**1. Introduction**

286 Psoriasis

Warren RB,Brown BC, Carmichael AJ, Griffiths CEM. Long-term control of recalcitrant

Dermatology, 34, 415-6.

psoriasis with combination infliximab and methotrexate. Clinical and Experimental

Cyclosporin was isolated in 1970, by Jean François Borel at Sandoz Laboratories (Basel, Switzerland), from the soil fungus *Tolypocladium inflatum* (Borel et al., 1995; Amor et al., 2010). The compound was initially identified as a possible antifungal agent, but it was subsequently shown to have limited antifungal activity. However, in 1976, the drug demonstrated potent immunosuppressive properties, and two years later, it was successfully shown to prevent renal allograft rejection in renal transplant recipients. A year later, a pilot study showed that cyclosporin improved psoriasis in patients treated for rheumatoid and psoriatic arthritis. Ultimately, in the early 1990s, cyclosporin was approved in Europe for the treatment of psoriasis and atopic dermatitis. In 1997, the United States Food and Drug Administration approved a microemulsion formulation of cyclosporin (Neoral®; Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA) for the treatment of severe psoriasis in adults. Worldwide, cyclosporin has been used extensively in various dermatological disorders: e.g. pyoderma gangrenosum, and refractory chronic idiopathic urticaria (Amor et al., 2010; Vena et al., 2006).

Despite such a distinguished clinical history, some dermatologists have been rather hesitant to use cyclosporin because of concerns about possible adverse effects (Amor et al., 2010; Ryan et al., 2010); however a 'framework' of detailed clinical data now widely supports the effective and safe use of cyclosporin within dermatologists' prescribing guidelines, especially when the drug is used as a 'rescue', or intermittent short-term treatment for severe psoriasis, psoriatic arthritis, or atopic dermatitis (Amor et al., 2010).

Another particularly pertinent consideration is that 'conventional' and generic (including generic microemulsion) formulations of cyclosporin are associated with marked intra- and interindividual variability in absorption, thus creating the potential for subtherapeutic dosing at one extreme and toxicity at the other (Colombo & Egan, 2010; Ryan et al., 2010). For this reason, generic formulations have not yet been approved in several countries. Conversely, the microemulsion Neoral® preparation is associated with low intra- and interpatient variability in cyclosporin absorption and with a consistent dose-exposure relationship. This highlights the importance of prescribing the most clinically appropriate

<sup>\*</sup> Corresponding Author

Systemic Cyclosporin in the Treatment of Psoriasis 289

threonine phosphatase that depends on calcium and calmodulin for activity (Amor et al., 2010; Giese et al., 2004; Stepkowski 2000). Consequently, calcineurin cannot dephosphorylate an important transcription factor: the cytoplasmic component of nuclear factor of activated T cells (NF-ATc) [Fig.1]. Transport of NF-ATc to the cell nucleus, and binding of NF-ATc to the promoter region of the IL-2 gene nuclear component of NF-AT (NF-ATn), is therefore blocked and T cells can no longer produce IL-2, a cytokine required for complete activation of the T-cell pathway, granulocyte-macrophage colony-stimulating factor, and interferon-γ production (Amor et al., 2010; Giese et al., 2004). The consequences

Downregulation of cellular adhesion molecule expression in the dermal capillary

Cyclosporin is a lipophilic molecule that is poorly absorbed from 'conventional' orally administered formulations, with major variations in intra- and inter-patient bioavailability (Ryan et al., 2010). A microemulsion preparation (Neoral®; Novartis, East Hanover, New Jersey, USA) was therefore developed with greater hydrophilicity, and higher bioavailability (Colombo & Egan, 2010). There is marked variability among conventional formulations, and for the microemulsion vs conventional formulations : oral forms of cyclosporin are generally not bioequivalent,(Colombo & Egan, 2010) except for Neoral® soft gelatin capsules and Neoral® oral solution, which are bioequivalent (Novartis Pharmaceuticals UK Ltd 2011). Conventional and generic (including generic microemulsion) formulations of cyclosporin are characterised by considerable intra- and inter-individual variability in absorption (Colombo & Egan, 2010; Ryan et al., 2010). By contrast, there is low variability in cyclosporin absorption from the microemulsion Neoral® preparation, which

Peak plasma cyclosporin concentrations are attained 1–6 hours after administration of a conventional soft gelatin capsule formulation (Sandimmune®; Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA), but 1.5–2.0 hours after oral administration of the microemulsion formulation (Neoral®) (Novartis Pharmaceuticals Corporation 2009; Novartis Pharmaceuticals UK Ltd 2011). Mean peak plasma cyclosporin concentration (Cmax) after administration of the microemulsion versus conventional preparation is 40–106% greater, and mean area under the plasma concentration versus time curve (AUC) is 20–50% greater (Novartis Pharmaceuticals Corporation 2009; Novartis Pharmaceuticals UK Ltd 2011). After 4 weeks' administration of Neoral® at a mean dosage of 2.48 mg/kg/day in 18 patients with psoriasis, mean Cmax was 655 ng/mL and mean AUC was 2324

Cyclosporin is extensively distributed throughout the body, in plasma (33–47% of an administered dose), lymphocytes (4–9%), granulocytes (5–12%), and erythrocytes (41–58%) (Novartis Pharmaceuticals Corporation 2009). In plasma, cyclosporin is extensively bound

Depletion of lymphocytes and macrophages in the epidermis and dermis

provides a consistent dose-exposure relationship (Colombo & Egan, 2010).

ng•h/mL.(Novartis Pharmaceuticals Corporation 2009)

Restricted activation of antigen-presenting cells, natural killer cells, and T cells

of cyclosporin action include (Amor et al., 2010):

 Inhibition of keratinocyte hyperproliferation Restricted release of histamine from mast cells.

**3. Pharmacokinetic properties** 

endothelium

cyclosporin preparation, and of avoiding any confusion between the various cyclosporin formulations available (Colombo & Egan, 2010). Indeed, a Canadian survey reported that up to 20% of new cyclosporin recipients may be given a cyclosporin formulation different from that actually prescribed (Davies & Gupta 2000).

This chapter will review the following with respect to psoriasis treatment:

