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 this variability with gestational age (GA) at birth in relation to renal maturation. Methods: Population PK values of amikacin were studied in 131 newborns (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 group). PK variables were Kel/Vol, Ks/Vs, Cl/Vol, Cls/Vs where: Kel=Kslope×GA+Kintercept, Cl=Clslope×GA+Clintercept, and Vol=Vs×body weight. Ki and Cli were held as constants. The nonparametric distribution of the probability density function (PDF) was obtained, as were mean, median, and SD values of each PK variable for each GA group. Results: Amikacin elimination increased linearly with GA, showing that GA is a good covariate of renal elimination. Amikacin volume of distribution increased 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, Vs, Cl, and Cls standard deviations increased linearly with GA, showing differential renal maturation. The higher 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 with high GA. Dosage regimens of amikacin and other aminoglycosides should be revised in newborns with high GA. Bayesian adaptive control of therapeutics might be particularly indicated to obtain efficacy for each neonate as early as the first dose.