A Review of Prednicarbate (Dermatop®)

A. K. Gupta, MD, PhD, FRCPC^1,2 and M. Chow, HBSc<sup>2

1</sup>Division of Dermatology, Department of Medicine, Sunnybrook and Women’s College Health Science Centre (Sunnybrook site) and the University of Toronto, Toronto, Canada.
²Mediprobe Reseach Inc, London, Ontario, Canada.

ABSTRACT
Prednicarbate is a nonhalogenated corticosteroid that is used in the treatment of inflammatory skin diseases, for example atopic dermatitis. It has a favorable benefit-risk ratio, with an inflammatory action similar to that of a medium potency corticosteroid, but with a low potential to cause skin atrophy. Thus, prednicarbate may be a consideration in the treatment of atopic dermatitis in children, and other inflammatory disorders in children and adults.

Key Words: prednicarbate, corticosteroid, atopic dermatitis, inflammatory skin disease

Prednicarbate is a nonhalogenated, double-ester derivative of prednisolone. Modification to the prednisolone molecule has resulted in a molecule that causes the suppression of inflammation, but maintains low skin atrophy potential.^1,2

Mechanism of Action

The anti-inflammation action of corticosteroids is associated with the inhibition of the Il-1a cytokine within keratinocytes.^3,4 Il-1a is also found in fibroblasts, where it is responsible for proliferation, collagenase induction and Il-6 synthesis, which are related to skin thickness.⁴ Fibroblasts are important in wound healing and tissue repair.⁵ The primary mechanism of action of corticosteroids is the suppression of Il-1a, which subsequently inhibits the cytokine in both keratinocytes and fibroblasts. The inhibition of Il-1a in keratinocytes results in anti-inflammatory effects, while in fibroblasts there is an atrophogenic effect.

Prednicarbate has different effects on keratinocytes and fibroblasts. In keratinocytes, prednicarbate produces a high degree of suppression of IL-1a that is almost similar to that produced by betamethasone-17-valerate.^4,6,7 In contrast, prednicarbate has only a minor effect on IL-1a and IL-6 suppression in fibroblasts; this results in a low potential to cause atrophy.^4,6,7

Clinical Efficacy

Several German and Spanish studies have reported the effectiveness of prednicarbate in a variety of formulations at a strength of 0.25%, for the treatment of dermatitis.⁸

In two multicenter, randomized, double-blind, parallel group studies (see Table 1), Hanifin et al.⁹ compared prednicarbate 0.1% emollient cream with both the emollient cream vehicle and betamethasone valerate 0.1% cream in the treatment of patients with atopic dermatitis, where males were 12 years or older and females were 18 years or older. Treatments were applied twice daily for 21 days. Prednicarbate had significantly greater efficacy than the vehicle emollient, with greater improvement ratings of total key signs/symptoms at all return visits; significant improvement was recorded as early as day 8 (P≤0.05). Prednicarbate demonstrated at least equivalent or numerically higher clearing and mean percent improvements of signs and symptoms at return visits compared to betamethasone valerate. Prednicarbate had an overall improvement of 76.4% compared to the vehicle emollient (29.7%) and demonstrated similar efficacy to betamethasone valerate.⁹

Adverse Events

Prednicarbate has been associated with few adverse events; these include burning sensation, pruritus, drying, scaling, cracking, and pain, as well as dizziness, paresthesia, urticaria, folliculitis and edema/rash.^2,9 In a study where prednicarbate was applied to children (4 months to 12 years) twice daily for 21 days no suppression of the hypothalamic-pituitary-adrenal (HPA) axis was observed.¹⁰ The low atrophogenic potential of prednicarbate has been supported in several studies.^1,4-7

Contact allergies to topical corticosteroids is also a concerning adverse event, particularly with long-term use. Corticosteroids have been ranked as the seventh most common allergen.¹¹ Sensitivity to corticosteroids can be difficult to diagnose because the anti-inflammatory action of the corticosteroid can camouflage the allergic reaction to the corticosteroid itself.¹² Corticosteroids may be classified into 4 groups (A-D) based on their allergenicity.^12,13 Prednicarbate (in Group D) is a prodrug corticosteroid.12 It rapidly de-esterfies at position C21 to prednisolone-17-ethylcarbonate, which eventually metabolizes to prednisolone.¹² The metabolites may exhibit allergenicity that is different from the parent molecule; furthermore, prednicarbate may cross-react with other corticosteroids.

In a study byHanifin, et al.⁹ evaluating prednicarbate emollient cream 0.1% versus vehicle, safety data were available for 211 patients. Adverse effects thought to be related to the study drug were reported in 12 patients (prednicarbate group: 4, vehicle group: 8). In the prednicarbate group, the adverse effects included pruritus, burning sensation of skin, rash, contact dermatitis, and edema. Skin atrophy was recorded in three and one patients in the prednicarbate and vehicle groups, respectively. The presence of atrophy in the vehicle group may be explained by preexisting atrophy that may have been the result of previous topical corticosteroid usage. Therefore, it is difficult to ascertain whether atrophy in a patient is the result of the current application of topical corticosteroid as opposed to previous topical corticosteroid use.

In the second Hanifin, et al.⁹ study comparing prednicarbate to betamethasone valerate, safety data are available for 200 patients. Adverse effects that were thought to be study drug related were seen in 7 and 5 patients in the prednicarbate and betamethasone valerate groups, respectively. The adverse effects in the prednicarbate group were burning sensation of the skin, rash, folliculitis, paresthesia and dizziness. None of the patients had skin atrophy.

Table 1: Summary of the efficacy of prednicarbate emollient cream 0.1% compared with vehicle and betamethasone valerate cream 0.1%.⁹

Indications

In Canada and the United States, prednicarbate (0.1% emollient cream and 0.1% ointment) has been approved for the treatment of inflammatory and pruritic manifestations of acute and chronic corticosteroid-responsive dermatoses.^14,15 It can be applied without occlusion twice daily for 2 weeks.^14,15 The emollient cream has been approved for the use in adults and children over 1 year old, and the ointment has approval in the US for use in individuals 10 years and older.^14,15 Prednicarbate should be used cautiously in children around the diaper area because the diaper and plastic pants may result in occlusion.

Conclusion

Prednicarbate has been demonstrated to be effective, with a high anti-inflammatory action and low potential for adverse events, particularly skin atrophy. This topical corticosteroid exhibits characteristics that may prove beneficial in the treatment of children and elderly patients, as well as adults who may require intermittent long-term treatment.

References

1. Kerscher MJ, Korting HC. Topical glucocorticoids of the non-fluorinated double-ester type: lack of atrophogenicity in normal skin as assessed by high-frequency ultrasound. Acta Derm Venereol (Stockh) 72(3):214-6 (1992).
2. Cornell RC, Cherill RJ, Abrams BB. Safety of prednicarbate emollient cream 0.1% and ointment 0.1%, nonhalogenated, midpotency topical steroid formulations. J Geriatr Dermatol 2:57-65 (1994).
3. Korting HC, Hulsebus E, Kerscher M, Greber R, Schafer-Korting M. Discrimination of the toxic potential of chemically differing topical glucocorticoids using a neutral red release assay with human keratinocytes and fibroblasts. Br J Dermatol 133(1):54-9 (1995 Jul).
4. Lange K, Kleuser B, Gysler A, et al. Cutaneous inflammation and proliferation in vitro differential effects and mode of action of topical glucocorticoids. Skin Pharmacol Appl Skin Physiol 13(2):93-103 (2000 Mar-Apr).
5. Hein R, Mauch C, Hatamochi A, Krieg T. Influence of corticosteroids on chemotactic response and collagen metabolism of human skin fibroblasts. Biochem Pharmacol 37(14):2723-9 (1988 Jul).
6. Lange K, Gysler A, Bader M, Kleuser B, Korting HC, Schafer-Korting M. Prednicarbate versus conventional topical glucocorticoids: pharmacodynamic characterization in vitro. Pharm Res 14(12):1744-9 (1997 Dec).
7. Gysler A, Kleuser B, Sippl W, et al. Skin penetration and metabolism of topical glucocorticoids in reconstructed epidermis and in excised human skin. Pharm Res 16(9):1386-91 (1999 Sep).
8. Spencer CM, Wagstaff AJ. Prednicarbate: A review of its pharmacological properties and therapeutic use in the treatment of dermatological disorders. BioDrugs 9:61-86 (1998).
9. Hanifin J, Abrams BB, Cherill RJ. Management of atopic dermatitis with prednicarbate emollient cream 0.1%, a nonhalogenated prednisolone derivative. J Geriatr Dermatol 2(4):119-27 (1994).
10. Moshang T. Prednicarbate emollient cream 0.1% in pediatric patients with atopic dermatitis. Cutis 68(1):63-9 (2001 Jul).
11. Degreef H, Dooms-Goossens A. The new corticosteroids: Are they effective and safe? Dermatol Clin 11(1):155-60 (1993 Jan).
12. 12. Matura M, Goossens A. Contact allergy to corticosteroids. Allergy 55(8):698-704 (2000 Aug).
13. Coopman S, Degreef H, Dooms-Goosens A. Identification of cross-reaction patterns in allergic contact dermatitis from topical corticosteroids. Br J Dermatol 121(1):27-34 (1989 Jul).
14. Dermatop® E Emollient Cream (prednicarbate emollient cream) 0.1% and Dermatop® E Emollient Ointment (prednicarbate ointment) 0.1% U.S. package insert. Dermik Laboratories Berwyn, PA, USA; June 2002.
15. Dermatop® Ointment (prednicarbate ointment 0.1%) and Dermatop® Emollient Cream (prednicarbate emollient cream 0.1%) Canadian package insert. Dermik Laboratories Canada, Inc. Mississauga, ON, Canada; November 15 2000.