Journal
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 27, Issue 2-3, Pages 123-132Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejps.2005.08.014
Keywords
liver slices; interspecies scaling; pharmacokinetics; succinylated albumin; HIV
Categories
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available