authors’ novel MMopt algorithm) bias was −9.2% (−16.7% to −1.5%, P=0.02). With two concentrations at 15 minutes and 4 hours bias was only 1.9% (−0.3% to 4.2%, P=0.08).
Conclusions
BestDose accurately calculates busulfan intravenous dosage requirements to achieve target plasma exposures in children up to 18 years of age and 110 kg using only two blood samples per adjustment compared to 6 – 9 samples for standard non-compartmental dose calculations.
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