**3. Pharmacokinetic properties**

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

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

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

Systemic Cyclosporin in the Treatment of Psoriasis 291

was 16–88% (Christophers et al., 1992; Faerber et al., 2001; Timonen et al., 1990). Moreover, in a 16-week study in 85 patients with severe psoriasis, cyclosporin 3–7.5 mg/kg/day reduced global disease severity score by 59–77% (Ellis et al., 1991); however, although major, additional efficacy benefits can be obtained at cyclosporin doses >5 mg/kg/day, these

Psychological distress is common in psoriatic patients (Colombo et al., 2010c; Finzi et al., 2007). A large, observational, follow-up study of more than 1500 psoriatic patients (the PSYCHAE study) revealed that methotrexate and topical corticosteroids were associated with a significantly increased risk of minor psychological distress, whereas cyclosporin significantly reduced such distress, perhaps because of patients' overall perceptions of efficacy and tolerability (Colombo et al., 2010c). This finding has potentially major clinical significance, since it outlines the possibility for markedly improved quality of life during cyclosporin therapy, but the possibility for detrimental effects on quality of life for certain other psoriasis treatments. Additional, comparative investigations are now warranted to clearly define the relative effects of cyclosporin and other antipsoriatic agents on quality of

Intermittent short-term therapy for 12–16 weeks is the most widely recommended dosing schedule for psoriasis: that is, short courses of cyclosporin are administered until marked improvement is evident, whereupon treatment is stopped; if relapse manifests, cyclosporin

Fig. 2. Maintained efficacy of intermittent short-term cyclosporin therapy during a large, 1 year, multicentre, randomised trial in patients with plaque psoriasis (Ho et al., 1999). Values shown are the probability of a PASI75 response after 12 weeks' treatment with cyclosporin

In a large, multicentre, randomised trial (the Psoriasis Intermittent Short Courses of Efficacy of Sandimmun Neoral® [PISCES] study), 400 patients with plaque psoriasis were initially treated with cyclosporin 2.5–5 mg/kg/day until clearance of psoriasis, or for a maximum of 12 weeks; patients were then randomised to abruptly or gradually discontinue (dosage reduction of 1 mg/kg/day each week) cyclosporin therapy. If relapse occurred, patients received another course of cyclosporin therapy. After 1 year of follow-up, 117 patients had

is re-started at the dosage that was earlier effective (Menter et al., 2009).

benefits are offset by increased toxicity (Amor et al., 2010).

life (see section 8).

2.5–5 mg/kg/day.

**4.1 Intermittent short-term therapy** 

to proteins (~90%), primarily lipoproteins,(Novartis Pharmaceuticals Corporation 2009) and transfer of the drug may occur between various lipoprotein subfractions, and between albumin and lipoproteins (Ryan et al., 2010). Cyclosporin is excreted in breast milk, such that mothers treated with the compound should not breastfeed (Novartis Pharmaceuticals Corporation 2009).

Cyclosporin is metabolised by the cytochrome P450 (CYP) system, primarily by isozymes CYP3A4 and CYP3A5 in the liver and small intestine; the p-glycoprotein pump also has a major influence on cyclosporin bioavailability and clearance (Novartis Pharmaceuticals Corporation 2009; Ryan et al., 2010). Cyclosporin is eliminated primarily via the bile. The terminal half-life of cyclosporin in plasma has varied from 6–24 hours in various populations,(Novartis Pharmaceuticals UK Ltd 2011; Ryan et al., 2010) but in patients with psoriasis, the value is probably closer to the lower end of this range (Berth-Jones 2005).
