Calcipotriene (Dovonex)
Calcipotriene
Dovonex®
Classification:
Dermatological Agents
Description: Calcipotriene (calcipotriol) is a vitamin D3 analog indicated for the topical symptomatic treatment of chronic plaque psoriasis. Calcipotriene is structurally similar to naturally occurring calcitriol. In 1986, vitamin D analogs were discovered to be effective in the treatment of psoriasis, however, oral vitamin D has limited usefulness due to side effects associated with the large dosages often needed for therapy. Hence, topical calcipotriene provides a safe and effective alternative to oral vitamin D. Marked improvement in clearing of psoriatic lesions occurs in approximately 50-70% of patients, although lesions can recur within 2-3 months following discontinuance of treatment. Clinical trials comparing calcipotriene with other antipsoriatic agents demonstrated that calcipotriene is at least as effective as betamethasone and is superior to short-contact anthralin. Although calcipotriene is considered the treatment of choice by some clinicians, clinical data and cost considerations do not support its use before an adequate trial of topical corticosteroids. Calcipotriene received FDA approval on December 29, 1993.
Mechanism of Action: The mechanism of action of calcipotriene, a synthetic analog of vitamin D3, is similar to naturally occurring 1,25-(OH)2-D3 (calcitriol). Calcitriol (i.e., active vitamin D3) is the metabolite of cholecalciferol (i.e., inactive vitamin D3). Calcipotriene binds to vitamin D receptors on epidermal cells and tissue cells. Activation of this ligand-receptor complex results in inhibition of cell proliferation and induction of cell differentiation in psoriatic skin. In addition, calcipotriene binds to vitamin D receptors on lymphocytes. Calcipotriene is also similar to calcitriol in its ability to suppress thymocyte proliferation, T-helper function, and lymphocyte proliferation. The exact role of these immunologic mechanisms in the reduction of psoriatic lesions is unknown.
The binding affinity of calcipotriene to intestinal calcitriol receptors is similar to that of calcitriol, however animal studies demonstrated that calcipotriene is 100-200 times less potent than calcitriol on calcium metabolism when given systemically. It has been suggested that rapid liver metabolism or extensive metabolism of calcipotriene in epidermal keratinocytes is responsible for this difference.
During short-term therapy of stable plaque psoriasis, calcium and bone metabolism in humans appear to be unaffected when calcipotriene is used at the recommended dosage (<100 grams/week). Calcipotriene administered for 4 weeks at the maximum weekly dosage (100 grams/week) resulted in significant increases in urine calcium.
Pharmacokinetics: Calcipotriene is administered topically. Approximately 6% of a topical dose of calcipotriene is systemically absorbed when applied to psoriatic skin. Although the distribution of absorbed calcipotriene and its metabolites have not been described, it is presumed to be similar to other vitamin D derivatives. It is unknown if calcipotriene and its metabolites cross the placenta or are distributed into breast milk (see Precautions). The half-life of the drug is 4 minutes during IV administration to animals. Clinical improvement of psoriatic lesions occurs within 2 weeks, with maximal benefits observed in 4 to 8 weeks. The drug demonstrates a dose-dependent effect on erythema, thickness, and scaling of lesions.
Absorbed calcipotriene is rapidly and extensively converted in the liver to a 24-ketone and a 22,23-hydrogenated derivative. In vitro data have shown that the parent compound is also metabolized by human keratinocytes. All metabolites identified thus far have negligible activity compared with the parent compound. Calcipotriene is minimally excreted in the urine and feces (<1%).
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References
. Kragballe K, Gjertsen BT, DeHoop D, et al. Double-blind, right/left comparison of calcipotriol and betamethasone valerate in the treatment of psoriasis vulgaris. Lancet 1991;337:193-6.
. Berth-Jones J, Chu A, Dodd W, et al. A multicentre, parallel-group comparison of calcipotriol ointment and short-contact dithranol therapy in chronic plaque psoriasis. Br J Derm 1992;127:266-71.
. Binderup L, Bramm E. Effects of a novel vitamin D analogue MC 903 on cell proliferation and differentiation in vitro and on calcium metabolism in vivo. Biochem Pharmacol 1988;37:889-93.
. Masuda S, Strugnell S, Calcerley MJ, et al. In vitro metabolism of the anti-psoriatic vitamin D analog, calcipotriol, in two cultured human keratinocyte models. J Biol Chem 1994;269:4794-4803.
. Berth-Jones J, Bourke JF, Iqbal SJ, et al. Urine calcium excretion during treatment of psoriasis with topical calcipotriol. Br J Derm 1993;129:411-4.
. Kragballe K, Beck HI, Sobaard H. Improvement of psoriasis by a topical vitamin D3 analogue (MC 903) in a double-blind study. Br J Derm 1988;119:223-30.
[ Revised 5/7/2005 9:40:00 AM ]
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