A Phase I/IIa Study with Succinylated Human Serum Albumin (Suc-HSA), a candidate HIV-1 Fusion Inhibitor

Autor: Vermeulen, Joost N., Dirk Meijer, Jan Over, Lange, Joep M. A., Johannes Proost, Bakker, Hester I., Leonie Beljaars, Wit, Ferdinand W. N. M., Prins, Jan M.
Přispěvatelé: Graduate School, Infectious diseases, Amsterdam institute for Infection and Immunity, Global Health, Nanomedicine & Drug Targeting
Rok vydání: 2007
Předmět:
Zdroj: Antiviral therapy, 12(2), 273-278. International Medical Press Ltd
Antiviral therapy, 12(2), 273-278
University of Groningen
ISSN: 2040-2058
1359-6535
Popis: Background Succinylated human serum albumin (Suc-HAS) is a negatively charged neo-glycoprotein that binds to the positively charged V3–loop of HIV-1 gp120, acting as HIV-1-fusion inhibitor in vitro (IC50: 0.5–5.0 μg/ml). Suc-HSA was safe in rats and monkeys, and showed antiretroviral effect in a human-to-mouse model. We evaluated safety and pharmacokinetics of single and multiple doses of Suc-HSA in HIV-1-infected individuals. Methods First, six untreated, chronically HIV-1-infected patients were randomized to a single dose of 1 or 10 mg/kg Suc-HSA intravenously. Second, five consecutive daily doses (10 mg/kg, based on the results of the single dose study) were given to four patients. Safety laboratory assessments, Suc-HSA plasma levels, plasma HIV-1 RNA (pVL), and CD4+ T-cell counts were determined. Results Increase of liver transaminases (grade 1/2) occurred in one of six patients in the single-dose phase and in three of four patients in the multiple-dosing phase. Suc-HSA plasma levels were undetectable 4 h after a single dose of 1 mg/kg. After a dose of 10 mg/kg, plasma levels were more sustained, but declined under the target plasma concentration (10 μg/ml) 12–24 h post-dosing. After multiple dosing, plasma levels reached peak values 2h post-dosing as predicted by our kinetic model. However, trough levels were below the target concentrations. There was no change in pVL or CD4+ T-cell count in either the single- or multiple-dosing phase. Conclusions At the chosen dosing regimens, adequate antiviral plasma levels were not maintained, probably because the hepatic clearance was more rapid than expected. This may partially explain the lack of effect on pVL and CD4+ T-cell count. The observed liver transaminase increases prohibit further dose escalation.
Databáze: OpenAIRE
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