Prednicarbate : a review

Journal of Drugs in Dermatology, Sept-Oct, 2004 by Aditya K. Gupta, Melody Chow

Abstract

Prednicarbate is a non-halogenated, double-ester derivative of prednisolone that has become of interest for the treatment of inflammatory skin diseases, for example atopic dermatitis. In the past, topical steroids have been a popular choice for treating these diseases; however, the potential for significant local and systemic adverse events, such as skin atrophy and hypothalamic-pituitary-adrenal (HPA) axis suppression have limited their use. Prednicarbate has been found to have a favorable benefit-risk ratio, with low skin atrophy potential, and a high anti-inflammatory action. Prednicarbate may be particularly advantageous when used intermittently in pediatric and elderly patients.

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Introduction

As early as the 1950s, topical steroids were a therapeutic option in the treatment of various cutaneous disorders (1). These diseases were first treated with hydrocortisone, introduced by Sulzberger and Witten in 1952 (2), which has since been modified in several ways. The early corticosteroids were especially popular for short-term treatment use, due to a low local and systemic toxicity potential when applied without occlusion; however, long-term treatments resulted in several side effects, especially skin atrophy. Modifications to the hydrocortisone template molecule originally focused on improvement of skin penetration, slower enzyme degradation and a greater affinity of the cytosol receptors (3). Recently, the focus has shifted with the search for a molecule that still maintains a high degree of efficacy but has a low potential for adverse events. Prednicarbate is one of the newer molecules that was developed with this goal in mind.

In Europe, prednicarbate 0.25% has been marketed since the late 1980s, while prednicarbate emollient cream 0.1% (Dermatop[R]) subsequently became available in the United States for the treatment of pediatric patients. Prednicarbate is a non-halogenated, double-ester derivative of prednisolone. The esterfication of prednisolone has resulted in a compound, which is functionally effective but with low skin atrophy potential (4). Prednicarbate has a mid-potency level of inflammation suppression (5), and has been found to be effective in treating cutaneous disorders including atopic dermatitis and psoriasis.

Mechanism of Action

The effectiveness of the corticosteroid molecule against inflammation is associated with the formation of IL-1[alpha] within keratinocytes in response to inflammatory stimuli and an inhibition of this cytokine release by corticosteroids (6,7). In fibroblasts, IL-1[alpha] is responsible for proliferation, collagenase induction and IL-6 synthesis, all of which are related to skin thickness (7). The inhibition of IL-1[alpha] in fibroblasts is associated with an atrophogenic effect. Fibroblasts also have a chemotactic response to different mediators, and this is important in wound healing (8).

Prednicarbate has differing effects on keratinocytes and fibroblasts; it causes a high degree of suppression of IL-1[alpha] in keratinocytes, almost equivalent to betamethasone-17-valerate (7,9,10). Despite this degree of anti-inflammatory potency, prednicarbate acts in a non-classic manner with respect to fibroblasts. Prednicarbate has only minor effects on IL-1[alpha] and IL-6 suppression in fibroblasts, resulting in a low atrophogenic potential (7,9,10).

The question of whether it is the native tissue repair molecule (i.e., prednicarbate) or its metabolites that cause IL-1[alpha] suppression has been addressed (10). Prednicarbate is hydrolyzed and converted to prednisolone-17-ethylcarbonate (P17EC), which converts to prednisolone-21-ethylcarbonate (P21EC) and finally to prednisolone (10). Prednisolone-17-ethylcarbonate has been found to be almost as effective as betamethasone-17-valerate in its ability to suppress IL-1[alpha]. While prednicarbate causes the initial anti-inflammatory effect, prednisolone-17-ethylcarbonate, a potent anti-inflammatory compound, continues this action in the subsequent hours (9). Prednisolone-17-ethylcarbonate also demonstrates a high atrophogenic potential; however, it is present in low concentrations within fibroblast cells and therefore its effects are of a negligible extent (9). The effects on the fibroblasts may thus be attributed to the native prednicarbate, and not its metabolites (9). Prednicarbate has a relatively small effect on cytokines in the fibroblasts that are associated with atrophy.

Clinical Efficacy

Hanifin et al (11) performed two multi-center, randomized, double blind, parallel group studies, in patients with atopic dermatitis. In the first study prednicarbate 0.1% emollient cream (N=98 evaluable subjects) was compared to emollient cream vehicle (N= 86 evaluable subjects). In the second study, prednicarbate emollient cream 0.1% (N=89 evaluable subjects) was compared against betamethasone valerate 0.1% cream (N=92 evaluable subjects). The studies had identical methodologies, where efficacy and safety were determined in patients (males at least 12 years old, females at least 18 years old) with atopic dermatitis of at least one-year duration. Treatment was applied twice daily to an assigned area for 21 days, with evaluation of erythema, induration, pruritus, and a visual assessment of skin atrophy. Endpoint was defined as the last valid return visit for each patient. In the first study, significantly more patients were cleared of total key signs/symptoms at each return visit and the endpoint in the prednicarbate group compared to the vehicle group. The greatest improvements with prednicarbate occurred in the first week of therapy. In the prednicarbate treated group, at the endpoint, clearing in erythema occurred in 45.9% of subjects, induration in 46.9% and pruritus in 69.4%. The corresponding values for the vehicle-treated patients were 11.6%, 17.4%, and 19.8%, respectively (11). In the second study it was observed that prednicarbate cleared total key signs/symptoms at least as effectively as betamethasone valerate. At the endpoint, the clearing for prednicarbate and betamethasone valerate was; erythema (50.6% vs. 40.2%), induration (62.9% vs. 58.7%), and pruritus (71.9% vs. 69.6%) (11).