Pharmacokinetics of sifuvirtide, a novel anti-HIV-1 peptide, in monkeys and its inhibitory concentration in vitro.
OBJECTIVE
To study the pharmacokinetics of sifuvirtide, a novel anti-human immunodeficiency virus (HIV) peptide, in monkeys and to compare the inhibitory concentrations of sifuvirtide and enfuvirtide on HIV-1-infected-cell fusion.


METHODS
Monkeys received 1.2 mg/kg iv or sc of sifuvirtide. An on-line solid-phase extraction procedure combined with liquid chromatography tandem mass spectrometry (SPE-LC/MS/MS) was established and applied to determine the concentration of sifuvirtide in monkey plasma. A four-(127)I iodinated peptide was used as an internal standard. Fifty percent inhibitory concentration (IC(50)) of sifuvirtide on cell fusion was determined by co-cultivation assay.


RESULTS
The assay was validated with good precision and accuracy. The calibration curve for sifuvirtide in plasma was linear over a range of 4.88-5000 microg/L, with correlation coefficients above 0.9923. After iv or sc administration, the observed peak concentrations of sifuvirtide were 10 626+/-2886 microg/L and 528+/-191 microg/L, and the terminal elimination half-lives (T(1/2)) were 6.3+/-0.9 h and 5.5+/-1.0 h, respectively. After sc, T(max) was 0.25-2 h, and the absolute bioavailability was 49%+/-13%. Sifuvirtide inhibited the syncytium formation between HIV-1 chronically infected cells and uninfected cells with an IC(50) of 0.33 microg/L.


CONCLUSIONS
An on-line SPE-LC/MS/MS approach was established for peptide pharmacokinetic studies. Sifuvirtide was rapidly absorbed subcutaneously into the blood circulation. The T(1/2) of sifuvirtide was remarkably longer than that of its analog, enfuvirtide, reported in healthy monkeys and it conferred a long-term plasma concentration level which was higher than its IC(50) in vitro.
Dai
Shu-jia
SJ
Laboratory of Metabolism of Biotechnology Derived Drugs, Beijing Institute of Radiation Medicine, Beijing 100850, China.
Dou
Gui-fang
GF
Qiang
Xiao-hong
XH
Song
Hai-feng
HF
Tang
Zhong-ming
ZM
Liu
De-sheng
DS
Liu
Xiu-wen
XW
Yang
Liu-meng
LM
Zheng
Yong-tang
YT
Liang
Qing
Q
D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D000077560:Enfuvirtide; D005260:Female; D015700:HIV Envelope Protein gp41 / Q000097:blood; D023581:HIV Fusion Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D015497:HIV-1; D020128:Inhibitory Concentration 50; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008253:Macaca mulatta; D008297:Male; D013058:Mass Spectrometry; D010446:Peptide Fragments / Q000097:blood / Q000493:pharmacokinetics; D010455:Peptides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D010455:Peptides; D000077560:Enfuvirtide; C505768:sifuvirtide