The influences of renal function and maturation on vancomycin elimination in newborns and infants

The purpose of this study was to describe the maturation of vancomycin (V) clearance and the influence of altered renal function in infants on vancomy cin using population pharmacokinetic methods. A population pharmacokinetic model was developed using NONMEM from clinical data obtained from 374 newbo rns and infants < 2 years of age (median age = 27 days)from four institutio ns. A total of 1103 serum V concentrations were used in the model developme nt, including 311 with elevated serum creatinine (CR) (> 0.8 mg/dl) and mor e than 104 evaluations in infants older than 2 months of age. The final mod el was evaluated against a second data set of 160 concentrations from 67 in fants at one of the institutions and then used to develop dosing guidelines . The data were best described by a two-compartment model. Weight and CR gr eatly influenced vancomycin elimination, while postnatal age and prematurit y(< 28 weeks) were significant but less important predictors of V eliminati on. For the typical study infant (age = 27 days, CR = 0.6, WT= 1.8 kg, gest ational age = 33.5 weeks), this results in Vd(ss) = 0.79 l/kg and CI = 0.06 6 l/h/kg. The validation data set showed the model to be unbiased, Dosing g uidelines from this model, based on serum creatinine and gestational age at birth, performed better than published guidelines based on postconceptiona l age. Vancomycin clearance is initially reduced in premature infants and i ncreases with postnatal age. Most of the age-related changes could be predi cted by the concomitant fall in serum creatinine. Dosing guidelines that in corporate these factors are more likely to produce therapeutic V concentrat ions in infants. (C) 2001 the American College of Clinical Pharmacology.