A phase I/IIa study with succinylated human serum albumin (Suc-HSA), a candidate HIV-1 fusion inhibitor.
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 microg/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 microg/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.
Vermeulen
Joost N
JN
IATEC, Amsterdam, The Netherlands. j.n.vermeulen@amc.uva.nl
Meijer
Dirk K F
DK
Over
Jan
J
Lange
Joep
J
Proost
Johannes H
JH
Bakker
Hester I
HI
Beljaars
Leonie
L
Wit
Ferdinand W N M
FW
Prins
Jan M
JM
D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D018791:CD4 Lymphocyte Count; D056486:Chemical and Drug Induced Liver Injury; D004334:Drug Administration Schedule; D005260:Female; D023581:HIV Fusion Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D007275:Injections, Intravenous; D008107:Liver Diseases / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood*; D012709:Serum Albumin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000075462:Serum Albumin, Human; D013386:Succinates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017211:Treatment Failure; D019562:Viral Load
D023581:HIV Fusion Inhibitors; D012367:RNA, Viral; D012709:Serum Albumin; C459126:Suc-HSA; D013386:Succinates; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000075462:Serum Albumin, Human