Metronidazole Population Pharmacokinetics in Preterm Neonates Using Dried Blood-Spot Sampling

OBJECTIVES: To characterize the population pharmacokinetics of metronidazole in preterm neonates.<br/>PATIENTS AND METHODS: Data were collected prospectively from 32 preterm neonates who received intravenous metronidazole for the treatment of or prophylaxis against necrotizing enterocolitis. Dried<br/>blood spots (n 203) on ?lter paper were analyzed by highperformance liquid chromatography, and the data were subjected to pharmacokinetic analysis performed by using nonlinear mixed-effect modeling.<br/>RESULTS: A 1-compartment model best described the data. Signi?cant covariates were weight (WT) and postmenstrual age (PMA). The ?nal population models for metronidazole clearance (CL) and volume of distribution (V) were: CL 0.0247 (WT/1.00)0.75 (1 0.107 [PMA 30]) and V 0.726 WT, where CL is in liters per hour, WT is in kilograms, PMA is in weeks, and V is in liters. This model predicts that the half-life of metronidazole decreases rapidly from 40 hours at 25 weeks’ PMA to 19 hours at 32 weeks’ PMA, after which it starts to plateau. This decrease in half-life is the result of a 5-fold increase in CL compared with only a 2.5-fold increase in V during the same period.<br/>CONCLUSIONS: Currently, there are no speci?c dose recommendations for metronidazole in preterm neonates. However, a dosing scheme for preterm neonates that takes into consideration both the weight and PMA has been suggested and should avoid administration of doses that are excessive or more frequent than necessary.