Pharmacokinetics

Pharmacokinetics of sifuvirtide, a novel anti-HIV-1 peptide, in monkeys and its inhibitory concentration in vitro

Abstract

Aim:

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-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.

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 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.

Conclusion:

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.

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Correspondence to Xiao-hong Qian.

Additional information

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

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Keywords

  • sifuvirtide
  • pharmacokinetics
  • HIV
  • HIV fusion inhibitors
  • enfuvirtide
  • on-line solid-phase extraction
  • macaque

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