Population pharmacokinetics of amikacin at birth and interindividual variability in renal maturation

Objective: Pharmacokinetic (PK) interindividual variability in amikacin has been shown to be wide in neonates. This study evaluated the evolution of t his variability with gestational age (GA) at birth in relation to renal mat uration. Methods: Population PK values of amikacin were studied in 131 newb orns (postnatal age 1 day, GA 24-41 weeks ) divided into 16 groups, defined by GA, from 24 to 41 weeks (with a mean of 8.2 infants per a group). PK va riables were Kel/Vol, K-s/V-s, Cl/Vol, Cl-s/V, where: Kel=K-slope X GA + K- intercept, Cl = Cl-slope X GA + Cl-intercept, and Vol=V-s X body weight. K- i and Cl-i were held as constants. The nonparametric distribution of the pr obability density function (PDF) was obtained, as were mean, median, and SD values of each PIC variable for each GA group. Results: Amikacin elimination increased linearly with GA. showing that GA i s a good covariate 4 renal elimination. Amikacin volume of distribution inc reased with body weight up to a GA of about 38 weeks and then decreased for highest GA values. However, the PDF for the individual GA groups showed a multimodal PK distribution. Kel, Vol, V-s, Cl, and Cl-s standard deviations increased linearly with GA, showing differential renal maturation. The hig her the GA, the more interindividual PK variability increased. Conclusions: These results show that amikacin elimination and the volume of distribution are dependent upon GA, and that differential renal maturation in neonates is responsible for the wider PK interindividual variability wi th high GA. Dosage regimens of amikacin and other aminoglycosides should be revised in newborns with high GA. Bayesian adaptive control of therapeutic s might be particularly indicated to obtain efficacy for each neonate as ea rly as the first dose.