Summary:A retrospective population pharmacokinetic (PPK) analysis was performed in 24 pediatric patients (PEDS) (0.45-16.7 years old) receiving i.v. busulfan/cyclophosphamide (i.v. Bu/Cy 4) regimen prior to allogeneic hematopoietic stem cell transplantation. I.V. Bu doses were given as a 2-hour infusion every 6 h over 4 days. Initial dosing of i.v. Bu was 1 mg/kg for children p4 years old and 0.8 mg/kg for patients 44 years old. Bu plasma concentrations at doses 1, 9 and 13 were analyzed through a multivariate NONMEM analysis. A close log-linear relationship between body weight (BW) and i.v. Bu clearance was demonstrated with no further age-dependency or gender effect. The interpatient coefficient of variation (CV) in Bu clearance significantly decreased from 56% (covariate-free model) to 19% (BW covariate model) and reproducible i.v. Bu exposure between doses was illustrated (intraindividual CV ¼ 9%). Based on the PPK model, a novel Bu dosing regimen (ie: doses in mg/kg adjusted to discrete weight categories) for a better AUC targeting was developed by simulation on 1000 patients. Age-based dosing was demonstrated not to be clinically relevant with i.v. Bu. Use of the new BW-based dosing appears to be more appropriate for the PEDS.
An IV form of busulfan (IV Bu) has recently become available for high dose conditioning regimen before haematopoietic stem cell transplantation (HSCT). This IV form is expected to reduce the high pharmacokinetic variability exhibited with oral busulfan and as a result, to better target the plasma area under the curve (AUC). Pharmacokinetics (PK) of IV Bu was investigated on 127 adult patients (333 PK administrations) who received 0.8 mg.kg-1 of Bu as a 2-h infusion every 6 h over 4 days, followed by cyclophosphamide (60 mg.kg-1 day-1x2). A retrospective population PK analysis was carried out to search for important predictive factors of IV Bu PK and to develop a limited sampling strategy (LSS) through Bayesian methodology. The analysis was conducted using the Non Linear Mixed Effect methodology and included a validation process on an independent data set. Adjusted Ideal Body Weight (AIBW) and Body Surface Area (BSA) were the best covariates to explain the inter-patient variability. The final inter-patient variability (CV=16%) in IV Bu clearance (Cltot) was estimated close to the intra-patient variability (CV=13%). There was neither age-dependency nor gender effect. IV Bu Cltot was not affected by elevated hepatic enzymes or by co-administration of either fluconazole or acetaminophen, and was not altered in heavily pre-treated or pre-transplanted patients. Normalised Cltot based on either AIBW or BSA was comparable between normal and obese patients (BMI=18-26.9 kg.m-2, >26.9 kg.m-2, respectively) whereas significant differences existed when based on either actual (ABW) or ideal body weight (IBW). As a consequence, no dose adjustment is required in obese patients when using a AIBW- or BSA-based dose calculation. A fixed dose of 0.80 mg.kg-1 of AIBW or 29 mg.m-2 of BSA yielded an average AUC of 1,200 microM.min, with 80% of patients within the "therapeutic" AUC range of 900-1,500 microM.min. Alternatively, 0.80 mg.kg-1 based on either ABW or IBW for normal patients and on AIBW for obese patients would achieve the same performance. A limited sampling strategy based on a Bayesian methodology was developed and validated on an independent dataset: AUCs obtained from one to two samplings were demonstrated to be reliably estimated.
The aim of this study was to develop a method to predict the glomerular filtration rate (GFR) in children by using the population pharmacokinetic approach. This powerful approach is widely used for drug development in order to study relationships between patients' characteristics (demographic, morphological, biological covariates) and pharmacokinetic parameters. For the first time, (51)Cr-EDTA plasma concentrations from 64 children (development data set) were analyzed using the Non-linear Mixed Effects Model (NONMEM) program to determine the most appropriate equation to relate (51)Cr-EDTA clearance (as a measurement of GFR) and patient characteristics. The most predictive equation was based on body weight, square height, and plasma creatinine (PCr, determined by the Jaffé method). This equation was then validated using the data from a further 33 patients. This equation produced estimates of GFR that were less biased and more precise than those obtained using the widely used Schwartz formula. The coefficient of correlation between estimated and actual GFR was 0.83, and the 10th to 90th percentiles for percentage errors were -20% to +30%. Finally, analysis of the whole data set (97 patients) led to an equation (i.e., GFR (ml/min)=[56.7 x Body weight (kg)+0.142 x Length(2)(cm)]/PCr ( microM)) very similar to that obtained from the development data set. This equation would be useful for estimating GFR in children when isotopic determination of the (51)Cr-EDTA clearance cannot be performed.
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