**7.1.2 Certolizumab pegol (CDP870)**

250 Psoriasis

on CV morbidity and mortality is likely independent of the induced blood lipid variations

Results derived from studies about the effects of anti-TNF- drugs on insulin resistance in psoriasis patients, appear to show an improvement in insulin sensitivity (Marra et al., 2007). This outcome seems to confirm the beneficial effects of anti-TNF- Moabs already documented in many RA studies (Huvers et al., 2007; Yazdani-Biuki et al., 2004). In particular, infliximab has proved capable of enhancing insulin sensitivity after the infusion to up to one year (Huvers et al., 2007). Lastly, there have been few isolated cases of psoriasis patients with diabetes developing unpredictable hypo- or hyperglycemia after commencing

In the table 3 are reported the side effects of adalimumab, etanercept and infliximab

Golimumab is a human immunoglobulin G1K Moab binding both soluble and transmembrane forms of TNF-, thereby neutralizing their bioactivity by blocking the

In a study with 337 patients, the pharmacokinetics of subcutaneously administered golimumab (50 or 100 mg every 4 weeks) were analyzed (Xu et al., 2009) and the following golimumab pharmacokinetic parameters were found: apparent clearance = 1.38 ± 0.04 L per day, apparent volume of distribution = 24.9 ± 1.04 L and absorption rate constant = 0.908 ± 0.121 per day. Significant covariants on apparent clearance were identified as body weight, baseline C-reactive protein level and smoking habits. However, only body weight was found to be a significant covariant on apparent volume of distribution. In addition, golimumab concentrations in patients (50 mg golimumab every 4 weeks) not receiving MTX were 30% lower as compared with patients receiving MTX (Xu et al., 2009). So far, no possible explanation for the different effects of MTX on the serum golimumab

A randomized, double-blind, placebo-controlled phase III multicenter study was conducted to evaluate the safety and efficacy of golimumab from week 0 to 20 in 405 patients with

Active PsA was defined as at least three swollen joints and three tender joints as well as active plaque psoriasis with a qualifying lesion of at least 2 cm in diameter. Concomitant MTX, non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids were permitted

A significant reduction in PASI 75 among patients receiving golimumab 50 or 100 mg at week 14 (40 and 58%) was observed when compared with patients receiving placebo (3%). PASI 75 scores in patients with golimumab (50 and 100 mg) further improved at week 24 in both golimumab groups (56 and 66%), whereas only 1% of patients in the placebo group

Golimumab significantly (*P* < 0.001) improved signs and symptoms of PsA compared with patients treated with placebo (Kavanaugh et al., 2009). An ACR 20 response at week 14

treatment with TNF inhibitors (Boulton & Bourne, 2007; Wu & Tsai 2008).

interaction with receptor (Kavanaugh et al., 2009; Xu et al., 2009).

concentrations has been provided (Xu et al., 2009).

active PsA (Kavanaugh et al., 2009).

reached a PASI 75 (Kavanaugh et al., 2009).

at stable doses.

(Soubrier et al., 2008).

treatment in psoriasis patients.

**7.1.1 Golimumab (CNTO148)** 

Certolizumab pegol, a pegylated Fab-9 fragment of a humanized anti-TNF-a Moab, has been approved for the treatment of patients with CD (Bourne et al., 2008) and it has also been investigated in RA patients (Barnes & Moots, 2007).

It binding to TNF-, blocks the interaction with specific receptors. Whereas adalimumab, etanercept and infliximab contain an IgG1 Fc region, which can induce antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), certolizumab lacking this Fc region, isn't able of inducing ADCC and CDC (European Medicines Agency [EMEA], 2008).

Pharmacokinetic analysis in the CDP870 trial showed a bioavailability of 85% (EMEA, 2008). Peak plasma concentrations were attained between 54 and 171 h after subcutaneous injection. The mean serum concentration (Cmax) after the subcutaneous administration of 400-mg certolizumab ranged from 46.3 ± 13.1 to 49.5 ± 8.2 mg· mL-1. An increase of Cmax and area under the curve (AUC) was observed with higher doses in a dose-proportional manner. The half-life of certolizumab was found to be approximately 14 days (EMEA, 2008)

Certolizumab pegol has been investigated in patients with moderate to severe psoriasis. In a phase II trial, patients were randomized to receive certolizumab pegol 200 mg, 400 mg or placebo subcutaneously every 2 weeks up to week 12. At week 12, significantly more patients receiving certolizumab pegol 200 or 400 mg achieved PASI 75 than in the placebo

The Role of Immune Response and the Impact of Biological Drugs in Psoriasis Patients 253

In a phase I trial with 64 healthy controls, the pharmacokinetics of briakinumab (0.1–5.0 mg·kg-1 subcutaneously or intravenously) were evaluated. A linear relationship between the Cmax and AUC (concentration-time) was found with increasing doses. The terminal phase half-life time was about 9 days. No dose dependency was found for the volume distribution at steady state and the clearance of the drug. Subcutaneous and intramuscular application

A phase II study with briakinumab was conducted (Kimball et al., 2008b) in patients with psoriasis. Patients were randomized in groups of 30 to receive either only one dose of briakinumab 200 mg at week 0, 100 mg briakinumab every other week for 12 weeks, 200 mg weekly for 4 weeks, 200 mg every other week for 12 weeks and 200 mg every week for 12

PASI 75 was significantly (*P* < 0.001) more often reached in patients in all five briakinumab treatment groups (63, 93, 90, 93, and 90% respectively) compared with the placebo group (3%). Statistically significant improvement to briakinumab therapy was rapid and could be registered in the briakinumab groups as early as at week 1. During the 12-week period, improvement could be sustained in briakinumab-treated patients even for patients in the

Besides injection site reactions, other common side effects the trial study comprised nasopharyngitis and upper respiratory infections. In addition, non-infectious serious adverse events reported in this study included costal chondritis in one patient. Significantly more patients in the briakinumab groups (36%) experienced adverse events compared with

Ustekinumab is a human monoclonal antibody binding with high affinity to the p40 subunit of IL 12 and IL 23 and therefore inhibiting the binding to specific receptor (IL-12Rb1)

In a phase I study, patients with constant 70% PASI improvement at weeks 8, 12 and 16 shown significant decreases in mRNA expression of different cytokines (IL-8, IL-18 and IFN-) as early as week 1 (*P* < 0.05), whereas, in patients without PASI improvement, no significant

The pharmacokinetics of ustekinumab were assessed in different studies (A. B. Gottlieb et al., 2007; Kaufmann et al., 2004; Wittig, 2007): after a single subcutaneous injection, ustekinumab was slowly absorbed into the systemic circulation (mean Tmax about 12 days) and was afterwards slowly eliminated from the circulation (mean t1/2 around 20 days) (A.

The terminal half-life (t1/2) was dose dependent and was found to range from 14.9 ± 4.6 days (0.27 mg·kg-1 dose group) to 28.6 ± 9.3 days (2.7 mg·kg-1 dose group) (A. B. Gottlieb et al., 2007). Similar results were also observed for t1/2 by Kaufman (Kaufmann et al., 2004), ranging from 18.5 ± 3.6 in the 0.3-mg group to 25.9 ± 3.7 in the 1.0-mg group. An increase of Cmax and AUC was observed with superior dosages (A. B. Gottlieb et al., 2007; Kaufmann

reduction of cytokine mRNA expression was observed(Wittig, 2007).

achieved an absolute bioavailability of 42 and 63% respectively (Ding et al., 2008).

weeks, or placebo respectively(Kimball et al., 2008b).

briakinumab 200 mg x 1 and 200 mg x 4 dosage groups.

the placebo group (10%) (Kimball et al., 2008b).

**7.3.2 Ustekinumab (CNTO1275)** 

B. Gottlieb et al., 2007; Wittig, 2007).

et al., 2004).

expressed on various cells.

group (74.6 and 82.8% vs. 6.8%) (Ortonne et al., 2007). The most frequently reported adverse events comprised headache, nasopharyngitis and pruritus. The frequency of adverse events was similar across all three groups. However, serious adverse events were more common in the 400-mg group (7.0%) than in the 200-mg group (3.3%) and in the placebo-group (1.7%) (Ortonne et al., 2007). According to the data from the phase II study, PASI 75 results and side effects were comparable with those observed in patients treated with the approved TNF- blockers adalimumab and infliximab. So far, no phase III studies or studies in patients with PsA have been conducted.
