Prediction of the pharmacokinetics of succinylated human serum albumin in man from in vivo disposition data in animals and in vitro liver slice incubations.
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(m) and Michaelis-Menten constant K(m) 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 microg h(-1) kg(-1) and K(m) 0.228 microg ml(-1). The predicted steady-state concentration after daily intravenous bolus doses of 1 mg kg(-1) is between 4 and 30 microg ml(-1), i.e. well above the IC50 of about 0.4 microg ml(-1). Additional loading doses of 8 mg kg(-1) in total are needed to reach steady-state within a few days.
Proost
Johannes H
JH
Groningen University Institute for Drug Exploration (GUIDE), Section Pharmacokinetics and Drug Delivery, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. j.h.proost@rug.nl
Beljaars
Leonie
L
Olinga
Peter
P
Swart
Pieter J
PJ
Kuipers
Mirjam E
ME
Reker-Smit
Catharina
C
Groothuis
Geny M M
GM
Meijer
Dirk K F
DK
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism*; D008252:Macaca fascicularis; D008297:Male; D008954:Models, Biological; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D012709:Serum Albumin / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000998:Antiviral Agents; D012709:Serum Albumin; C034877:succinylalbumin