Comparison of nonlinear mixed-effect and non-parametric expectation maximisation modelling for Bayesian estimation of carboplatin clearance in children

Objective: The pharmacodynamic-pharmacokinetic relationships for carboplati n involve the area under the curve of ultrafiltrable plasma concentrations versus time (AUC). The objective of the study was to compare two specific p opulation pharmacokinetic methodologies, nonlinear mixed-effect model (NON- MEM) and non-parametric expectation maximisation (NPEM), when they are appl ied to sparse carboplatin pharmacokinetic data in order to obtain an indivi dual value for carboplatin clearance by Bayesian estimation. Methods: The data from 117 patients (from 1 month to 18 years old) were ava ilable. For 20 patients randomly selected, the carboplatin clearance obtain ed by Bayesian estimation using two plasma ultrafiltrable concentrations wa s compared with that obtained by individual analysis using all concentratio ns. Results: Both methodologies were unbiased with mean relative percentage err ors (95%CI) of -1.9% (-7.8; + 4.1%) and + 6.4% (-2.1; + 14.9%) for NONMEM a nd NPEM, respectively. A comparison of precision between the two methods sh owed that they were not significantly different (12.5% for NONMEM, and 18.9 % for NPEM), but the percentage error ranged between -21% and +19% for NONM EM, and -35% and +42% for NPEM. A NONMEM analysis was also performed with a ll the data available (117 children) in order to update an equation describ ing the relationship between carboplatin clearance and the patients' covari ates. The best relationship corresponded to the equation: clearance (ml/min ) = [4.47 x body weight x (1 -0.22 x Np)/(1 + 0.0156 x Scr)] + 6.4, with bo dy weight in kilograms and where Scr is serum creatinine in micromoles per litre and Np = 1 or 0 for unilateral nephrectomy or not, respectively. Conclusion: These methodologies may be useful for dose individualisation an d drug monitoring of carboplatin in paediatric patients. Since the mode of administration of carboplatin in paediatric practice in some protocols is d aily 1-h i.v. infusion repeated up to five times, dose individualisation ma y be performed from the clearance observed after the first administration, given an overall target AUC.