Short versus Long Infusion of Meropenem in Very-Low-Birth-Weight Neonates

Prolonged infusion of meropenem has been suggested in studies with population pharmacokinetic modeling but has not been tested in neonates. We compared the steady-state pharmacokinetics (PK) of meropenem given as a short (30-min) or prolonged (4-h) infusion to very-low-birth-weight (gestational age, <32 weeks; birth weight, <1,200 g) neonates to define the appropriate dosing regimen for a phase 3 efficacy study. Short (n = 9) or prolonged (n = 10) infusions of meropenem were given at a dose of 20 mg/kg every 12 h. Immediately before and 0.5, 1.5, 4, 8, and 12 h after the 4th to 7th doses of meropenem, blood samples were collected. Meropenem concentrations were measured by ultrahigh-performance liquid chromatography. PK analysis was performed with WinNonlin software, and modeling was performed with NONMEM software. A short infusion resulted in a higher mean drug concentration in serum (C-max) than a prolonged infusion (89 versus 54 mg/liter). In all but two patients in the prolonged-infusion group, the free serum drug concentration was above the MIC (2 mg/liter) 100% of the time. Meropenem clearance (CL) was not influenced by postnatal or postmenstrual age. In population PK analysis, a one-compartment model provided the best fit and the steady-state distribution volume (V-ss) was scaled with body weight and CL with a published renal maturation function. The covariates serum creatinine and postnatal and gestational ages did not improve the model fit. The final parameter estimates were a V-ss of 0.301 liter/kg and a CL of 0.061 liter/h/kg. Meropenem infusions of 30 min are acceptable as they balance a reasonably high C-max with convenience of dosing. In very-low-birth-weight neonates, no dosing adjustment is needed over the first month of life.