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.
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-127I iodinated peptide was used as an internal standard. Fifty percent inhibitory concentration (IC50) of sifuvirtide on cell fusion was determined by co-cultivation assay.
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 μg/L, with correlation coefficients above 0.9923. After iv or sc administration, the observed peak concentrations of sifuvirtide were 10 626±2 886 μg/L and 528±191 μg/L, and the terminal elimination half-lives (T1/2) were 6.3±0.9 h and 5.5±1.0 h, respectively. After sc, Tmax 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 IC50 of 0.33 μg/L.
An on-line SPE-LC/MS/MS approach was established for peptide pharmacokinetic studies. Sifuvirtide was rapidly absorbed subcutaneously into the blood circulation. The T1/2 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 IC50 in vitro.
Locatelli GA, Cancio R, Spadari S, Maga G . HIV-1 reverse transcriptase inhibitors: current issues and future perspectives. Curr Drug Metab 2004; 5: 283–90.
Imamichi T . Action of anti-HIV drugs and resistance: reverse transcriptase inhibitors and protease inhibitors. Curr Pharm Des 2004; 10: 4039–53.
Mocroft A, Katlama C, Johnson AM, Pradier C, Antunes F, Mulcahy F, et al. AIDS across Europe, 1994–98: the EuroSIDA study. Lancet 2000; 356: 291–6.
Li Y, McDonald AM, Dore GJ, Kaldor JM . Improving survival following AIDS in Australia, 1991–1996. National HIV Surveillance Committee. AIDS 2000; 14: 2349–54.
Stolk LM, Luers JF . Increasing number of anti-HIV drugs but no definite cure. Review of anti-HIV drugs. Pharm World Sci 2004; 26: 133–6.
Ruprecht RM, Ferrantelli F, Kitabwalla M, Xu W, McClure HM . Antibody protection: passive immunization of neonates against oral AIDS virus challenge. Vaccine 2003; 21: 3370–3.
Wild CT, Shugars DC, Greenwell TK, McDanal CB, Matthews TJ . Peptides corresponding to a predictive alpha-helical domain of human immunodeficiency virus type 1 gp41 are potent inhibitors of virus infection. Proc Natl Acad Sci USA 1994; 91: 9770–4.
Williams IG . Enfuvirtide (Fuzeon): the first fusion inhibitor. Int J Clin Pract 2003; 57: 890–7.
Steinbrook R . HIV infection-a new drug and new costs. N Engl J Med 2003; 348: 2171–2.
Dai SJ, Song HF, Dou GF, Qian XH, Zhang YJ, Cai Y, et al. Quantification of sifuvirtide in monkey plasma by an on-line solid-phase extraction procedure combined with liquid chromatography/electrospray ionization tandem mass spectrometry. Rapid Commun Mass Spectrom 2005; 19: 1273–82.
Tejedor F, Ballesta JP . Iodination of biological samples without loss of functional activity. Anal Biochem 1982; 127: 143–9.
Wang Q, Wang YT, Pu SP, Zheng YT . Zinc coupling potentiate anti-HIV-1 activity of baicalin. Biochem Biophys Res Commun 2004; 324: 605–10.
Dunne A . Statistical moments in pharmacokinetics: models and assumptions. J Pharm Pharmacol 1993; 45: 871–5.
US Food and Drug Administration [homepage on the internet]. Rockville MD: Food and Drug Administration; 2003 [date created 2003 Jul 23; cited 2005 Feb, 19]. Available from: http://www.fda.gov/cder/foi/nda/2003/021481_fuzeon_review.htm.
Project supported by the National Natural Science Foundation of China (No 39930180, 20275046, 30321003, 30371669), the National High Technology Research and Development Program (No 2003AA2Z347B, 2002BA711A11, 2004BA711A18, 2004BA719A14), and Key Scientific and Technological Projects of Yunnan (No 2004NG12).
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Dai, Sj., Dou, Gf., Qian, Xh. et al. Pharmacokinetics of sifuvirtide, a novel anti-HIV-1 peptide, in monkeys and its inhibitory concentration in vitro. Acta Pharmacol Sin 26, 1274–1280 (2005). https://doi.org/10.1111/j.1745-7254.2005.00163.x
- HIV fusion inhibitors
- on-line solid-phase extraction
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