Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2019 Publisher: LEO Pharma Ltd, Auckland, New Zealand Toll Free No. 0800 497 456
Calcipotriol is a non-steroidal antipsoriatic agent, derived from vitamin D. Calcipotriol exhibits a vitamin D-like effect by competing for the 1,25(OH)2D3 receptor. Calcipotriol is as potent as 1,25(OH)2D3, the naturally occurring active form of vitamin D, in regulating cell proliferation and cell differentiation, but much less active than 1,25(OH)2D3 in its effect on calcium metabolism.
Calcipotriol induces differentiation and suppresses proliferation (without any evidence of a cytotoxic effect) of keratinocytes, thus reversing the abnormal keratinocyte changes in psoriasis. The therapeutic goal envisaged with calcipotriol is thus a normalisation of epidermal growth.
Clinical trials with Daivonex Ointment undertaken in adults and children are summarised below.
Two double-blind, multicentre, randomised studies assessed the efficacy and safety of calcipotriol ointment 50 µg/g twice daily vs betamethasone 17-valerate ointment 0.1% twice daily in patients with psoriasis. The mean study duration was 6 weeks. The primary efficacy endpoint was the percentage reduction of the Psoriasis Area & Severity Index (PASI) score. The mean reduction in PASI score was statistically significant (p<0.001) favouring calcipotriol in one study (MC 288); there was no significant difference between treatments in the second study (MC 188).
Table 1. Twice-daily administration of calcipotriol 50 µg/g ointment in adults:
Two double-blind, multicentre, randomised, vehicle-controlled studies of 8 weeks duration assessed the efficacy and safety of calcipotriol ointment 50 µg/g once daily. Efficacy was assessed using the Psoriasis Grading Scale to score erythema, scaling, plaque elevation and overall severity. The primary efficacy parameter was the plaque elevation subscore. There was a statistically significant difference (p<0.001) favouring calcipotriol.
Table 2. Once daily administration of calcipotriol 50 µg/g ointment in adults (Intention to treat population):
| Study | DE 127-007 | DE 127-009 | |||||
|---|---|---|---|---|---|---|---|
| Treatment administered: | Calcipotriol (n=118) Vehicle (n=116) | Calcipotriol (n=99) Vehicle (n=99) | |||||
| Results (mean±sd): | Baseline | End | p value | Baseline | End | p value | |
| Plaque elevation subscore | Calcipotriol | 5.22±1.28 | 2.02±1.94 | <0.001 | 5.05±1.12 | 2.00±1.41 | <0.001 |
| Vehicle | 5.09±1.26 | 3.70±1.74 | 4.79±0.94 | 3.39±1.51 | |||
| Erythema subscore | Calcipotriol | 4.86±1.69 | 2.33±1.70 | <0.001 | 4.75±1.37 | 2.51±1.25 | <0.001 |
| Vehicle | 4.86±1.59 | 3.88±1.75 | 4.54±1.27 | 3.66±1.41 | |||
| Scaling subscore | Calcipotriol | 5.51±1.66 | 1.68±1.79 | <0.001 | 4.96±1.47 | 1.68±1.14 | <0.001 |
| Vehicle | 5.22±1.59 | 2.91±1.82 | 4.62±1.24 | 2.64±1.28 | |||
| Overall Severity subscore | Calcipotriol | 4.81±1.72 | 2.15±1.73 | <0.001 | 4.60±1.43 | 2.12±1.36 | <0.001 |
| Vehicle | 4.73±1.62 | 3.65±1.76 | 4.25±1.29 | 3.30±1.27 | |||
One double-blind, randomised, multicentre, vehicle-controlled study assessed the efficacy and safety of calcipotriol ointment 50 µg/g twice daily with cyclosporin 2 mg/kg/day in patients with severe psoriasis for 6 weeks. Change in PASI score was the primary efficacy endpoint. There was a statistically significant difference (p<0.01) favouring combination therapy.
Table 3.1. Administration of calcipotriol 50 µg/g ointment with cyclosporin A in adults:
| Treatment administered: | Calcipotriol + cyclosporin 2 mg/kg/day (n=32) | Vehicle + cyclosporin 2 mg/kg/day (n=34) |
|---|---|---|
| Results (mean±sd): | ||
| Baseline PASI | 25.25±5.90 | 25.40±4.16 |
| End PASI | 4.88±6.79 | 10.71±8.98 |
| Change in PASI from baseline | 20.37±8.55 | 14.64±8.58 |
| p<0.01 | ||
One double-blind, multicentre, randomised, vehicle-controlled study assessed the efficacy and safety of calcipotriol ointment 50 µg/g twice daily with acitretin (20-70 mg/day) for 12 weeks in patients with severe/extensive psoriasis unresponsive to topical treatment alone. The percentage of patients achieving marked improvement or clearance at the end of treatment was the primary efficacy endpoint. There was a statistically significant difference (p<0.01) favouring combination therapy.
Table 3.2. Administration of calcipotriol 50 µg/g ointment with acitretin in adults (Intention to treat population):
| Treatment administered: | Calcipotriol + acitretin 20-70 mg/day (n=76) | Vehicle + acitretin 20-70 mg/day (n=59) |
|---|---|---|
| Results: | ||
| Patients with marked improvement or clearance | 67.1% | 40.7% |
| Baseline PASI (mean±sd) | 17.8±8.9 | 17.4±8.6 |
| End PASI (mean±sd) | 4.6±5.4 | 8.6±8.4 |
| p<0.01 | ||
One double-blind, multicentre, randomised, vehicle-controlled study assessed the safety and efficacy of calcipotriol 50 µg/g ointment in children of 2 to 14 years with mild to moderate psoriasis not involving more than 30% of the body surface area. The study was of 8 weeks duration. The primary efficacy end point was the change in PASI score. Nine of the 77 children in the trial were under the age of 7 years; 22.2% of children below 7 years of age received calcipotriol. There was no statistically significant change observed over placebo.
Table 4. Administration of calcipotriol 50µg/g ointment in children (Intention to treat):
| Treatment administered: | Calcipotriol (n=43) | Vehicle (n=34) |
|---|---|---|
| Results (mean±sd): Reduction in PASI from baseline to end | ||
| Baseline: | 6.70±5.80 | 6.33±3.51 |
| End: | 2.89±4.49 | 3.74±2.96 |
| Change: | -3.47±5.82 | -2.60±3.54 |
| p=n.s. | ||
Pharmacokinetic studies with 3 H-calcipotriol have been performed in rats and minipigs. Oral absorption of calcipotriol was approximately 60% in rats and 40% in minipigs. The half-life of calcipotriol was 12 minutes in rats and 60 minutes in minipigs. The major metabolite of calcipotriol, MC1080, was present in the first plasma sample at 5 minutes; its half life was 54 minutes in rats and 1.8 hours in minipigs. Drug-related radioactivity was excreted in urine and faeces, and clearance was considered to be almost exclusively metabolic, as less than 5% of the administered radioactivity was excreted at the time of disappearance of all calcipotriol from plasma. Determination of the tissue distribution of calcipotriol was complicated by the appearance of 3H-H2O from the metabolic degradation of 3H-calcipotriol. Autoradiography studies performed in rats, however, established that calcipotriol concentrations were highest in the liver, kidney and intestine. No drug-related radioactivity was present 24 hours after administration of 3H-calcipotriol.
Two main metabolites of calcipotriol, MC1046 and MC1080, were present in supernatants from minipigs, rabbit and human liver homogenates, and in plasma samples from rats and minipigs. Although the necessity of using very high dosages of calcipotriol precludes the study of calcipotriol metabolism in humans, the present evidence strongly suggests that calcipotriol metabolism is qualitatively similar in rats, minipigs, rabbits and humans.
Bioavailability studies of calcipotriol ointment in psoriatic and healthy patients demonstrated that approximately 2-10% of calcipotriol from the applied dose was systemically absorbed.
A dermal carcinogenicity study with calcipotriol in mice showed no indications of increased carcinogenic risks. Calcipotriol solution was applied topically for up to 24 months at doses of 3, 10 and 30 µg/kg/day (corresponding to 9, 30 and 90 µg/m²/day). The high-dose was considered to be the Maximum Tolerated Dose for dermal treatment of mice with calcipotriol. Survival was decreased at 10 and 30 µg/kg/day, particularly in the males. The reduced survival was associated with an increased incidence of obstructive uropathy, most probably caused by treatment-related changes in the urinary composition. This is an expected effect of treatment with high doses of calcipotriol or other vitamin D analogues. There were no dermal effects and no dermal or systemic carcinogenicity.
In a study where albino hairless mice were repeatedly exposed to both ultraviolet (UV) radiation and topically applied calcipotriol for 40 weeks at the same dose levels as in the dermal carcinogenicity study, a reduction in the time required for UV radiation to induce the formation of skin tumours was observed (statistically significant in males only), suggesting that calcipotriol may enhance the effect of UV radiation to induce skin tumours. The clinical relevance of these findings is unknown.
Calcipotriol did not elicit any genotoxic effects in in vitro assays for gene mutations (Ames mutagenicity assay and mouse lymphoma TK locus assay) or chromosomal damage (human lymphocyte chromosome aberration test or mouse micronucleus test).
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