Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Pharmacokinetics and Pharmaceutics

Pharmacokinetic and pharmacodynamic study of LFA3Ig fusion protein in healthy volunteers and patients with psoriasis

Abstract

Aim:

To evaluate the pharmacokinetics (PK) and pharmacodynamics of the LFA3Ig fusion protein (LFA3IgFP) in healthy volunteers and patients with chronic plaque psoriasis.

Methods:

The clinical trials included 2 phase I open studies. Study 1 was an open-label dose escalation study in 24 healthy volunteers, and study 2 was a single-group, open-label study in 12 patients with chronic plaque psoriasis. The serum drug concentrations were measured, and the concentration-time data were analyzed by compartmental analysis using the Practical Pharmacokinetic Program.

Results:

In study 1, after intramuscular (im) administration at a dosage of 5, 15, and 25 mg, the concentration-time curves of LFA3IgFP fitted well to a 1 compartment open model. Areas under the concentration-time curves increased linearly with dose. Clearance rates (Cls F) and elimination half-lives (T1/2ke) had no significant difference between different dose groups. A transient, slight decline of CD4+ and CD8+ T-cell subsets was observed after administration. In study 2, after im administration at a dosage of 15 mg weekly for 8 weeks, the concentration-time curve was best fitted to a 1 compartment open model, with a T1/2ke of 307.9±32.7 h. The steady state was attained after the fifth administration.

Conclusion:

The PK behaviors of LFA3IgFP in healthy volunteers and patients with chronic plaque psoriasis complied with linear kinetics within the examined dose range. A significant accumulation was observed after repeated administration at a dose of 15 mg weekly for 8 weeks.

References

  1. 1

    Austinl M, Ozawa M, Kikuchi T, Walters IB, Krueger JG . The majority of epidermal T cells in Psoriasis vulgaris lesions can produce type 1 cytokines, interferon-γ, interleukin-2, and tumor necrosis factor-α, denning TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients. J Invest Dermatol 1999; 113: 752–9.

    Article  Google Scholar 

  2. 2

    Vaishnaw AK, TenHoor CN . Pharmacokinetics, biologic activity, and tolerability of alefacept by intravenous and intramuscular administration. J Pharmacokinet Pharmacodyn 2002; 29: 415–26.

    CAS  Article  Google Scholar 

  3. 3

    Gordon KB, Vaishnaw AK, O'Gorman J, Haney J, Menter A . Alefacept Clinical Study Group. Treatment of psoriasis with alefacept: correlation of clinical improvement with reductions of memory T-cell counts. Arch Dermatol 2003; 139: 1563–70.

    CAS  Article  Google Scholar 

  4. 4

    Robert C, Kupper TS . Inflammatory skin diseases, T cells, and immune surveillance. N Engl J Med 1999; 341: 1817–28.

    CAS  Article  Google Scholar 

  5. 5

    Danielian S, Fagard R, Alcover A, Acuto O, Fischer S . The tyrosine kinase activity of p561ck is increased in human T cells activated via CD2. EurJ Immunol 1991; 21: 1967–70.

    CAS  Article  Google Scholar 

  6. 6

    June CH, Fletcher MC, Ledbetter JA, Samelson LE . Increases in tyrosine phosphorylation are detectable before phospholipase C activation after T cell receptor stimulation. J Immunol 1990; 144: 1591–9.

    CAS  PubMed  Google Scholar 

  7. 7

    Krueger GG, Papp KA, Stough DB, Loven KH, Gulliver WP, Ellis CN, et al. A randomized, double-blind, placebo-controlled phase III study evaluating efficacy and tolerability of 2 courses of alefacept in patients with chronic plaque psoriasis. J Am Acad Dermatol 2002; 47: 821–33.

    Article  Google Scholar 

  8. 8

    Lebwohl M, Christophers E, Langley R, Ortonne JP, Roberts J, Griffiths CE, et al. An international, randomized, double-blind, placebo-controlled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis. Arch Dermatol 2003; 139: 719–27.

    CAS  Article  Google Scholar 

  9. 9

    Gordon KB, Langley RG . Remittive effects of intramuscular alefacept in psoriasis. J Drugs Dermatol 2003; 2: 624–8.

    PubMed  Google Scholar 

  10. 10

    Cather J . Investigational therapies for psoriasis. J Am Acad Dermatol 2003; 49: 133–8.

    Article  Google Scholar 

  11. 11

    Lin B, Tan M, Li J, Wang H, Xue J, Hua J, et al. Bioassay of the recombinant human lymphocyte function-associated antigen 3-IgG fusion protein in vitro and in vivo. Curr Immunol 2006; 26: 357–61.

    CAS  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Fei Hao or Ya-jun Guo.

Additional information

Project supported by the National Natural Science Foundation of China, Shanghai Commission of Science and Technology(No 044319204), Ministry of Science and Technology of China (973 & 863 program projects, No 2004CB720100, 2006AA02A248), and Shanghai Pudong Commission of Science and Technology.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Li, Xp., Li, J., Yan, H. et al. Pharmacokinetic and pharmacodynamic study of LFA3Ig fusion protein in healthy volunteers and patients with psoriasis. Acta Pharmacol Sin 29, 1077–1085 (2008). https://doi.org/10.1111/j.1745-7254.2008.00832.x

Download citation

Keywords

  • LFA-3
  • fusion protein
  • pharmacokinetic
  • pharmacodynamic
  • chronic plaque psoriasis
  • ELISA
  • flow cytometry

Search

Quick links