Topical Retinoids

Structure

The structures of several of the retinoids discussed in this chapter are shown in Fig. 46.1 . Q46.1 Note that tretinoin represents an oxidized form of all- trans retinol. It is endogenously synthesized in the skin from all- trans retinol after delivery of this compound to basal keratinocytes via the bloodstream. Alitretinoin (9- cis retinoic acid) is also a naturally occurring endogenous retinoid. Because all- trans retinoic acid (tretinoin), all- trans retinol, and alitretinoin are naturally occurring retinoids, the human body has the binding proteins and enzymatic machinery in place to properly metabolize these retinoids. In comparison, significant structural differences are evident for adapalene, tazarotene, and bexarotene, which are not naturally occurring retinoids, making metabolic pathways more challenging to predict. The structure of the different retinoids is important because it determines how they are transported in the bloodstream and within cells. Affinity to binding proteins, both cytoplasmic and nuclear, is critical for retinoid effects on gene transcription and resultant biologic activity.

Mechanism of Action

Q46.2 The topical retinoid drug mechanisms ( Table 46.2 ) and additional important pharmacologic concepts are summarized in Table 46.3 . This allows easy comparison between the natural and synthetic topical retinoids discussed in this chapter. The following paragraphs concerning each specific drug discuss further details concerning: (1) serum and cellular binding proteins; (2) nuclear receptors/transcription factors; (3) other details of each drug’s mechanism, including gene regulation; and (4) absorption, metabolism, and excretion.

Teratogenicity

Many tissues require vitamin A for normal growth and differentiation. Q46.3 Excessive quantities adversely affect the developing embryo and fetus of a number of animal species. Thus, although topical absorption of retinoids is generally slight, there is a potential concern for systemic effects when large surface areas are treated. For example, patients with psoriasis potentially have large surface areas involved with disruption of the epidermal barrier; therefore, the rate of retinoid absorption is likely to be significantly increased. A pregnancy test is recommended before the use of tazarotene and bexarotene in women of childbearing potential, and appropriate birth control measures should be in place for the duration of treatment. Although there are studies that demonstrated the safety of tretinoin, all topical retinoids should be avoided during pregnancy.

All- Trans Retinol and All- Trans Retinoic Acid

Q46.4 The pathway of metabolism for all- trans retinol and all- trans retinoic acid is illustrated in a summary manner in Fig. 46.2 . All- trans retinol is the natural alcohol form of vitamin A. It is transported in the bloodstream from storage in the liver to peripheral target tissues bound to the serum transport protein, retinol-binding protein (RBP) ( Table 46.4 ). All- trans retinol then traverses the interstitial spaces in the papillary dermis and is taken up by basal keratinocytes. As these cells divide and move up through the epidermis, vitamin A is distributed across the epidermis. When all- trans retinol is topically applied to the skin, this drug is taken up by the keratinocytes in the outer epidermis and diffuses through the skin as a fat-soluble drug. Within keratinocytes, excess all- trans retinol is esterified to long-chain fatty acids to form retinyl esters, which form lipid droplets; this is similar to how vitamin A is stored in the liver.

There are two different enzyme systems in keratinocytes that direct esterification and hydrolysis of retinyl esters: acyl CoA:retinol acyltransferase (ARAT), which is more important for topically applied retinol; and lecithin:retinol acyltransferase (LRAT), which is dominant for endogenously supplied all- trans retinol. When all- trans retinol exists free within the cell, it binds to the cellular RBP (CRBP). All- trans retinol is oxidized to form all- trans retinoic acid when needed by the cell. All- trans retinoic acid formed by this mechanism binds to cytosolic all- trans retinoic acid-binding protein (CRABP). CRABP-II is predominant in human skin and may be the determining factor in the bioavailability of retinoids.

Q46.5 From this pool, all- trans retinoic acid is transported to the nucleus by CRABP type II, where it binds to nuclear retinoic acid receptor (RAR) and fatty acid-binding protein 5 (FABP5) and serves as a ligand for peroxisome proliferator-activated receptor β/δ (PPARβ/δ). All- trans retinoic acid induces genes that are involved in cell proliferation and antiapoptosis by providing a ligand for the PPARβ/δ. Each of the drug–RAR complexes subsequently binds to retinoic acid response elements (RARE), which are enhancing elements for gene transcription ( Table 46.5 ) that lead to inhibition of cell growth. All- trans retinoic acid isomerizes to form 9- cis retinoic acid, which binds to retinoid X receptor (RXR). RAR and RXR bind together as heterodimers to function as transcription factors. Further details on the resultant gene transcription are beyond the scope of this chapter.

A number of all- trans retinoic acid-responsive genes have been identified, including (1) type I epidermal transglutaminase, (2) CRBP, (3) CRABP, (4) RAR and (5) PPARβ/δ. All- trans retinoic acid has also been shown to reduce the release of certain inflammatory mediators, including interleukin (IL)-1β, IL-6, IL-12, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ. One of the most pronounced effects of either all- trans retinol or all- trans retinoic acid treatment of the skin is on epidermal hyperplasia. For thin or atrophic photoaged epidermis, the effect of topical retinoids is to cause epidermal thickening or hyperplasia with increased procollagen I and III protein expression through the upregulation of genes for COL1A1 and COL3A1.

In hypertrophic skin, such as that found in actinic keratoses (AK) or psoriasis, the net effect is normalization of the epidermal thickness.

Adapalene

Adapalene is available as a 0.1% gel, cream, and solution and 0.3% gel for the treatment of acne. Although adapalene is similar to all- trans retinoic acid in its effects on acne, it is more stable chemically, less photolabile, and more lipophilic, which enables it to penetrate follicles quickly. It has a selective affinity for retinoid receptors, including RAR-β, and RAR-γ also acts indirectly on cellular function through the anti-activating protein-1 (AP-1) mechanism. It does not bind to cytosolic receptor protein, and therefore has no affinity for CRABP, but induces CRABP-II messenger ribonucleic acid (mRNA) when applied under occlusion for 4 days to human skin. Adapalene inhibits chemotaxis of polymorphonuclear leukocytes and release of free oxygen radicals from neutrophils. It also inhibits the lipo-oxygenase pathway and arachidonic acid metabolism, leading to decreased leukotriene and prostaglandin production. When adapalene is applied to skin, a comedolytic reaction is seen using the Rhino mouse in vivo model. Fluorescence microscopy shows that adapalene microcrystals penetrate follicular openings to the level of the sebaceous gland within 5 minutes after topical application. The selective uptake by follicles is thought to be attributed to its lipophilicity and may contribute to adapalene’s success in the treatment of acne. It is theorized that, after follicular penetration, the lipophilicity of adapalene will result in dissolution within sebum, thus preventing appreciable systemic exposure. Recently, newer possible anti-inflammatory mechanisms for adapalene that could contribute to its efficacy have been defined (see Table 46.2 ). These include the decreased expression of Toll-like receptor-2 (TLR-2) and decreased secretion of IL-10 cytokine along with increased expression of CD1d. There are also in vitro antiproliferative and proapoptotic effects of adapalene on certain cancer cell lines.

Pharmacokinetic studies have demonstrated that only trace amounts of adapalene are systemically absorbed and are excreted through the hepatobiliary route. There have been no reported carcinogenic, mutagenic, or genotoxic effects of topical adapalene in either in vivo or in vitro studies. There have also been no significant teratogenic effects of topical adapalene at its maximal optimal recommended human dose and it has a relatively low risk while breastfeeding as a result of low blood levels (<0.25 μg/L).

Minimal adverse effects (AE) have been observed in rats at 24 times the maximal human recommended dose. However, it is still recommended that adapalene be discontinued during pregnancy, as there are no controlled studies in pregnant women.

There are no clinical studies showing that adapalene may be photosensitizing. It has also been shown that adapalene gel 0.1% is much more photostable than tretinoin 0.0025% gel. However, it is still recommended that patients exercise caution with respect to ultraviolet (UV) light exposure, based on recommendations from the use of other topical retinoids. Adapalene 0.1% gel is also now available over the counter. The most common AE of adapalene include erythema, scaling, dryness, pruritus, and a persistent burning and stinging sensation. A 2013 split-face study found adjunctive use of a noncomedogenic moisturizer helped improve tolerance of adapalene 0.1% gel. Adapalene 0.3% has shown comparable efficacy to tretinoin 0.05% cream.

Tazarotene

Q46.6 Tazarotene is a prodrug that is rapidly hydrolyzed in tissues to the active metabolite termed tazarotenic acid. Tazarotenic acid has a high affinity to the RAR-γ nuclear receptor that is the predominant receptor present in the epidermis. Tazarotenic acid also binds to RAR-α and RAR-β (see Table 46.5 ), but not to RXR. By binding to the various RARs, tazarotenic acid modulates the expression of retinoid-responsive genes, including those that regulate cell proliferation, cell differentiation, and inflammation. Modulation of these genes occurs in psoriasis, a disease characterized by increased epidermal proliferation and inflammation. Tazarotene downregulates the abnormal expression of keratinocyte transglutaminase I (Tgase I), epidermal growth factor receptor, involucrin, skin-derived antileukoproteinase (SKALP), small praline-rich protein 2 expression, and hyperproliferative keratins K6 and K16. Migration inhibitory factor-related protein (MRP-8), a marker of inflammation, is reduced by tazarotene treatment along with antagonization of AP-1. Decreased inflammation and proliferation with tazarotene is observed in psoriasis from the downregulation of AP-1. Tazarotene also induces tazarotene-inducible gene (TIG-1, TIG-2, and TIG-3) in patients with psoriasis. Although the role of these genes and proteins in psoriasis pathophysiology remains to be determined, the expression of TIG-1, TIG-2, and TIG-3 is very low in psoriatic lesions compared with normal uninvolved skin. Similar observations have been reported with low TIG-2 and TIG-3 expression in cutaneous squamous cell carcinoma and other malignancies such as gastrointestinal malignancy. The increased expression of TIG-2 and TIG-3 can reduce keratinocyte proliferation and proliferation of atypical keratinocytes, while increasing epidermal thickness on histological studies.

Tazarotene gel produces high cutaneous concentrations, but the systemic absorption of the prodrug is practically nonexistent because of its rapid skin metabolism to tazarotenic acid. Total systemic absorption is up to 5% of the drug applied in normal skin and 15% of the amount applied in psoriatic skin. The maximal concentration of tazarotenic acid in the blood occurs 9 hours after tazarotene application. The half-life of tazarotene is less than 20 minutes. Small amounts of tazarotene, which are absorbed systemically and not degraded, are excreted in both the urine and feces. The degradation of tazarotenic acid is via oxidation to inactive sulfoxide and sulfone derivatives that are excreted in the urine. The terminal half-life of tazarotenic acid is approximately 18 hours.

Tazarotene was determined to be nonmutagenic and had no chromosomal effects in a series of in vitro mutagenicity tests. No carcinogenicity was found with topical administration; however, in the hairless mouse model, tazarotene was found to produce increased photocarcinogenicity associated with UV radiation (UVR). Oral administration of tazarotene at high doses was found to be teratogenic in rats and rabbits. However, no teratogenicity was seen in either species with topical application at high doses (limited only by topical irritation).

AE observed are those typical for topical retinoids and are discussed later in the chapter and in Table 46.6 . They include erythema, pruritus, and a burning sensation. The product carries a pregnancy category X warning, indicating that tazarotene therapy should be completely avoided during pregnancy. Chronic administration of topically applied tazarotene in animal and human studies was otherwise found to be safe from a systemic standpoint. This safety record includes no clinically significant systemic, ophthalmologic, hematologic, or clinical chemistry abnormalities. It is recommended that tazarotene usage should be limited during nursing to less than 20% body surface area involvement.

Bexarotene

Bexarotene is a synthetic retinoid that binds selectively to the RXR ligand. Many authors use the term ‘rexinoid’ (given the RXR binding) to categorize bexarotene; however, for consistency, the term ‘retinoid’ will be used for all drugs in this chapter. Topical bexarotene is available as a 1% gel formulation. Bexarotene binds to and activates RXR nuclear receptors, resulting in the inhibition of the cell cycle, leading to decreased proliferation and increased apoptosis. Bexarotene downregulates cellular differentiation by the decreased expression of cyclin D and inhibition of the G1, G2, and M phases of the cell cycle. RXR also form heterodimers with nonretinoid nuclear receptors, including vitamin D and thyroid hormone receptors, PPAR, and other orphan receptors. The mechanism of action with respect to PPAR has been postulated to be by the reduction of inflammatory cytokines through the nuclear factor of activated T cells (NFAT) and nuclear factor κ B (NFκB) nuclear transcription factor pathways by directly reducing multidrug resistance-1 (MDR1) mRNA and P-glycoprotein (P-gp) expression. Bexarotene has also been shown to have an inhibitory effect on angiogenesis through PPARγ and reduction of matrix metalloproteinase (MMP), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF). It also increases tissue inhibitors of matrix metalloproteinases (TIMP), which could help in the prevention of metastasis of certain tumors. Thus, bexarotene has substantial potential clinical utility for its antitumor effects.

Pharmacokinetic studies have shown that plasma concentrations of topical bexarotene are generally low. In clinical trials, patient plasma concentrations ranged from 5 to 55 ng/mL, with 93% of samples less than 5 ng/mL. Increases in plasma concentration of bexarotene are directly related to the percentage of body surface area treated. Plasma concentrations of bexarotene are extremely low compared with the concentration associated with mutagenicity in animal studies.

Oral bexarotene is highly bound to plasma proteins (>99%) and metabolized through the cytochrome P-450 (CYP) 3A4 enzyme pathway. Similar studies and results are not available for topical bexarotene. Hence, it is difficult to draw any conclusions regarding drug–drug interactions and the impact on pharmacokinetics of topical bexarotene with respect to renal or hepatic insufficiency.

However, patients using bexarotene therapy should not use products containing N , N -diethyl- m -toluamide (DEET) because of an increased potential for DEET toxicity. There are also no studies to indicate that topical bexarotene results in central hypothyroidism from decreased thyrotropin levels as reported with oral bexarotene. Clinical studies have also failed to confirm in vitro studies that bexarotene gel may be photosensitizing. However, it is still recommended that patients exercise caution with respect to UV light exposure.

Many of the labeled ‘Precautions’ and ‘Contraindications’ (such as pregnancy) were derived from studies of oral bexarotene. Because of the teratogenic potential of retinoids, bexarotene gel is considered a pregnancy category X drug.

Topical bexarotene 1% gel is effective for the treatment of the early stages of CTCL. It is currently US Food and Drug Administration (FDA)-approved for early-stage (IA and IB) persistent or refractory CTCL. The mechanism of action in both of these conditions is unclear. In vitro studies have shown that bexarotene may downregulate the antiapoptotic protein survivin, as well as upregulating caspase-3, and cleaving poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP), with the net effect being to promote apoptosis of CTCL cell lines.

Better efficacy has been demonstrated with an increased frequency of application to affected areas. It is recommended that application frequency is titrated as follows: once every other day for the first week, then increased at weekly intervals to once daily, then twice daily, then three times daily, and finally four times daily according to individual lesion tolerance. In clinical trials, most responses were seen in patients applying bexarotene 1% gel two to four times daily. Response to bexarotene gel in CTCL can occur as early as 4 weeks, with a median response by 20 weeks. In clinical trials, the overall response rate has varied between 44% and 54%. Topical bexarotene has also been reported to be effective in lymphomatoid papulosis, chronic severe hand dermatitis, psoriasis, and alopecia. The most common AE observed from topical bexarotene are application site reactions and include rash, pruritus, ‘nonspecific skin disorder,’ contact dermatitis, and pain. Application site reactions can generally be controlled by reducing the frequency of application or adding a topical corticosteroid (TCS). Less common AE are infection, headache, edema, and hyperlipidemia.

Alitretinoin (9- Cis Retinoic Acid)

Alitretinoin is a naturally occurring retinoid routinely present in the skin and circulation. It is available as a 0.1% gel for the treatment of acquired immunodeficiency syndrome (AIDS)-related Kaposi sarcoma (KS). Two hypotheses attempt to explain the reduction of growth of KS cell lines. First, retinoids may induce a downregulation of IL-6, a growth factor for KS cells. Second, retinoids may alter the expression of virally encoded oncogenes that are present and active in KS.

Q46.7 Alitretinoin effectively binds all retinoic acid receptors (RAR-α, -β, -γ) and all retinoid X receptors (RXR-α, -β, -γ). Alitretinoin has a slightly greater affinity for RAR than for RXR. Recall that binding of these receptors activates them to serve as transcription factors. In general, the RAR receptors are associated with inducing cellular differentiation, whereas the RXR receptors are associated with inducing apoptosis.

Systemic absorption of alitretinoin has been evaluated in clinical trials. Individuals who were applying alitretinoin had plasma levels of the drug similar to those in untreated individuals, suggesting that systemic absorption is minimal. In addition, there was no correlation between plasma levels of alitretinoin and the number of lesions being treated or the frequency of application. Despite these findings, alitretinoin is pregnancy risk category D. Alitretinoin is a known teratogen in rabbits and mice when administered at high concentrations.

Alitretinoin may cause local irritation at the application site. This may include erythema, edema, and vesiculation. It is otherwise well tolerated. As with any topical retinoid, the potential for photosensitivity exists and sun-protective measures should be encouraged. However, there were no reports of photosensitivity in the pivotal clinical studies of alitretinoin in AIDS-related KS, although it is not clear how often these KS lesions were in sun-exposed body sites. Care should be taken to avoid the topical application of DEET while using alitretinoin gel. Animal studies have shown an increase in DEET toxicity when used in combination with alitretinoin.

Indications

Q46.8 The indications for the topical retinoids are shown in Table 46.7 . The contraindications, AE, and drug interactions are summarized in Table 46.6 .