title: Population pharmacokinetics of vancomycin in premature Malaysian neonates: identification of predictors for dosing determination.
abstract: The present study determined the pharmacokinetic profile of vancomycin in premature Malaysian infants. A one-compartment infusion model with first-order elimination was fitted to serum vancomycin concentration data (n = 835 points) obtained retrospectively from the drug monitoring records of 116 premature newborn infants. Vancomycin concentrations were estimated by a fluorescence polarization immunoassay. Population and individual estimates of clearance and distribution volume and the factors which affected the variability observed for the values of these parameters were obtained using a population pharmacokinetic modeling approach. The predictive performance of the population model was evaluated by visual inspections of diagnostic plots and nonparametric bootstrapping with replacement. Dosing guidelines targeting a value of > or =400 for the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC(24)/MIC ratio) were explored using Monte Carlo simulation. Body size (weight), postmenstrual age, and small-for-gestational-age status are important factors explaining the between-subject variability of vancomycin pharmacokinetic parameter values for premature neonates. The typical population parameter estimates of clearance and distribution volume for a 1-kg premature appropriate-for-gestational-age neonate with a postmenstrual age of 30 weeks were 0.0426 liters/h and 0.523 liters, respectively. There was a 20% reduction in clearance for small-for-gestational-age infants compared to the level for the appropriate-for-gestational-age control. Dosage regimens based on a priori target response values were formulated. In conclusion, the pharmacokinetic parameter values for vancomycin in premature Malaysian neonates were estimated. Improved dosage regimens based on a priori target response values were formulated by incorporating body size, postmenstrual age, and small-for-gestational-age status, using Monte Carlo simulations with the model-estimated pharmacokinetic parameter values.
authors.affiliation: Department of Pharmacy, Faculty of Medicine, University of Malaya, Lembah Pantai, Kuala Lumpur, Malaysia. yllo@um.edu.my
authors.forename: Yoke-Lin
authors.initials: YL
authors.lastname: Lo
authors.forename: Johan G C
authors.initials: JG
authors.lastname: van Hasselt
authors.forename: Siow-Chin
authors.initials: SC
authors.lastname: Heng
authors.forename: Chin-Theam
authors.initials: CT
authors.lastname: Lim
authors.forename: Toong-Chow
authors.initials: TC
authors.lastname: Lee
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Charles
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature / Q000097:blood*; D007236:Infant, Small for Gestational Age / Q000097:blood; D008296:Malaysia; D008954:Models, Biological; D009010:Monte Carlo Method; D012189:Retrospective Studies; D018805:Sepsis / Q000097:blood / Q000188:drug therapy; D018709:Statistics, Nonparametric; D014640:Vancomycin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000900:Anti-Bacterial Agents; D014640:Vancomycin
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