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Objectives: Gentamicin is an aminoglycoside antibiotic commonly used in the prophylaxis and treatment of gram negative infections in the neonatal population. Gentamicin is eliminated almost exclusively by glomerular filtration, and changes in gentamicin clearance (CL) in the neonate are likely to correlate with the functional maturation of the glomerular filtration rate. The aim of the present study was to describe the population pharmacokinetics (PK) of gentamicin in preterm and term newborn infants and to identify predictive covariates relevant for new improved dosing regimens. A second aim was to evaluate cystatin C (CysC) as a marker for renal function in the neonatal population.

Methods: A total of 592 plasma concentrations from 42 neonates (4-33 samples per subject) were collected in a prospective clinical trial performed at the neonatal intensive care unit, University Children’s Hospital, Uppsala, Sweden. Investigated covariates included; body weight (BW) (495-4760 gram), gestational age (GA) (163-290 days), postnatal age (PNA) (0-70 days), gender, creatinine (19-154 µmol/L), CysC (1.09-2.39 mg/L) and CL_CysC (24-77 ml/min) calculated according to the formula of Larsson et al. (pediatric and adult patients). The data was analyzed using NONMEM (version VI beta) together with the standardized covariate model building method within the PsN toolkit.

Results: A two-compartment model with a combined additive and proportional residual error model described the gentamicin PK in the neonates. Inter individual variability (IIV) was significant for clearance and central volume of distribution (V1). Body weight was included as the primary covariate according to an allometric power model. GA and PNA were significant covariates for CL and inclusion resulted in a reduction in the unexplained IIV. No significant covariates besides BW were found for V1 or for the other parameters.

Conclusions: A PK model including the covariates BW, GA, and PNA was developed describing the developmental PK of gentamicin in preterm and term neonates. Based on these data, CysC was not found to be correlated with gentamicin clearance. Therefore CysC is not likely to be a predictive marker of renal function in this patient population.

References
1. Larsson A, et al. Scand J Clin Lab Invest 2004; 64: 25-30