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.
Tartu University Hospital, Tartu, Estonia. helgi.padari@kliinikum.ee
Helgi
H
Padari
Tuuli
T
Metsvaht
Lenne-Triin
LT
Kõrgvee
Eva
E
Germovsek
Mari-Liis
ML
Ilmoja
Karin
K
Kipper
Koit
K
Herodes
Joseph F
JF
Standing
Kersti
K
Oselin
Irja
I
Lutsar
D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D020345:Enterocolitis, Necrotizing / Q000188:drug therapy / Q000382:microbiology; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000254:growth & development; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases / Q000188:drug therapy* / Q000382:microbiology; D019102:Infant, Very Low Birth Weight; D007262:Infusions, Intravenous; D008297:Male; D000077731:Meropenem; D015233:Models, Statistical; D011014:Pneumonia / Q000188:drug therapy / Q000382:microbiology; D018805:Sepsis / Q000188:drug therapy / Q000382:microbiology; D012984:Software; D013845:Thienamycins / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics
D000900:Anti-Bacterial Agents; D013845:Thienamycins; D003404:Creatinine; D000077731:Meropenem