RESUMO
Many factors have been reported that contribute to the wide intra- and inter-patient variability of Busulfan [Bu] disposition. The purpose of this study was to develop a population pharmacokinetic model and to determine the covariates affecting the pharmacokinetics [PK] of Bu in Iranian adult patients who received oral high-dose as a conditioning regimen before Hematopoietic Stem Cell Transplantation [HSCT]. A population PK analysis was performed in 30 patients who received an oral Bu and cyclophosphamide regimen before HSCT. Bu was given orally according to the protocol of the institution. In order to prevent seizures caused by Bu, phenytoin was administered orally one hour before each dose of Bu. A total of 180 blood samples were analyzed by HPLC and PK parameters were estimated by the non-linear mixed effect model by MONOLIX 3.1 program. A one-compartment model with an additive error model was used to describe the concentration-time profile of Bu. CL=13.4[1+ [0.141xDisease]], Vd=42.6[1+0.010x [Weight - 63.9]] Patients' disease and weight was found to be the determinant factors for clearance [CL] and the volume of distribution [Vd] according to Monolix analysis. The covariate entered in final model followed by these equations: In this limited study, the age [15-43 years] had no significant effect. For a patient weighting 60 kg, the typical CL and Vd were estimated to be 13.4 l/hr and 42.6 L, respectively. The interindividual variability of CL and Vd were 13.6 and 6.3%, respectively. There was no significant metabolic induction in these four days as is evident by comparing the trough levels of Bu. However it should be mentioned that, one tailed t-test p-values of the days of two and three, two and four and three and four were 0.083, 0.069 and 0.388, respectively. Results of this study showed that the type of disease was a determinant of CL and the weight of patient was a determinant of Vd for Bu population PK parameters. A reliable PK parameters and Css, estimated from only one plasma concentrations [5 hrs after the first dose], were validated. Since these methods require few sampling and are easy to be used, the limited sampling methods might be advantageous in the routine clinical practice
RESUMO
Large inter-individual variability has been reported for vancomycin pharmacokinetics in pediatric patients. On the other hand, the pharmacokinetic parameters of vancomycin should be known in order to individualize its dosage regimen. Therefore, this study was designed and conducted to assess the steady-state vancomycin serum concentration and pharmacokinetics in a population of Iranian pediatric patients. Vancomycin serum concentration at steady-state was determined in 62 children who were treated with vancomycin intermittent intravenous infusion. Also individual steady-steady pharmacokinetic parameters [total body clearance, apparent volume of distribution and elimination half-life] were determined in 30 patients who had both peak and trough vancomycin levels assuming one-compartment model. Calculated pharmacokinetic parameters were compared among patients with different underlying diseases and also with the results of similar studies that used one-compartment pharmacokinetic model for description of serum concentration of vancomycin at steady-state. More than half of the measured vancomycin serum concentrations were outside the recommended therapeutic range. Median trough concentration was significantly lower in critically ill patients as compared to patients of other disease categories. Although critically care patients showed greater values of apparent volume of distribution and also vancomycin clearance, no statistically significant difference of the calculated pharmacokinetic parameters could be detected among different groups of patients. While calculated volume of distribution for patients of this study was greater than those of similar studies, this difference could not be considered statistically significant in the majority of disease categories. It may be concluded that design of vancomycin dosage regimens according to the recommended and general guidelines in literature [e.g. based on patient creatinine clearance] could not result in the desired therapeutic serum concentrations in the study population