Pharmacokinetics of Gentamicin Components C1, C1a, and C2/C2a/C2b and Subsequent Decline in Glomerular Filtration Rate in Neonates

Gentamicin is a commonly used antibiotic in neonates. Its components C1, C1a, C2, C2a, and C2b may have different nephrotoxic potential. We aimed to describe pharmacokinetics and nephrotoxic potential of gentamicin components in a joint model in neonates. Neonates with gestational age >= 32 weeks treated with gentamicin blood samples were collected at a steady state. Pharmacokinetics of C1, C1a, and C2/C2a/C2b were modelled in NONMEM and included competitive uptake into kidney proximal tubular cells and decrease in glomerular filtration rate. The nephrotoxic potential of total gentamicin, C1, C1a, and C2/C2a/C2b was evaluated by simulations. A total of 30 neonates (median (range) gestational age 36.4 (32-42) weeks, postnatal age 3 (1-5) days, creatinine value 47.5 (17-78) mu mol/L) were included. Pharmacokinetics of all components was best described by a two-compartment model. Clearance of C1 was smaller than clearances of C1a and C2/C2a/C2b, and other parameters were similar. The model with different K-m (concentration for which half-maximal uptake into kidney proximal tubular cells is achieved) for C1, C1a, and C2/C2a/C2b (37.5, 18, 15 mg/L) provided a better fit than the model with equal K-m (15 mg/L). According to simulations, decrease in glomerular filtration rate in the case of once-daily dosing of 4 mg/kg/day was the largest for C2/C2a/C2b (median (5th and 95th percentile) 0.22% (0.00-8.12%)), followed by total gentamicin (0.20% (0.00-4.10%)), C1a (0.11% (0.00-7.57%)), and C1 (0.04% (0.00-1.55%)). Different gentamicin components C1, C1a, and C2/C2a/C2b exhibited different pharmacokinetic profiles. Once-daily dosing of 4 mg/kg/day results in low nephrotoxicity in neonates, in line with previous studies.

Automated summary

The study aimed to describe the pharmacokinetics and nephrotoxic potential of gentamicin components in neonates. The results showed that once-daily dosing of 4 mg/kg/day resulted in low nephrotoxicity in neonates, with increasing nephrotoxicity observed for total gentamicin, C1, C1a, and C2/C2a/C2b.