Prediction of the pharmacokinetics of succinylated human serum albumin in man from in vivo disposition data in animals and in vitro liver slice incubations

JH Proost*, Leonie Beljaars, Peter Olinga, PJ Swart, Maria Kuipers, C Reker-Smit, GMM Groothuis, DKF Meijer

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

13 Citations (Scopus)

Abstract

Suc-HSA is a potent HIV-inhibitor with possible application in man. To facilitate the assessment of dosing regimens for future phase I clinical studies, we predicted the pharmacokinetic properties of Suc-HSA in man. Slices prepared from rat, monkey and human liver were incubated with succinylated albumin, and the maximum uptake rate V. and Michaelis-Menten constant K. were calculated. The pharmacokinetics after multiple doses of Suc-HSA were studied in rats. The pharmacokinetic parameters of Suc-HSA in man were predicted from the results and data from literature, using pharmacokinetic modeling and interspecies scaling techniques, and potential intravenous dose regimens for HIV treatment in man were calculated. On the basis of in vitro uptake studies in rat, monkey and human liver slices and in vivo disposition data in monkey (data from earlier study) and rat, we predicted the following parameters for liver uptake in humans: V-m 82.5 mu g h(-1) kg(-1) and K-m 0.228 mu g ml(-1). The predicted steady-state concentration after daily intravenous bolus doses of 1 mg kg(-1) is between 4 and 30 mu g ml(-1), i.e. well above the IC50 of about 0.4 mu g ml(-1). Additional loading doses of 8 mg kg(-1) in total are needed to reach steady-state within a few days. (C) 2005 Elsevier B.V. All rights reserved.

Original languageEnglish
Pages (from-to)123-132
Number of pages10
JournalEuropean Journal of Pharmaceutical Sciences
Volume27
Issue number2-3
DOIs
Publication statusPublished - Feb-2006

Keywords

  • liver slices
  • interspecies scaling
  • pharmacokinetics
  • succinylated albumin
  • HIV
  • HUMAN-IMMUNODEFICIENCY-VIRUS
  • NEGATIVELY CHARGED ALBUMINS
  • ANTI-HIV ACTIVITY
  • MILK-PROTEINS
  • POTENT ACTIVITY
  • RAT-LIVER
  • PLASMA
  • REPLICATION
  • RECEPTORS
  • MECHANISM

Cite this