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

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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. Afour-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 g/L, with correlation coefficients above 0.9923. After iv or sc administration, the observed peak concentrations of sifuvirtide were 10 626±2 886 g/L and 528±191 g/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 g/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 IC50in vitro.
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Keywords: HIV; HIV fusion inhibitors; enfuvirtide; macaque; on-line solid-phase extraction; pharmacokinetics; sifuvirtide

Document Type: Research Article

Affiliations: 1: Laboratory of Metabolism of Biotechnology Derived Drugs, Beijing Institute of Radiation Medicine, Beijing 100850; 2: Laboratory of Drug Metabolism and Pharmacokinetics, Beijing Institute of Transfusion Medicine, Beijing 100850; 3: Laboratory of Molecular Immunopharmacology, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223; 4: FusoGen Pharmaceuticals Inc, Tianjin 300051, China

Publication date: 2005-10-01

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