Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antipsoriatics. Other antipsoriatics for topical use, Calcipotriol, combinations. ATC Code: D05AX52.
Mechanism of action:
Enstilar foam combines the pharmacological effects of calcipotriol hydrate as a synthetic vitamin D3 analogue and betamethasone dipropionate as a synthetic corticosteroid.
In psoriasis, vitamin D and its analogues act mainly to inhibit keratinocyte proliferation and induce keratinocyte differentiation. The underlying antiproliferative mechanism of vitamin D in keratinocytes involves the induction of the growth inhibitory factor transforming growth factor-β and of cyclin-dependent kinase inhibitors, with subsequent growth arrest in the G1 phase of the cell cycle plus down-regulation of the two proliferation factors early growth response-1 and polo-like kinase-2.
In addition, vitamin D has an immunomodulatory effect, suppressing activation and differentiation of Th17/Th1 cells while inducing a Th2/Treg response.
In psoriasis, corticosteroids suppress the immune system, particularly pro-inflammatory cytokines and chemokines, thereby inhibiting T-cell activation. At the molecular level, corticosteroids act via the intracellular glucocorticoid receptor and the anti-inflammatory function is due to transrepression of pro-inflammatory transcription factors such as nuclear factor κB, activator protein-1, and interferon regulatory factor-3.
In combination, calcipotriol monohydrate and betamethasone dipropionate promote greater anti-inflammatory and anti- proliferative effects than either component alone.
Pharmacodynamic effects:

Under maximum use conditions, in subjects with extensive psoriasis on the body and scalp treated for up to 4 weeks, adrenal response to ACTH was determined by measuring serum cortisol levels. None of 35 subjects had suppressed serum cortisol levels at 30 or 60 minutes post ACTH stimulation. Thus it appears that for Enstilar, the risk of adrenal suppression is low when applied to extensive psoriasis vulgaris for 4 weeks. Similarly, there was no indication of abnormal calcium metabolism following application of Enstilar to extensive psoriasis vulgaris for 4 weeks.
Clinical efficacy:
The efficacy of once daily use of Enstilar has been investigated in three randomised, double-blind or investigator-blind, 4- week clinical trials including more than 1,100 subjects with psoriasis on the body (also scalp in Trial Two) of at least mild severity according to the Physician's Global Assessment of disease severity (PGA), affecting at least 2% body surface area (BSA), and with a modified Psoriasis Area Severity Index (m-PASI) of at least 2. The physician's global assessment is made using a 5-point scale (clear, almost clear, mild, moderate, and severe) based on the average psoriatic lesion.
The m-PASI is a composite score assessing severity (erythema, scale, and induration) and affected area (excluding face and skin folds).
The number of subjects in each of the three trials and the number of subjects randomised to each treatment group are included in the tables below.
The primary endpoint was subjects with 'treatment success' ('clear' or 'almost clear' for subjects with at least moderate disease at baseline, 'clear' for subjects with mild disease at baseline) according to the PGA at Week 4.

Disease-related baseline characteristics

Trial One                       Trial Two                         Trial Three (N=426)                         (N=302)                           (N=376) 
Baseline disease severity
(PGA):
Mild                            65 (15.3%)                      41 (13.6%)                        63 (16.8%) Moderate                        319 (74.9%)                     230 (76.2%)                       292 (77.7%) Severe                          42 (9.9%)                       31 (10.3%)                        21 (5.6%) 
Mean BSA (range)                7.5% (2-30%)                    7.1% (2-28%)                      7.5% (2-30%) 
Mean m-PASI (range)             7.5 (2.0-47.0)                  7.6 (2.0-28.0)                    6.8 (2.0-22.6) 
Percentage of subjects with 'treatment success' according to the PGA of the body at Week 4 

Enstilar         Foam vehicle       BDP in foam         Calcipotriol in       Daivobet          Ointment vehicle             foam vehicle          Ointment          vehicle

Trial One       (N=323)          (N=103)            –                   –                     –                 – 53.3%            4.8%

Trial Two       (N=100)          –                  (N=101)             (N=101)               –                 –                 45.0%                               30.7%               14.9%

Trial Three     (N=141)          (N=49)             –                   –                     (N=135)           (N=51) 54.6%            6.1%                                                         43.0%             7.8% 
Results for the primary endpoint 'treatment success' (PGA) of body at Week 4 showed Enstilar to be statistically significantly more effective than all the comparators included and responses were observed in all categories of baseline disease severity.
In Trial Two, the effect of Enstilar on scalp psoriasis was investigated as the percentage of subjects with 'treatment success' according to the PGA of the scalp at Week 4.
Percentage of subjects with 'treatment success' according to the PGA of the scalp at Week 4 

Enstilar                            BDP in foam vehicle               Calcipotriol in foam vehicle 
Trial Two               (N=100)                             (N=101)                           (N=101) 53.0 %                              47.5 %                            35.6 % 
Enstilar was statistically significantly more effective compared to calcipotriol and also associated with a higher rate of treatment success than BDP but this comparison did not reach statistical significance.
The effect of Enstilar on itch and itch-related sleep loss was investigated in Trial One using a visual analogue scale (VAS) ranging from 0 mm (no itch/no sleep loss at all) to 100 mm (worst itch you can imagine/worst possible sleep loss).
A statistically significantly higher number of subjects in the Enstilar group compared to vehicle achieved a 70% reduction in itch and itch-related sleep loss from Day 3 and throughout the treatment period.

The effect of Enstilar on quality of life was investigated in Trial One using the generic EQ-5D-5L questionnaire and the dermatologically specific DLQI questionnaire. Statistically significantly greater improvement in quality of life in favour of Enstilar was demonstrated for DLQI from Week 1 and throughout the treatment period and for EQ-5D-5L at Week 4.

Paediatric population
The effects on calcium metabolism were investigated in an uncontrolled, open-label, 4-week trial in 106 adolescents aged 12 to 17 years with scalp and body psoriasis. The subjects used up to 105 g Enstilar per week. No cases of hypercalcaemia and no clinically relevant changes in urinary calcium were reported.
The adrenal response to ACTH challenge was measured in a subset of 33 subjects with extensive plaque psoriasis involving at least 20% of the scalp and 10% of the body surface area. After 4 weeks of treatment with Enstilar, 2 subjects had a cortisol level ≤18 mcg/dL at 30 minutes after ACTH challenge, but had normal response at 60 minutes. A third subject had minimal cortisol response to the ACTH challenge test at baseline resulting in inconclusive results after the treatment. None of these cases had any clinical manifestations.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Following systemic exposure, both active ingredients – calcipotriol and betamethasone dipropionate – are rapidly and extensively metabolised.
The main route of excretion of calcipotriol is via faeces (rats and minipigs) and for betamethasone dipropionate it is via urine (rats and mice). In rats, tissue distribution studies with radiolabelled calcipotriol and betamethasone dipropionate showed that the kidney and liver had the highest level of radioactivity.
The extent of percutaneous absorption of the two active ingredients following topical application of Enstilar was determined in the HPA axis trial in subjects with extensive psoriasis vulgaris (see section 5.1). Calcipotriol and betamethasone dipropionate were below the lower limit of quantification in most samples from 35 patients treated once daily for 4 weeks for extensive psoriasis involving the body and scalp. Calcipotriol was quantifiable at some time point in 1 subject, betamethasone dipropionate in 5 subjects and metabolites of calcipotriol and betamethasone dipropionate were detectable in 3 and 27 subjects, respectively.