Calcipotriol/Betamethasone Dipropionate: Daivobet®/Dovobet®
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DRUG PROFILE Calcipotriol/betamethasone dipropionate: Daivobet®/Dovobet® Lyn C Guenther Psoriasis is a common skin condition that causes significant morbidity. Treatments can be 835 Richmond St., complex and time consuming. Calcipotriol plus betamethasone dipropionate ointment London, Ontario, (Daivobet® or Dovobet®) is a stable, convenient, once-daily topical treatment for psoriasis. N6A 3H7, Canada Tel.: +1 519 435 1738 Compared with its individual ingredients or tacalcitol, it has a faster speed of onset and Fax: +1 519 435 1740 greater efficacy. Consistent Psoriasis Area Severity Index reductions of approximately 40% [email protected] after 1 week and 70% after 4 weeks were seen in multicenter studies involving more than 6000 patients. After 4 weeks of once-daily therapy, approximately 50% of patients are clear or almost clear. This product is associated with a similar safety profile to betamethasone dipropionate ointment, 50% fewer cutaneous adverse events than calcipotriol ointment and 75% fewer than tacalcitol ointment. Psoriasis affects 0.3 to 2.6% of the population and receptor, acts as a heterodimer with the retinoid X has a significant impact on the patient’s quality of receptor (RXR) [9]. Keratinocytes and lympho- life [1–4]. A 1998 US survey of 17,488 National cytes have vitamin D receptors. In psoriasis, Psoriasis Foundation patient members showed that vitamin D analogues normalize differentiation psoriasis had a significant impact on psychosocial and proliferation, induce apoptosis in inflamma- activities (e.g., interacting in the workplace and tory cells, induce a T-helper (Th)1 to 2 switch with family/spouse, making and keeping friends, and are antiangiogenic [10–12]. Studies have shown getting a job, and exclusion from public facilities) that twice-daily monotherapy is more efficacious and activities of daily living (e.g., sleeping, sexual than vehicle [13], tar [14], short-contact anthralin activities, using hands, walking, sitting or standing [15] and fluocinonide ointment [16], and at least as for long periods, and performing their job) [5]. A efficacious as betamethasone 17-valerate 0.1% total of 10% of respondents in the 18- to 34-year ointment [17,18]. Calcipotriol has an excellent old age group contemplated suicide. long-term safety profile [19–23]. Calcipotriol is Traditionally, treatment has occurred in a commonly used in combination with other treat- stepwise approach with topical agents acting as ments, particularly topical steroids [8]. Such a first-line therapy for mild-to-moderate disease [6]. combination results in increased efficacy, faster onset of clinical response and decreased irritation. Overview of the market However, due to drug incompatibility, each med- Combination therapy is commonly used in the ication must be applied at a different time of the treatment of psoriasis [7,8]. By combining medi- day (e.g., morning or afternoon) [24]. Calcipotriol cations with a different mechanism of action and and topical steroids are stable at different safety profile, efficacy can be enhanced and/or pHs [25]. Corticosteroids are stable in acidic con- safety improved. Unless drug stability is known, ditions, while calcipotriol is stable in alkaline and compounding should be avoided since it may rapidly inactivated in acidic conditions. result in drug degradation due to incompatibility. Betamethasone dipropionate is a Class III Application of different medications at different topical steroid that has been used once or twice times of the day increases treatment complexity. daily to treat psoriasis for several years [26]. Treatment complexity and the time requirement Once-daily use in the evening for 6 weeks in a Keywords: betamethasone for frequent application of medication can morning/afternoon regimen with calcipotriol, dipropionate, calcipotriene, calcipotriol, Daivobet®, hinder compliance. There is a need for a stable is more efficacious with fewer adverse events Dovobet®, fixed once-daily combination treatment. than twice-daily calcipotriol [27]. Irritation may combination, psoriasis be minimized when calcipotriol is used in an Introduction to the compound morning/afternoon regimen with a medium- Calcipotriol is a standard acute and chronic strength steroid(e.g., clobetasone 17-butyrate- part of treatment for plaque psoriasis. It is a vitamin D cream) [28]. In order to enhance efficacy, a analog, which, after binding to the vitamin D potent (e.g., betamethasone) or superpotent 10.2217/14750708.2.3.343 © 2005 Future Medicine Ltd ISSN 1475-0708 http://www.futuremedicine.com Therapy (2005) 2(3), 343–348 343 DRUG PROFILE – Guenther (e.g., halobetasol) steroid is required [28,29]. In patients treated with the combination product, contrast to the vitamin D analogues, cortico- compared with 5.0% with calcipotriol, 4.1% steroids bind to cytoplasmic glucocorticoid with betamethasone dipropionate and 5.3% receptors and rapidly translocate to the with vehicle. nucleus where they inhibit or stimulate genes regulating inflammation [30]. This results in Phase III studies inhibition of cytokine production Six large international, multicenter, randomized, (e.g., interleukin-1 and -8, as well as tumor blinded studies involving more than necrosis factor-α and interferon-γ) and 6000 patients have shown Psoriasis Area Severity reduced levels of nitric oxide, prostaglandins Index (PASI) reductions of approximately and leukotrienes [31,32]. 40 and 70% after 1 and 4 weeks, respectively, of calcipotriol plus betamethasone dipropionate Chemistry therapy [37–42]. Baseline disease severity did not Calcipotriol/betamethasone dipropionate affect the percentage reduction in PASI, (Daivobet® or Dovobet®) is a stable (for although fewer people with a baseline PASI of 2 years at room temperature), fixed-combina- more than 17were clear or almost clear at the tion ointment containing the vitamin D3 ana- end of treatment [43]. Approximately 50% were log, calcipotriol hydrate 50 µg/g, combined clear or almost clear after 4 weeks of once-daily with the Class III steroid, betamethasone therapy [40,41]. In all of these studies, patient dipropionate 0.5 mg/g. The vehicle contains demographics were similar: polyoxypropylene-15-stearyl ether [33]. • Mean age: approximately 48 years • Mean duration of psoriasis: approximately Pharmacodynamics 19 years In a vasoconstrictor assay using both an objective • Mean baseline PASI: approximately 10 chromametric measurement of skin blanching and visual evaluation, calcipotriol/betametha- • Gender: approximately 60% males sone dipropionate and diprosone had equiva- Since the head was not treated or assessed, the lent biological activity [34]. A sonographic maximum possible PASI score was 64.8 rather study of skin thickness showed almost identi- than the standard 72. The PASI in the study was cal skin atrophy after treatment with calcipot- calculated as follows: riol/betamethasone dipropionate or 0.2(redness + thickness + scaling scores for betamethasone dipropionate, with skin thick- arms) × area for arms + 0.3(redness + ness returning to normal shortly after a 4-week thickness + scaling scores for trunk) × area for treatment course [35]. trunk + 0.4(redness + thickness + scaling scores for legs) × area for legs Pharmacokinetics Pharmacokinetic studies have shown that the Area, thickness and scaling were rated on a 0- to new vehicle and presence of the other active 4-point scale and area on a 0- to 6-point scale. component do not affect the absorption of A total of 1043 patients were randomized in a either of the two active components [33,36]. Sys- 3:3:3:1 ratio to 4 weeks of twice-daily calcipotriol temic absorption of calcipotriol from plus betamethasone dipropionate, betamethasone Daivonex® and calcipotriol/betamethasone dipropionate in the new vehicle, calcipotriol in dipropionate was minimal as was the absorption the new vehicle, or vehicle alone [37]. Mean per- of betamethasone dipropionate from calcipotriol/ centage decreases in PASI at 1 week were 48.1, betamethasone dipropionate. 41.4, 28.4 and 21.5, respectively (p < 0.001 for the combination product versus each of the oth- Clinical efficacy ers). After 4 weeks of therapy, the mean percent- Phase II study age decreases in PASI were 73.2, 63.1, 48.8 and In a study involving 25 patients, greater 28.8%, respectively (p < 0.001). reduction in inflammation and restoration of In a second study, 1106 patients were rand- normal differentiation were noted with cal- omized in a 1:1:1 ratio to 4 weeks of twice-daily cipotriol plus betamethasone dipropionate combination, betamethasone dipropionate or cal- than with the individual components or vehi- cipotriol ointment [38]. After 1 week, the mean per- cle alone [25]. The percentage of vimentin-pos- centage reductions in PASI were 47.4, 39.8 and itive cells (inflammatory cells) were 1.6% in 31.0%, respectively (p < 0.001). After 4 weeks, the 344 Therapy (2005) 2(3) Calcipotriol/betamethasone dipropionate – DRUG PROFILE mean PASI reductions were 74.4, 61.3 and 55.3%, with the combination product, maximal respectively (p < 0.001) and the percentage of improvement was noted after 5 weeks of ther- patients with at least 75% improvement was 68.0, apy and maintained for the following 3 weeks. 46.6 and 38.9%, respectively (p < 0.001). After the After the 8 weeks of treatment, those in the first 4-week double-blind period, there was a 4-week group (i.e., those who had received 8 weeks of open-label period in which patients were treated once-daily combination therapy) were switched with calcipotriol ointment. At the end of the open- to 4 weeks of once-daily calcipotriol therapy; label period, the PASI in the combination group those on intermittent combination/calcipotriol rose from 2.5 to 3.6; the PASI in the betametha- were maintained on the same therapy, and sone dipropionate group from 3.9 to 4.1, and in those on twice-daily calcipotriol were main- the calcipotriol group it decreased from 4.4 to 3.7. tained on this regimen. At 12 weeks, there was In a third study, 1603 patients were rand- no significant difference in PASI reduction omized in a 3:3:3:1 ratio to once-daily treatment between the three groups.