Etretinate A Review of its Pharmacological Properties and Therapeutic Efficacy in Psoriasis and Other Skin Disorders

Publisher Website
Google Scholar
Abstract
Synopsis: Etretinate1 (Ro 10-9359) is a new aromatic retinoic acid derivative for the treatment of severe psoriasis and other dyskeratoses. The pharmacological profile of etretinate suggests that it acts by normalising pathological changes in epidermal and dermal skin, particularly inhibiting hyperkeratinisation and cell differentiation, although its specific mode of action in different disorders remains to be elucidated. Etretinate is rapidly and presystemically metabolised to an active metabolite which appears in plasma at about the same time as parent drug. A ‘deep’ storage compartment with a very extended elimination half-life gives rise to detectable plasma levels of drug for at least 3 to 4 months after discontinuation of long term therapy. Studies suggest that etretinate at an initial dose of 1 mg/kg/day, reducible during maintenance therapy, is an effective alternative to PUVA and other conventional therapy in severe psoriasis. Its greatest immediate value is in the control of eruptive and treatment-resistant psoriasis, and in its potential for use in combination with other therapy to improve the response. In Darier’s disease it appears to be the treatment of choice, and preliminary studies also suggest its usefulness in ichthyosis, and most other dyskeratoses and possibly in basal cell carcinoma. Side effects affecting the mucocutaneous system occur in nearly all patients, but rarely lead to drug withdrawal. When withdrawal does become necessary, the primary reason is usually hair loss. A few paradoxical observations of raised and lowered liver enzyme levels have been reported, and also a few cases of suspected liver damage. Etretinate is strictly contraindicated in women of child-bearing potential due to its severe teratogenic properties. Pharmacodynamic Studies: The lack of suitable animal models has restricted the pharmacodynamic study of etretinate in many areas. In vitro studies, mainly in rodent tissue, show inhibition of chemically induced increased mitosis, and inhibition of keratinisation and differentiation in epidermal tissues. In vivo studies in rodents show marked inhibition of chemically and virally induced tumourigenesis, and regression of established and transplanted tumours. Similar effects are seen in a variety of human tumour cell lines. In human psoriatic skin, etretinate produces enhanced or decreased epidermal inflammatory activity, depending on the type of psoriasis, increased keratohyalin synthesis and the reappearance of the stratum corneum layer. Some investigators report accumulation of a ‘mucus-like’ material in the stratum corneum, although others merely report a non-mucin staining amorphous substance. Etretinate inhibits ornithine decarboxylase, and reduces raised epidermal polyamine levels. Normalisation of pathological changes in the dermis also occurs. Immunostimulation of cell-mediated cytotoxicity and T-killer cells, suppression of mitogenic response in lymphocytes, and inhibition of polymorphonuclear leucocyte function also occur. Hepatic enzyme levels may be raised or lowered, unaccountably, in different individuals during etretinate therapy, although no conclusive overall trends occur. Bilirubin tends to be raised, as do abnormally low pretreatment serum zinc levels in patients with psoriasis. Significantly increased triglyceride and cholesterol levels occur during therapy, although effects on high density lipoprotein cholesterol are not clear. Severe teratogenicity in rats, mice and rabbits occurs with low doses (2 to 4 mg/kg/day) administered early in pregnancy. Late exposure to etretinate also increases fetal abnormalities and mortality. Pharmacokinetic Studies: Peak plasma concentrations of etretinate, following single oral administration, occur after 2.5 to 6 hours and vary widely (< 500 to 1030 ng/ml) in healthy subjects, being slightly lower in patients with psoriasis. Steady-state concentrations are between 100 and 500 ng/ml, with levels of 20 to 50 ng/ml still detectable 140 days after discontinuation of long term administration. Bioavailability after oral dosing is about 40%. Multiple-dose studies show a 3-compartment model best represents the pharmacokinetic behaviour of etretinate with a ‘deep’ storage compartment and a half-life of 80–100 days in healthy subjects treated for up to 1 year. Autoradiography studies in rats show that the liver is the major site of uptake, accounting for 16% of a dose after 6 hours. There is no significant accumulation of etretinate or the active primary metabolite (Ro 10-1670) in the skin. Both the parent drug and Ro 10-1670 are bound primarily to albumin in plasma, at several binding sites on the protein molecule. Affinity for retinol binding protein is similar, but as it is present in much lower concentrations in plasma, albumin remains the principal carrier. There is also extensive binding to serum lipoproteins, and the total bound fraction is more than 98%. The volumes of distribution after single oral doses in patients with psoriasis were 150L and 210L for etretinate and Ro 10-1670, respectively. There is rapid presystemic hydrolysis of etretinate to the active metabolite, Ro 10-1670, the only important metabolite found in plasma. However, further systemic metabolism produces another 16 inactive metabolites (representing 12% of total oral dose), all of which are excreted renally. Faecal excretion, including unabsorbed or unaltered etretinate, accounts for 75% of a dose. Therapeutic Trials: Clinical trials with etretinate have been mostly open studies, using subjective assessments. Due to almost ubiquitous side effects, usual ‘double-blind’ techniques are of limited value. Except in psoriasis, comparative or combination therapy studies have not been undertaken. Early studies revealed etretinate to have an unsuitable therapeutic ratio for use in milder forms of psoriasis, but at a dosage of 1 mg/kg/day initially, reduced after 2 to 4 weeks, impressive improvements in severe disease have been reported with acceptable levels of toxicity in most patients. The extent of lesions, erythema, scaling and dermal infiltration are all reduced with etretinate therapy. Particularly good results occur in palmoplantar, pustular, erythrodermic and other eruptive psoriasis variants, and in patients unresponsive to other therapy, with ‘good to excellent’ results at 3 months in about 60 to 70% of such patients. Despite long term maintenance therapy, relapse occurs in some patients, with high rates having been recorded in some studies. Results in psoriatic arthropathy are inconclusive, but the majority of reports find beneficial effects on lesions and joint involvement. Combined therapy with PUVA does not increase clinical efficacy of PUVA in patients who respond to phototherapy but lowers the necessary irradiation dose and duration, and is successful in most patients who failed to respond to etretinate or PUVA alone. The incidence of relapse is decreased by combined therapy. Similar findings occur with etretinate and UV-B or corticosteroid therapies although more controlled studies in well defined patient populations are required to more clearly elucidate any advantages of combining etretinate with these treatments. In ichthyosis, impressive rates of remission up to 100% have been achieved with etretinate (1 mg/kg/day initially and decreased maintenance doses) in lamellar, erythrodermic and x-linked variants, although when assessing overall efficacy the small numbers of patients in these studies must be considered. Horny layer thickness, keratohyalin synthesis and desmosome-tonofilament complexes are all decreased, whilst cellular oedema and infiltration are increased. Relapses may occur during maintenance therapy. Less impressive results are seen in bullous forms of ichthyosis. In Darier’s disease, etretinate offers the first consistently successful pharmacological treatment. At doses of 0.5 to 1.0 mg/kg/day, improvement is rapid, with lesions showing diminution in the majority of patients (up to 94%). The disease may be successfully controlled by maintenance therapy, although high rates of relapse in patients previously resistant to treatment have occurred upon discontinuation of etretinate. Etretinate may act in an immunomodulatory capacity in this disease, resulting in improvements in acanthosis, dyskeratosis and hyperkeratosis. A variety of other disorders of hyperkeratinisation have on occasion been treated successfully, including pityriasis rubra pilaris and some types of porokeratosis. Etretinate also produces dramatic improvements in about 90% of buccal or atrophic lesions in lichen planus, and to a lesser extent in non-erosive oral and cutaneous lesions. Relapse may occur after discontinuation of etretinate, although the reported frequency varies considerably. In leucoplakias, a recognised precancerous condition, etretinate produces a good to excellent remission in about 75% of instances and a follow-up study of 48 patients showed that 50% remained in partial or complete remission at 2 years. Comparisons with 13-cis-retinoic acid and all-trans-retinoic acid reveal trends towards better therapeutic response and improved tolerability with etretinate. A moderate degree of success has been recorded in the treatment of other premalignant and malignant diseases, such as epidermodysplasia verruciformis and mycosis fungoides, and there is some evidence of clinical efficacy in about 50% of patients with basal cell carcinomas. Etretinate does not significantly improve nodulocystic acne, and is less effective in this condition than isotretinoin (13-cis-retinoic acid). Side Effects: The incidence of side effects during treatment with etretinate is relatively high, involving mainly the mucocutaneous system. Cheilitis occurs in about 80% of patients, dry oral and nasal mucous membranes and skin desquamation in about 35% each and thinning of skin in 25% of patients. However, these side effects rarely necessitate discontinuation of therapy. Hair loss occurs with an incidence of 22% and is the major reason for drug withdrawal during therapy. Other side effects occur less frequently, mainly affecting the integumentary system. The side effects reminiscent of hypervitaminosis A syndrome are initially dose-related, but appear to diminish gradually with long term therapy. Hair loss is an exception to this, being related to both dose and duration of therapy. Hepatitis has been reported rarely, as has liver necrosis, although liver enzyme studies do not reveal any clear pathological effects attributable to etretinate. It remains to be seen if combined etretinate-PUVA therapy results in lowered UV-A toxicity or in any unique effects during long term trials. Dosage and Administration: Initial dosage, in all age groups, is 0.75 to 1 mg/kg/day for 2 to 4 weeks, with a maximum of 75 mg/day. Thereafter the dose is individually adjusted according to response and toxicity, being reduced to the lowest effective dose. Etretinate is contraindicated in women of child-bearing potential, and pregnancy must be avoided for at least 1 year after its discontinuation. It is also contraindicated in hepatic and renal disease.