Population pharmacokinetic analysis of netilmicin in neonates and infants with use of a nonparametric method

Background: Although the therapeutic and toxic effects of netilmicin are re lated to its plasma concentration, its pharmacokinetics in neonates and inf ants and the influence of clinical and biological variables have been only partially assessed. Methods: Therapeutic drug monitoring data collected from 186 neonates and 9 5 infants receiving netilmicin were analyzed with a nonparametric populatio n approach. The influence of gestational and postnatal age, weight, Apgar s core, and creatinine and urea plasma concentrations on the pharmacokinetic parameters was assessed. The neonate and infant groups were each randomly d ivided into a learning sample and a validation sample. The population analy sis was performed on each learning subgroup with the nonparametric maximum likelihood (NPML) method. In the validation group, the data were used to as sess the concentration predictability. Because there is no specific netilmi cin formulation for neonates and infants, an error model was proposed to ac count for errors attributable to dilution processes when preparing the infu sion. Results: In neonates, the covariates that reduced expected variance of plas ma clearance by more than 10% were postnatal age, body weight, and plasma c reatinine, as well as plasma urea and creatinine in infants, Body weight an d sex Flared a significant role in explaining the variability of the volume of distribution. The accuracy of the concentration predictability assessed in the validation samples was satisfactory, and no significant bias a-as f ound. Conclusion: These findings help explain the large interindividual variabili ty of the pharmacokinetics of netilmicin and the influence of the clinical and laboratory covariates in neonates and infants.