title: Prediction of pharmacokinetics of antibiotics in patients with end-stage renal disease.
abstract: A novel and convenient method to predict the pharmacokinetics of several kinds of antibiotic agents in patients with end-stage renal disease (ESRD) was examined based on the in vitro extraction ratios and pharmacokinetic parameters in healthy volunteers. The dializability of 17 antibiotic agents in 4% human serum albumin solution were determined using a high-performance hemodialytic membrane for clinical use. We assumed that the off-hemodialysis clearance approximated the non-renal clearance, while the on-hemodialysis clearance was considered to be sum of the off-hemodialysis clearance and the hemodialytic clearance. The estimated on- and off-hemodialysis clearances were compared with the ones observed in ESRD patients. In order to confirm the method prospectively, an in vivo pharmacokinetic study was performed in dogs with mercury chloride-induced experimental renal failure. The in vitro extraction ratios of 9 beta-lactams were broadly ranged from 10.9 to 75.6% depending on their physicochemical properties. In contrast, those of the other antibiotics were consistent with their chemical classes: 60.5-63.2% for fluoroquinolone, 48.8-51.1% for aminoglycoside and 18.7-25.6% for glycopeptide. Both the estimated on- and off-hemodialysis clearances of the 17 antibiotics coincided well with the observed values in the literature, regardless of their physicochemical and pharmacokinetic properties. The validity and applicability of this method to three cefems, cefmetazole, cefotaxime and cefoperazone, was prospectively confirmed in the animal study. In conclusion, this new method enables the prediction of the on- and off-hemodialysis clearances of several kinds of antibiotics in ESRD patients from minimal information of their pharmacokinetics in healthy subjects and their in vitro dializability.
authors.affiliation: Clinical Pharmacology and Biostatistics Department, Sankyo Co., Ltd., Tokyo, Japan. tajima_naoyuki@sankyo.co.jp
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Tajima
authors.forename: Satoru
authors.initials: S
authors.lastname: Nagashima
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Uematsu
authors.forename: Hideki
authors.initials: H
authors.lastname: Torii
authors.forename: Masami
authors.initials: M
authors.lastname: Tajima
authors.forename: Akira
authors.initials: A
authors.lastname: Hishida
authors.forename: Hideo
authors.initials: H
authors.lastname: Naganuma
mesh_terms: D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood*; D007700:Kinetics; D008970:Molecular Weight; D006435:Renal Dialysis
chemical_list: D000900:Anti-Bacterial Agents