Reducing inter-individual variability in amikacin clearance in preterm neonates

The bactericidal efficacy of amikacin mainly relates to intermittent, discontinuous peak concentrations due to the post-antibiotic effect, while renal side effects and oto-toxicity relate to the average plasma concentration, based on saturation of renal and cochlear cell binding sites. This combination of efficacy and safety has resulted in the concept of administration of relative larger doses with extended dosing intervals between consecutive administrations. However, the important interindividual variability in amikacin pharmacokinetics (PK) due to renal maturation makes it difficult to achieve a safe and effective dosing regimen in the individual premature neonate, most prominent in extremely preterm neonates and at birth. We report on the consecutive steps we took over a period of 7 years to reduce inter-individual variability in order to achieve a safe and effective dosing regimen in preterm neonates at birth. Individual amikacin pharmacokinetics were calculated in 273 preterm neonates (546 paired observations, <31 weeks postmenstrual age (PMA), on respiratory support). Based on different dosing regimes used during consecutive time intervals, we were able to illustrate the PMA-dependent clearance, the negative effect of co-administration of a non-selective cyclo-oxygenase inhibitor on amikacin clearance and the impact of implementation of these observations on the amikacin trough levels observed. However, still important unexplained interindividual variability was observed. The subsequent introduction of a paediatric vial in a more recently treated cohort further reduced the variability in amikacin clearance observed. We have illustrated (i) the influence of perinatal renal function on amikacin clearance and (ii) the impact of a paediatric vial on the further reduction of the observed variability in amikacin clearance to dosing regimens.