Interindividual changes in volume of distribution of cefazolin in newborn infants and its prediction based on physiological pharmacokinetic concepts

The purpose of this study was to investigate factors affecting the volume of distribution of cefazolin (a β‐lactam antibiotic) in newborn infants with bacterial infections, and to propose a method for predicting the volume of distribution at steady state per body weight (Vd_ss/BW). Cefazolin and tobramycin (an aminoglycoside) were simultaneously given to newborn infants (aged 2 to 28 d), and plasma concentration‐time data were analyzed on the basis of model‐independent moment analysis. The Vd_ss/BW values ranged from 0.212 to 0.373 L/kg for cefazolin and from 0.384 to 0.541 L/kg for tobramycin. The unbound fraction of cefazolin in plasma (f_p) fluctuated widely, from 0.22 to 0.83, among patients. The Vd_ss/BW value for cefazolin was characterized by both large extracellular water volume and a remarkable change in f_p, and could be predicted as a function of f_p using physiological pharmacokinetic concepts. Moreover, interindividual changes in the unconjugated bilirubin:albumin molar ratio were predominantly responsible for the individual variation in the f_p values of cefazolin in newborn infants.