Daivobet Mechanism of Action

Pharmacology: Pharmacodynamics: Calcipotriol is a vitamin D analogue. In vitro data suggests that calcipotriol induces differentiation and suppresses proliferation of keratinocytes. This is the proposed basis for its effect in psoriasis.
Like other topical corticosteroids, betamethasone dipropionate has anti-inflammatory, antipruritic, vasoconstrictive and immunosuppressive properties, however, without curing the underlying condition.
Through occlusion the effect can be enhanced due to increased penetration of the stratum corneum. The incidence of adverse events will increase because of this. The mechanism of the anti-inflammatory activity of the topical steroids, in general is unclear.
A safety study in 634 psoriasis patients has investigated repeated courses of Daivobet Ointment used once daily as required, either alone or alternating with Daivonex, for up to 52 weeks, compared with Daivonex used alone for 48 weeks after an initial course of Daivobet Ointment. Adverse drug reactions were reported by 21.7% of the patients in the Daivobet Ointment group, 29.6% in the Daivobet Ointment/Daivonex alternating group and 37.9% in the Daivonex group. The adverse drug reactions that were reported by more than 2% of the patients in the Daivobet Ointment group were pruritus (5.8%) and psoriasis (5.3%). Adverse events of concern possibly related to long-term corticosteroid use (e.g. skin atrophy, folliculitis, depigmentation, furuncle and purpura) were reported by 4.8% of the patients in the Daivobet Ointment group, 2.8% in the Daivobet Ointment/Daivonex alternating group and 2.9% in the Daivonex group.
Adrenal response to ACTH was determined by measuring serum cortisol levels in patients with both extensive scalp and body psoriasis, using up to 106 g per week combined Daivobet Gel and Daivobet Ointment. A borderline decrease in cortisol response at 30 minutes post ACTH challenge was seen in 5 of 32 patients (15.6%) after 4 weeks of treatment and 2 of 11 patients (18.2%) who continued treatment until 8 weeks. In all cases, the serum cortisol levels were normal at 60 minutes post ACTH challenge. There was no evidence of change of calcium metabolism observed in these patients. With regard to HPA suppression, therefore, this study shows some evidence that very high doses of Daivobet Gel and Ointment may have a weak effect on the HPA axis.
Paediatric population: The adrenal response to ACTH challenge was measured in an uncontrolled 4-week study in 33 adolescents aged 12-17 years with body psoriasis who used up to 56 g per week of Daivobet Ointment. No cases of HPA axis suppression were reported. No hypercalcaemia was reported but one patient had a possible treatment-related increase in urinary calcium.
Pharmacokinetics: Clinical studies with radiolabelled ointment indicate that the systemic absorption of calcipotriol and betamethasone from Daivobet Ointment is less than 1% of the dose (2.5 g) when applied to normal skin (625 cm²) for 12 hours. Application to psoriasis plaques and under occlusive dressings may increase the absorption of topical corticosteroids. Absorption through damaged skin is approx. 24%.
Following systemic exposure, both active ingredients - calcipotriol and betamethasone dipropionate - are rapidly and extensively metabolised. Protein binding is approx. 64%. Plasma elimination half-life after intravenous application is 5-6 hours. Due to the formation of a depot in the skin, elimination after dermal application is in order of days. Betamethasone is metabolised especially in the liver, but also in the kidneys to glucuronide and sulfate esters. 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, respectively, showed that the kidney and liver had the highest level of radioactivity.
Calcipotriol and betamethasone dipropionate were below the lower limit of quantification in all blood samples of 34 patients treated for 4 or 8 weeks with both Daivobet Gel and Daivobet Ointment for extensive psoriasis involving the body and scalp. One metabolite of calcipotriol and one metabolite of betamethasone dipropionate were quantifiable in some of the patients.
Toxicology: Preclinical Safety Data: Studies of corticosteroids in animals have shown reproductive toxicity (cleft palate, skeletal malformations). In reproduction toxicity studies with long-term oral administration of corticosteroids to rats, prolonged gestation and prolonged and difficult labour was detected. Moreover, reduction in offspring survival, body weight and body weight gain was observed. There was no impairment of fertility. The relevance for humans is unknown.
A dermal carcinogenicity study with calcipotriol in mice and an oral carcinogenicity study in rats revealed no special risk to humans.
Photo(co)carcinogenicity studies in mice suggest that calcipotriol may enhance the effect of UVR to induce skin tumours.
A dermal carcinogenicity study in mice and an oral carcinogenicity study in rats revealed no special risk of betamethasone dipropionate to humans. No photocarcinogenicity study has been performed with betamethasone dipropionate.