Pharmacokinetics and Pharmaceutics

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

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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.

  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.

  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.

  4. 4

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

  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.

  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.

  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.

  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.

  9. 9

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

  10. 10

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

  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.

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Author information

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.

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Keywords

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