Population Pharmacokinetics of Amikacin in Korean Neonates

신생아에서 Amikacin의 집단약동학

Background: Population pharmacokinetics of amikacin were analyzed to evaluate the relationship between its pharmacokinetic characteristics and clinical covariates in Korean neonates and to provide initial dosage regimen according to the pathophysiological characteristics of each patients as well as to provide the population parameters required for Bayesian approach in TDM. Methods : 314 steady-state amikacin plasma concentrations were obtained from 157 Korean neonates with a mean postconceptional age (PCA) of $38.1{\pm}4.1$ weeks and mean postnatal age (PNA) of $10.4{\pm}11.2$ days. All subjects were classified to group A (PCA<33 weeks, n=25), group B $(33\;weeks{\leq}PCA<37\;weeks,\;n=35)$ and group C (PCA>37 weeks, n=97) according to their PCA. The individual pharmacokinetic parameters of serum amikacin concentrations were analyzed from one-compartment model in each subject. The population model employed assumes the existence of residual variability in the serum concentrations and interindividual variability in the pharmacokinetic parameters. The effects of demographic variables on the clearance(Cl), volume of distribution(Vd) of amikacin were evaluated from multiple nonlinear regression using $NOMEN^{\circledR}$. Results : Peak concentration/dose ratio was higher in group A than in group Band C. PCA and 5-min Apgar score were good predictive variables of the Cl, body weight was a good variable to determine the Cl and the Vd of amikacin in neonates. From the best fitted pharmacokinetic model, the population average Cl was 0.103 L/kg/h and was reduced in neonates with $33{\leq}PCA>37$ weeks $({\times}0.633)$, whit PCA<37 weeks $({\times}0.588)$, with PCA<33 weeks and with 5-min Apgar score <7 $({\times}0.752)$. The population average Vd was estimated to 0.626 L/kg. The inter-individual variability for Cl and Vd were 24.5 % and <5 %, respectively. Residual variability was estimated to 12.3 %. Conclusions : Amikacin pharmacokinetics of neonates seems to be influenced by PCA and 5-min Apgar score as well as body weight. From the population pharmacokinetic parameters, we predicted the priori dose regimen to achieve desired concentrations within the therapeutic range in Korean neonates.