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Acitretin : A Review of its Pharmacology and Therapeutic Use.
Drugs. 1992 Apr; 43(4):597-627.D

Abstract

SYNOPSIS

Acitretin (etretin), a second generation monoaromatic retinoid for use in the treatment of severe psoriasis and other dermatoses, is the major active metabolite of etretinate and possesses a similar therapeutic index; i.e. a similar ratio of clinical efficacy to adverse effects. When used alone at a maintenance dosage of 30 to 50mg daily, acitretin is effective in the treatment of psoriasis, causing a reduction in the severity of scaling, erythema and induration. Efficacy appears to be further enhanced by combination with psoralen-ultraviolet A photochemotherapy (PUVA) or ultraviolet B irradiation (UVB). These combinations reduce the time to lesion clearance and reduce the total radiation dose, improving overall safety. Comparative studies have confirmed the equivalence of acitretin and etretinate with regard to efficacy and toxicity. Adverse reactions are dose-related and generally typical of hypervitaminosis A. Alopecia and mucocutaneous symptoms such as cheilitis and drying of the mucous membranes are particularly prevalent. Hypertriglyceridaemia and elevation of cholesterol levels also occur. Examination of the pharmacokinetic profile of acitretin reveals its main advantage over etretinate. Acitretin is less lipophilic than etretinate, and its lack of sequestration into 'deep' fatty storage sites is reflected in a comparatively short terminal elimination half-life of 50 to 60 hours, compared with 120 days for etretinate. Due to its teratogenic potential, acitretin is strictly contraindicated in women of childbearing potential unless effective contraceptive measures are employed. Etretinate has been identified in plasma samples of some patients treated with acitretin. Thus, acetretin has an established place in the treatment of keratinising disorders, although its use in women of child-bearing potential must be accompanied by effective contraceptive measures, with a further 2-year contraceptive period after therapy completion.

PHARMACODYNAMIC PROPERTIES

Investigation of the pharmacodynamic properties of acitretin has been restricted to some extent by the lack of a suitable experimental model. While in vitro results using normal human skin fibroblasts have been conflicting, acitretin generally modulates cell proliferation in cultures from hyperproliferative conditions such as psoriasis or neoplasia, and inhibits epidermal cell growth and differentiation. Acitretin also inhibits chemically induced hyperplasia, and causes regression or inhibits further growth and development of a number of established or transplantable carcinoma cell lines. The mechanism of action of acitretin in hyperproliferative disorders has yet to be fully elucidated; however, there appear to be a number of cellular effects. Target receptor site candidates include the cellular retinoic acid binding protein (CRABP), the epidermal growth factor (EGF) receptor, and retinoic acid nuclear receptors (RARs). Acitretin binds competitively to CRABP, a protein present in high concentrations in psoriatic plaques, and induces a marked elevation of CRABP levels in normal epidermis. However, 13-cis-acitretin does not bind to CRABP and acitretin may act via activation of RARs following conversion to a substance which binds to these receptors. In addition, the EGF receptor may be involved since acitretin has been found to influence its normal modulation of cell growth in both normal fibroblasts and squamous carcinoma cell lines. Cyclic adenosine monophosphate (cAMP)-dependent protein kinases and ornithine decarboxylase are probable mediators of the clinical response. In addition, acitretin demonstrates immunomodulatory and anti-inflammatory effects. It is hypothesised that the mechanisms entail inhibition of polymorphonuclear leucocyte accumulation in the stratum corneum, inhibition of lymphocytic blastogenesis by mitogens and stimulation of T cell-mediated cytotoxicity.

PHARMACOKINETIC STUDIES

Following oral administration of the drug to patients with psoriasis, peak plasma acitretin concentrations range from 98 to 526 µg/L and are reached approximately 1.9 hours after a single 40mg dose. Acitretin is widely distributed in the body and systemic bioavailability is approximately 60%. It is extensively bound to albumin and has a high affinity for CRABP. Less than 5% of acitretin is bound to lipoproteins and this is reflected in its comparative lack of sequestration into fatty 'deep' storage sites and its short terminal elimination half-life relative to etretinate. Multiple dose studies have indicated an elimination half-life of 50 to 60 hours, and neither acitretin nor its isomeric counterpart, 13-cis-acitretin, is detectable in plasma 3 to 4 weeks after cessation of long term therapy. Isomeric interconversion is prevalent following oral administration of acitretin: mean maximum plasma concentrations of the 13-cis-isomeric metabolite are lower and occur slightly later than with acitretin. Plasma trough concentrations of this metabolite following long term administration of acitretin are about 5 times higher than those of the parent drug and the terminal elimination half-life is about 15 times longer. Acitretin is excreted predominantly via the renal and hepatic routes, as glucuronides in bile or as products with shortened side chains in urine. In blood, 13-cis-acitretin and 3 other metabolites have been identified. Liquid chromatography/mass spectroscopy has identified etretinate in plasma samples of some patients treated with acitretin. The results obtained so far are of concern with regard to a potential teratogenic effect in female patients. Therefore, an increase in the post therapy contraception period to 2 years instead of the 2 months previously advocated is appropriate until clarification of these recent results have been obtained.

THERAPEUTIC EFFICACY

Trials with an initial double-blind phase and a subsequent noncomparative phase of up to 6 months duration have demonstrated the efficacy of orally administered acitretin (generally 25 to 75 mg/day) in the treatment of severe psoriasis. Variants of psoriasis vulgaris are notably susceptible to treatment and acitretin also appears to be effective against severe forms of pustular and erythrodermic psoriasis. Preliminary studies in small patient populations and a number of individual case reports suggest that acitretin, 30 to 50 mg/day, is beneficial in a variety of other cutaneous disorders including Darier's disease, lupus erythematosus and severe recessive x-linked ichthyosis. The rarity of these conditions prevents adequate extensive trials. Double-blinding in placebo-controlled trials is difficult to maintain due to the ubiquitous and distinctive nature of acitretin-induced adverse effects. However, double-blinding strategies have been used effectively in studies in which a dose-finding phase preceded a longer term noncomparative phase. Subjective assessments have revealed good to excellent (⩾ 50%) clearance of severe psoriasis in > 75% of patients: the severity of scaling, erythema and epidermal induration, and the percentage of body surface involvement, are reduced. Comparative studies in patients with psoriasis indicate that acitretin is comparable with etretinate in terms of therapeutic efficacy and adverse effects. When acitretin is combined with psoralen-ultraviolet A photochemotherapy (PUVA), clinical efficacy is improved, as evidenced by a higher complete remission rate and a reduced time to clearance of psoriasis. Total irradiation requirement is also reduced. Similar results are also achieved when acitretin is combined with ultraviolet B irradiation.

ADVERSE EFFECTS

Acitretin therapy has distinctive adverse effects generally typical of hypervitaminosis A. While the incidence of mucocutaneous clinical adverse effects is high, their severity does not usually necessitate withdrawal of therapy, and they are completely reversed on cessation of treatment. Adverse effects are usually dose-related, although alopecia is also dependent on the duration of therapy. Mucocutaneous reactions are most common - drying of mucous membranes of the eyes, nose and lips, and cheilitis occurs in nearly all patients. Other clinical symptoms include alopecia, desquamation of the skin, pruritus and 'sticky' skin. Changes in the lipid profile are often observed. Hypertriglyceridaemia occurs in 35% of patients treated with acitretin 50 mg/day, but increases in serum cholesterol are less frequently reported. Liver enzyme levels are also adversely affected, hepatitis has been reported and acitretin therapy may have an adverse effect on bone. As with etretinate, acitretin is a potent teratogen.

DOSAGE AND ADMINISTRATION

Initial acitretin dosage has usually ranged from 10 to 75 mg/day orally. After a few weeks, the dose should be individually adjusted to obtain optimum therapeutic response with tolerable adverse effects. Maintenance doses in such trials have ranged from 30 to 50 mg/day. Some authorities advocate low-dose therapy initially followed by a progressive dosage increase. Because of its potent teratogenicity and the detection of etretinate in patients treated with acitretin, the drug is contraindicated in women of childbearing potential unless effective contraceptive measures are adopted. It is essential that pregnancy be avoided for a full 2 years after therapy finishes, instead of the 2 months previously advocated.

Authors+Show Affiliations

Adis International Limited, Private Bag 65901, 41 Centorian Drive, Mairangi Bay, Auckland 10, New Zealand.Adis International Limited, Private Bag 65901, 41 Centorian Drive, Mairangi Bay, Auckland 10, New Zealand.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28421560

Citation

Pilkington, Tania, and Rex N. Brogden. "Acitretin : a Review of Its Pharmacology and Therapeutic Use." Drugs, vol. 43, no. 4, 1992, pp. 597-627.
Pilkington T, Brogden RN. Acitretin : A Review of its Pharmacology and Therapeutic Use. Drugs. 1992;43(4):597-627.
Pilkington, T., & Brogden, R. N. (1992). Acitretin : A Review of its Pharmacology and Therapeutic Use. Drugs, 43(4), 597-627. https://doi.org/10.2165/00003495-199243040-00010
Pilkington T, Brogden RN. Acitretin : a Review of Its Pharmacology and Therapeutic Use. Drugs. 1992;43(4):597-627. PubMed PMID: 28421560.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Acitretin : A Review of its Pharmacology and Therapeutic Use. AU - Pilkington,Tania, AU - Brogden,Rex N, PY - 2017/4/20/entrez PY - 1992/4/1/pubmed PY - 1992/4/1/medline SP - 597 EP - 627 JF - Drugs JO - Drugs VL - 43 IS - 4 N2 - SYNOPSIS: Acitretin (etretin), a second generation monoaromatic retinoid for use in the treatment of severe psoriasis and other dermatoses, is the major active metabolite of etretinate and possesses a similar therapeutic index; i.e. a similar ratio of clinical efficacy to adverse effects. When used alone at a maintenance dosage of 30 to 50mg daily, acitretin is effective in the treatment of psoriasis, causing a reduction in the severity of scaling, erythema and induration. Efficacy appears to be further enhanced by combination with psoralen-ultraviolet A photochemotherapy (PUVA) or ultraviolet B irradiation (UVB). These combinations reduce the time to lesion clearance and reduce the total radiation dose, improving overall safety. Comparative studies have confirmed the equivalence of acitretin and etretinate with regard to efficacy and toxicity. Adverse reactions are dose-related and generally typical of hypervitaminosis A. Alopecia and mucocutaneous symptoms such as cheilitis and drying of the mucous membranes are particularly prevalent. Hypertriglyceridaemia and elevation of cholesterol levels also occur. Examination of the pharmacokinetic profile of acitretin reveals its main advantage over etretinate. Acitretin is less lipophilic than etretinate, and its lack of sequestration into 'deep' fatty storage sites is reflected in a comparatively short terminal elimination half-life of 50 to 60 hours, compared with 120 days for etretinate. Due to its teratogenic potential, acitretin is strictly contraindicated in women of childbearing potential unless effective contraceptive measures are employed. Etretinate has been identified in plasma samples of some patients treated with acitretin. Thus, acetretin has an established place in the treatment of keratinising disorders, although its use in women of child-bearing potential must be accompanied by effective contraceptive measures, with a further 2-year contraceptive period after therapy completion. PHARMACODYNAMIC PROPERTIES: Investigation of the pharmacodynamic properties of acitretin has been restricted to some extent by the lack of a suitable experimental model. While in vitro results using normal human skin fibroblasts have been conflicting, acitretin generally modulates cell proliferation in cultures from hyperproliferative conditions such as psoriasis or neoplasia, and inhibits epidermal cell growth and differentiation. Acitretin also inhibits chemically induced hyperplasia, and causes regression or inhibits further growth and development of a number of established or transplantable carcinoma cell lines. The mechanism of action of acitretin in hyperproliferative disorders has yet to be fully elucidated; however, there appear to be a number of cellular effects. Target receptor site candidates include the cellular retinoic acid binding protein (CRABP), the epidermal growth factor (EGF) receptor, and retinoic acid nuclear receptors (RARs). Acitretin binds competitively to CRABP, a protein present in high concentrations in psoriatic plaques, and induces a marked elevation of CRABP levels in normal epidermis. However, 13-cis-acitretin does not bind to CRABP and acitretin may act via activation of RARs following conversion to a substance which binds to these receptors. In addition, the EGF receptor may be involved since acitretin has been found to influence its normal modulation of cell growth in both normal fibroblasts and squamous carcinoma cell lines. Cyclic adenosine monophosphate (cAMP)-dependent protein kinases and ornithine decarboxylase are probable mediators of the clinical response. In addition, acitretin demonstrates immunomodulatory and anti-inflammatory effects. It is hypothesised that the mechanisms entail inhibition of polymorphonuclear leucocyte accumulation in the stratum corneum, inhibition of lymphocytic blastogenesis by mitogens and stimulation of T cell-mediated cytotoxicity. PHARMACOKINETIC STUDIES: Following oral administration of the drug to patients with psoriasis, peak plasma acitretin concentrations range from 98 to 526 µg/L and are reached approximately 1.9 hours after a single 40mg dose. Acitretin is widely distributed in the body and systemic bioavailability is approximately 60%. It is extensively bound to albumin and has a high affinity for CRABP. Less than 5% of acitretin is bound to lipoproteins and this is reflected in its comparative lack of sequestration into fatty 'deep' storage sites and its short terminal elimination half-life relative to etretinate. Multiple dose studies have indicated an elimination half-life of 50 to 60 hours, and neither acitretin nor its isomeric counterpart, 13-cis-acitretin, is detectable in plasma 3 to 4 weeks after cessation of long term therapy. Isomeric interconversion is prevalent following oral administration of acitretin: mean maximum plasma concentrations of the 13-cis-isomeric metabolite are lower and occur slightly later than with acitretin. Plasma trough concentrations of this metabolite following long term administration of acitretin are about 5 times higher than those of the parent drug and the terminal elimination half-life is about 15 times longer. Acitretin is excreted predominantly via the renal and hepatic routes, as glucuronides in bile or as products with shortened side chains in urine. In blood, 13-cis-acitretin and 3 other metabolites have been identified. Liquid chromatography/mass spectroscopy has identified etretinate in plasma samples of some patients treated with acitretin. The results obtained so far are of concern with regard to a potential teratogenic effect in female patients. Therefore, an increase in the post therapy contraception period to 2 years instead of the 2 months previously advocated is appropriate until clarification of these recent results have been obtained. THERAPEUTIC EFFICACY: Trials with an initial double-blind phase and a subsequent noncomparative phase of up to 6 months duration have demonstrated the efficacy of orally administered acitretin (generally 25 to 75 mg/day) in the treatment of severe psoriasis. Variants of psoriasis vulgaris are notably susceptible to treatment and acitretin also appears to be effective against severe forms of pustular and erythrodermic psoriasis. Preliminary studies in small patient populations and a number of individual case reports suggest that acitretin, 30 to 50 mg/day, is beneficial in a variety of other cutaneous disorders including Darier's disease, lupus erythematosus and severe recessive x-linked ichthyosis. The rarity of these conditions prevents adequate extensive trials. Double-blinding in placebo-controlled trials is difficult to maintain due to the ubiquitous and distinctive nature of acitretin-induced adverse effects. However, double-blinding strategies have been used effectively in studies in which a dose-finding phase preceded a longer term noncomparative phase. Subjective assessments have revealed good to excellent (⩾ 50%) clearance of severe psoriasis in > 75% of patients: the severity of scaling, erythema and epidermal induration, and the percentage of body surface involvement, are reduced. Comparative studies in patients with psoriasis indicate that acitretin is comparable with etretinate in terms of therapeutic efficacy and adverse effects. When acitretin is combined with psoralen-ultraviolet A photochemotherapy (PUVA), clinical efficacy is improved, as evidenced by a higher complete remission rate and a reduced time to clearance of psoriasis. Total irradiation requirement is also reduced. Similar results are also achieved when acitretin is combined with ultraviolet B irradiation. ADVERSE EFFECTS: Acitretin therapy has distinctive adverse effects generally typical of hypervitaminosis A. While the incidence of mucocutaneous clinical adverse effects is high, their severity does not usually necessitate withdrawal of therapy, and they are completely reversed on cessation of treatment. Adverse effects are usually dose-related, although alopecia is also dependent on the duration of therapy. Mucocutaneous reactions are most common - drying of mucous membranes of the eyes, nose and lips, and cheilitis occurs in nearly all patients. Other clinical symptoms include alopecia, desquamation of the skin, pruritus and 'sticky' skin. Changes in the lipid profile are often observed. Hypertriglyceridaemia occurs in 35% of patients treated with acitretin 50 mg/day, but increases in serum cholesterol are less frequently reported. Liver enzyme levels are also adversely affected, hepatitis has been reported and acitretin therapy may have an adverse effect on bone. As with etretinate, acitretin is a potent teratogen. DOSAGE AND ADMINISTRATION: Initial acitretin dosage has usually ranged from 10 to 75 mg/day orally. After a few weeks, the dose should be individually adjusted to obtain optimum therapeutic response with tolerable adverse effects. Maintenance doses in such trials have ranged from 30 to 50 mg/day. Some authorities advocate low-dose therapy initially followed by a progressive dosage increase. Because of its potent teratogenicity and the detection of etretinate in patients treated with acitretin, the drug is contraindicated in women of childbearing potential unless effective contraceptive measures are adopted. It is essential that pregnancy be avoided for a full 2 years after therapy finishes, instead of the 2 months previously advocated. SN - 1179-1950 UR - https://www.unboundmedicine.com/medline/citation/28421560/Acitretin_:_A_Review_of_its_Pharmacology_and_Therapeutic_Use_ L2 - https://dx.doi.org/10.2165/00003495-199243040-00010 DB - PRIME DP - Unbound Medicine ER -
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