Population Pharmacokinetics of Amikacin in Very Premature Malaysian Neonates

Background: Amikaicn is an aminoglycoside used in the treatment of early onset neonatal sepsis. Nephrotoxicity and ototoxicty induced by aminoglycosides are closely associated with the duration of treatment and the high plasma peak or trough levels. Therapeutic drug monitoring of amikacin has routinely been carried out in neonatal intensive units.

Aim: To characterize the population pharmacokinetic parameters and the sources of variability following treatment of very premature Malaysian neonates with amikacin, using retrospective data.

Methods: A mixed-effect pharmacokinetic model of amikacin was developed using NONMEM V (version 1.1) with a PowerStation compiler, based on serial amikacin concentrations extracted retrospectively from routine therapeutic drug monitoring database. Pre-term neonates with gestational age of less than 32 weeks and body weight less than 2 kg were included. Weight, gestational age, postnatal age, post-conceptional age, serum creatinine concentration, ventilation support, Apgar scores (1-, 5-minute) were screened as potential influential covariates  (p ≤ 0.01).

Results: Data from 106 subjects were obtained. A total of 304 serum concentrations were analyzed using a one-compartment open model with first order elimination. A body weight of 1.1 ±0.3 kg, a gestational age of 28.5±1.9 weeks and a post-conceptional age of 31.3±3.2 weeks described the characteristics of the population. The typical clearance (CL) was 0.0488 L/h, while the volume of distribution was 0.567 L. Post-conceptional age was a significant predictor of clearance, independent of body size. The between-subject variability (BSV) for volume of distribution was 14.2% (CV%). The BSV for clearance was reduced from an initial 61.1% (base model) to 48.1% when allometric size model was added; a further reduction to 36.5% was observed when post-conceptional age was added. The between-occasion variability (BOV) of volume of distribution was 8.6% and the BOV for clearance was 18.5%. Using a combined residual unexplained variance model, the proportional error (CV%) component and the additive error component was 26% and 0.79 mg/L respectively.

Conclusions: Body size and post-conceptional age are significant predictors for clearance and body size alone is the major contributor for interindividual variability in volume of distribution. Premature neonates are not “little adults” with respect to amikacin pharmacokinetics as their volume of distribution per kg is larger and their clearance lower than that for a 70-kg adult.  A high unexplained variability (36.5%) in clearance was observed. There may be other issues for warranting therapeutic drug monitoring of amikacin in these neonates in addition to the BOV being much less than the BSV.