Pharmacokinetics of tazarotene and acitretin in psoriasis.

INTRODUCTION: Psoriasis is a prevalent cutaneous condition with severe physical and psychological manifestations. Since the advent of biologics, clinical outcomes in psoriasis have improved. However, retinoids are useful in the correct clinical context. Tazarotene and acitretin are currently the only US Food and Drug Administration approved retinoids for treatment of psoriasis. Both topical tazarotene and oral acitretin act on retinoic acid receptors and retinoid-X-receptors, resulting in altered gene expression of inflammatory cytokines and inhibition of keratinocyte proliferation. Areas covered: This article provides an in-depth pharmacologic and clinical review on the use of tazarotene and acitretin in psoriasis. The PubMed database was searched using combinations of keywords: acitretin, bioavailability, dosing, efficacy, etretinate, interactions, mechanism, pharmacodynamics, pharmacokinetics, pharmacogenetics, psoriasis, safety, tazarotene, tolerability, and toxicity. Expert opinion: Tazarotene and acitretin are effective treatments for psoriasis. Benefits include lack of immunosuppression and success treating inflammatory psoriasis. When combined with other topical and systemic agents, both retinoids improve clinical efficacy while lowering the treatment threshold. However, topical adherence and bothersome side effects can limit retinoid use. Acitretin and tazarotene both improve outcomes through a unique mechanism that especially benefits subsets of patients, despite side effects and limitations.

Skin metabolism established with the use of MetaSite for selected retinoids employed in topical and systemic treatment of various skin disorders and found in cosmeceuticals.

PURPOSE: Besides being widely used in cosmetics, retinoids are potent therapeutic agents used topically and systemically as anti-acne agents. The aim of this study was to predict with the use of MetaSite the skin metabolism of selected retinoids employed in treatment of skin disorders and found in cosmeceuticals. The following compounds were studied: retinol, retinaldehyde, retinoic acid, retinyl acetate, retinyl palmitate, acitretin, etretinate, adapalene and bexarotene. METHODS: MetaSite, Molecular Discovery Ltd. is a computational model that enables prediction of cytochrome P450-dependant metabolism. This software indicates atoms in the molecule structure that are mostly vulnerable to metabolic changes and predicts the metabolite structures. RESULTS: MetaSite indicated that retinol and retinal metabolites were obtained through hydroxylation of the methyl group located in the position 3 of the aliphatic chain, whereas retinoic acid biotransformation would occur principally in the carbon atom situated in the position 4 in the cyclohexene ring. In acitretin molecule, carbon atom of the methoxy group attached to the benzene ring displayed the highest probability of biotransformation. In etretinate, metabolic reactions would occur principally on the carbon atom of the final ethyl group of the molecule. CONCLUSIONS: MetaSite metabolism predictions for retinoic acid, acitretin, etretinate, adapalene and bexarotene were in agreement with experimental findings. In case of compounds being converted by catalysts other than cytochrome P450 enzymes, the primary metabolites predicted by MetaSite differ from those reported previously. In conclusion, MetaSite is a useful tool that can aid identification of the major metabolites of compounds being administered topically.

Acitretin in dermatology.

Acitretin, a synthetic retinoid has gradually replaced etretinate in today's dermatologic practice because of its more favorable pharmacokinetics. Acitretin over the past 20 years has proven useful in a number of difficult-to-treat hyperkeratotic and inflammatory dermatoses and nonmelanoma skin cancers. It is effective both as monotherapy and in combination with other drugs for hyperkeratotic disorders. It is considered to be an established second line treatment for psoriasis and exerts its effect mainly due to its antikeratinizing, antiinflammatory, and antiproliferative effect. Its antineoplastic properties make it a useful agent for cancer prophylaxis. Evidence-based efficacy, side-effect profile, and approach to the use of acitretin would be discussed in this review. In addition to its approved uses, the various off label uses will also be highlighted in this section. Since its use is limited by its teratogenic potential and other adverse effects, including mucocutaneous effects and hepatotoxicity, this review would summarize the contraindications and precautions to be exercised before prescribing acitretin.

Guidelines for the use of acitretin in psoriasis. Psoriasis Group of the Spanish Academy of Dermatology and Venereology.

Phototherapy, classic systemic treatments (methotrexate, acitretin, and ciclosporin), and biologic agents (etanercept, infliximab, adalimumab, and ustekinumab) constitute a broad therapeutic arsenal that increases the likelihood of achieving control of severe and extensive disease in patients with psoriasis. Acitretin continues to be a very valuable tool in both monotherapy, in which it is combined with other systemic treatments (classic or biologic), and in sequential therapy. Thanks to its lack of a direct immunosuppressive effect and its ability to achieve a long-term response, acitretin has an important role in the treatment of psoriasis, although this has not always been acknowledged in relevant treatment guidelines. We present consensus guidelines for the use of acitretin in psoriasis drawn up by the Psoriasis Group of the Spanish Academy of Dermatology and Venereology. These guidelines provide a detailed account of acitretin, including pharmacological properties, indications and contraindications, adverse effects, and factors that should be taken into account to enhance the safe use of this drug. They also propose treatment strategies for use in routine clinical practice. The overall aim of these guidelines is to define the criteria for the use and management of acetretin in psoriasis.

The effects of alcohol on the metabolism and toxicology of anti-psoriasis drugs.

INTRODUCTION: Alcohol has long been suspected to be a triggering and precipitating factor of psoriasis. Alcohol misuse is common in patients with moderate-to-severe psoriasis and appears to impair treatment outcome. AREAS COVERED: In this article, the authors review the available data regarding the metabolic and toxicological interactions between anti-psoriasis systemic drugs and ethanol and/or alcoholic beverages. Special attention is given to the influence of alcohol consumption on the hepatotoxic risk of some anti-psoriasis drugs. The article was prepared using a MEDLINE literature search. EXPERT OPINION: The available knowledge highlights the existence of a few significant pharmacological interactions, such as the reduced exposure to cyclosporine by red wine, the possible increase of cyclosporine levels following a heavy acute alcohol intake, and, especially, the conversion of acitretin to etretinate, in the presence of ethanol, with important implications in females of child-bearing potential. There are limited data on the contributing role of alcohol in the hepatotoxicity induced by some anti-psoriasis drugs and the existing information on this topic is still controversial. However, further investigation is needed to assess the relevance of interactions between alcohol consumption and drug therapy for psoriasis, under both pharmacological and toxicological perspectives. Long-term prospective studies on large cohorts of patients are warranted to disclose the actual significance of such potential interactions in clinical practice.

Acitretin in dermatology: a review.

INTRODUCTION: Acitretin is a systemic retinoid drug used in the treatment of severe psoriasis. It has also been used for a spectrum of other difficult-to-treat dermatoses, including hyperkeratotic and inflammatory dermatoses and non-melanoma skin cancers. Here we review the available data regarding both FDA-approved and off-label uses of acitretin, clinically relevant adverse events, precautions and monitoring. METHODS: A PubMed literature search was conducted utilizing the search term "acitretin," which yielded 714 hits. Results were further limited to English language clinical trials in human subjects. Of 78 articles evaluated for relevance, 60 were included for review. RESULTS: Acitretin is effective as monotherapy and in multidrug therapeutic regimens for the treatment of psoriasis and other hyperkeratotic and inflammatory disorders, as well as for malignancy chemoprevention. Its use is limited by its teratogenic potential and other adverse effects, including mucocutaneous effects and hepatotoxicity. Potential adverse effects may be reduced or avoided by using lower doses of acitretin or in combination with other therapies. LIMITATIONS: The reviewed studies include many small trials and case reports of the use of acitretin for psoriasis. Studies of acitretin therapy for the treatment of other cutaneous disorders are limited. CONCLUSION: Acitretin is a beneficial treatment for psoriasis, and should be considered when not contraindicated. Particularly when used in combination with ultraviolet (UV) phototherapy, is a safe and cost effective therapeutic strategy.

Stability-indicating validation of acitretin and isoacitretin in human plasma by LC-ESI-MS/MS bioanalytical method and its application to pharmacokinetic analysis.

LC- ESI- MS/MS simultaneous bioanalytical method was developed to determine acitretin and its metabolite isoacitretin in human plasma using acitretin-d3 used as the internal standard for both analytes. The compounds were extracted using protein precipitation coupled with liquid-liquid extraction with flash freezing technique. Negative mass transitions (m/z) of acitretin, isoacitretin and acitretin-d3 were detected in multiple reactions monitoring (MRM) mode at 325.4 → 266.3, 325.2 → 266.1 and 328.3 → 266.3, respectively, with a turbo ion spray interface. The chromatographic separation was achieved on an Ascentis-RP amide column (4.6 × 150 mm, 5 µm) with mobile phase delivered in isocratic mode. The method was validated over a concentration range of 1.025-753.217 ng/mL for acitretin and 0.394-289.234 ng/mL for isoacitretin with a limit of quantification of 1.025 and 0.394 ng/mL. The intra-day and inter-day precisions were below 8.1% for acitretin and below 13.8% for isoacitretin, while accuracy was within ±7.0 and ±10.6% respectively. For the first time, the best possible conditions for plasma stability of acitretin and isoacitretin are presented and discussed with application to clinical samples.

A review of acitretin for the treatment of psoriasis.

BACKGROUND: Acitretin is an oral retinoid that is approved for the treatment of psoriasis. It is unique compared to other systemic therapies for psoriasis such as methotrexate and cyclosporine in that it is not immunosuppressive. It is, therefore, safe for use in psoriasis patients with a history of chronic infection such as HIV, hepatitis B, hepatitis C or malignancy who have a contraindication to systemic immunosuppressive therapy and require systemic therapy because topical therapy is inadequate and they are unable to commit to phototherapy. Acitretin is one of the treatments of choice for pustular psoriasis. Even though acitretin is less effective as a monotherapy for chronic plaque psoriasis, combination therapy with other agents, especially UVB or psoralen plus UVA phototherapy, can enhance efficacy. OBJECTIVE: To provide an updated review of the safety and efficacy of acitretin in the treatment for psoriasis. METHODS: Literature review of journal articles from 2008 to 2009 since the last review of acitretin evaluated medical literature from 2005 to 2008. RESULTS/CONCLUSION: Acitretin is an effective systemic therapy for psoriasis and is generally well tolerated at low doses for long-term use. If monotherapy with acitretin is inadequate, it can be used in combination with other treatments, particularly UVB phototherapy, to increase efficacy.

A fully validated HPLC method for the simultaneous determination of acitretin and etretinate in plasma and its application to a pharmacokinetic study in healthy Korean subjects.

OBJECTIVE: Acitretin is used for the treatment of psoriasis. The purpose of this study was to validate an HPLC method for the determination of acitretin and etretinate and to investigate the pharmacokinetic characteristics of acitretin in healthy Korean subjects. MATERIALS AND METHODS: Plasma samples or calibrators were mixed with acetonitrile and retinyl acetate (internal standard). Butanol: acetonitrile (1:1 v/v) and K2HPO4 were added later. After vortexing, 30 microl of the supernatant was injected directly into the analytical column of an HPLC system. The samples were separated by C18 reversed phase HPLC and UV detection was performed at 350 nm. Various assay performances were evaluated. RESULTS: The linearity of acitretin and etretinate was adequate up to 500 ng/ml (R2 = 0.9937 for acitretin and R2 = 0.9923 for etretinate). The accuracy was 89.5 - 113.5% and the precision was satisfactory (within-run CV, 4.4 - 15.8%; between-run CV, 3.3 - 17.4%). The LLOQ was 2 ng/ml and the stability and specificity were satisfactory. However, after storage at room temperature for 24 h under light exposure, the concentrations of acitretin and etretinate decreased by 26.0 - 66.5%. Extraction recovery was 75.1 - 91.5%. Nine healthy Korean subjects were evaluated to study the pharmacokinetics of acitretin. A single oral dose of 30 mg acitretin (Neotigason, Roche Pharmaceuticals) was given to all volunteers. The mean +/- SD pharmacokinetics of acitretin in Koreans were as follows: Cmax 148.7 +/- 93.0 ng/ml, tmax 3.2 +/- 1.3 h, t1/2 81.2 +/- 26.5 h, and AUClast 2641.9 +/- 1274.8 ng h/ml. CONCLUSION: A simple HPLC method for the simultaneous determination of acitretin and etretinate was validated, and the pharmacokinetic characteristics of acitretin in the Korean population were investigated.

Evaluation of the transfusion safety of blood products and determination of plasma concentrations of acitretin and etretinate in patients receiving transfusions.

BACKGROUND: Acitretin and etretinate are potentially teratogenic. Many people taking acitretin for psoriasis have donated blood during the deferral period in Korea. Therefore, many of the blood products from these donors treated with acitretin have been circulated in Korea. STUDY DESIGN AND METHODS: A high-performance liquid chromatography system (HP 1050, Agilent Technologies) was used to measure the drug concentrations in five blood products and in patients. Sixty patients taking acitretin were enrolled to determine their plasma drug levels. Forty-one female patients were recruited to investigate the residual plasma levels of acitretin and etretinate in relation to their teratogenicity. We calculated the elimination rate of acitretin and etretinate during the manufacturing process. RESULTS: Sixty individuals taking acitretin expressed variable acitretin (<2.0-206.8 ng/mL) and etretinate levels (<2.0-9.1 ng/mL). All patients that had a transfusion had concentrations of acitretin and etretinate lower than the lower limit of quantification (LLOQ; 2 ng/mL). The concentrations of acitretin and etretinate in five blood products were less than the LLOQ. Approximately 98.84 percent (log value, 1.94) of the acitretin and 99.93 percent (log value, 3.14) of the etretinate was eliminated during the manufacturing process of albumin. More than 99.99 percent (log values, 5.95-15.76) of acitretin and etretinate was eliminated during the manufacturing processing of immunoglobulin and blood coagulation factors. CONCLUSIONS: We confirmed the effective manufacturing processing of various blood products. We also demonstrated that individuals receiving transfusions with blood products originating from donors treated with acitretin were not at risk for significant exposure to the acitretin and etretinate.

An updated review of acitretin--a systemic retinoid for the treatment of psoriasis.

BACKGROUND: Acitretin is a systemic retinoid used for psoriasis. It normalizes cellular differentiation and maturation and is also used as a chemopreventive agent against cutaneous malignancies. However, it is not used frequently because of its side-effect profile. OBJECTIVE: Safety and efficacy of acitretin was evaluated as monotherapy, as well as in combination with other systemic agents. METHODS: Medical literature from 2005 to 2008 was reviewed. The most scientifically rigorous clinical trials were selected for Psoriasis Area and Severity Index. Articles were limited to case reports or clinical trials, human subjects and English language journals. RESULTS/CONCLUSION: Acitretin is effective as monotherapy for pustular and erythrodermic psoriasis and for plaque psoriasis (with other systemic agents). Side effects of acitretin use occur more commonly with high doses. Hence, acitretin is safe and effective for psoriasis.

Systemic retinoids in chemoprevention of non-melanoma skin cancer.

BACKGROUND: The incidence of non-melanoma skin cancer is increasing worldwide. Systemic retinoids are useful for the chemoprophylaxis of non-melanoma skin cancers. Retinoids have pleiotropic effects, but their exact cancer chemopreventive mechanism is still not clear. OBJECTIVE: The aim of this study was to review published literature evaluating the use of oral retinoids in the chemoprevention of non-melanoma skin cancers. METHODS: The study reviewed all relevant papers found through a search of the electronic databases MEDLINE (from 1966 to January 2008) and Embase (from 1974 to January 2008). RESULTS/CONCLUSION: General and specific indications for retinoid chemoprophylaxis are defined. The pharmacokinetics and dose regimens of the two most commonly used oral retinoids (isotretinoin and acitretin) in the chemoprevention of non-melanoma skin cancers are presented. The use of oral retinoids is associated with adverse effects, which are discussed in detail. The future of retinoid cancer chemoprevention depends on the development and research of novel retinoids with improved bioavailability and minimized toxicity.

Interferon-gamma-dependent in vitro model for the putative keratin 17 autoimmune loop in psoriasis: exploration of pharmaco- and gene-therapeutic effects.

In 1999, A.S. Gudmundsdottir et al. have envisaged an epitope on keratin 17 (K17) as a putative psoriasis major autoantigen recognized by T cells. In a HaCaT keratinocyte model, we now demonstrate that IFN-gamma and to a less extent also TNF-alpha and TGF-alpha are able to induce K17 protein expression, in contrast to IL-1alpha, IL-1beta, IL-6, IL-8 and IL-18. This supports our hypothesis of an existing proinflammatory cytokine/K17 autoimmune loop as a presumptive positive feedback mechanism driving psoriasis etiopathogenesis. K17 overexpression was now found to also coincide with suppression of keratinocyte proliferation, e.g. induced by NF-kappa B inhibitors (Bay 11-7082 and Bay 11-7085), and thereby correlated hyperapoptosis to be encountered in psoriatic epidermis. Acitretin as an established antipsoriatic drug and the tyrosine kinase inhibitor imatinib decreased, whereas hydrocortisone as well as dexamethasone increased the IFN-gamma-induced K17 overexpression. The latter might be another mechanism explaining the well-known rebound phenomena after abrupt withdrawal of corticosteroids in psoriasis treatment. Finally, we defined a K17-directed and effective antisense oligodesoxynucleotide which may hold promise for future gene-therapeutic approaches in psoriasis.

Biopharmaceutics of beta-cyclodextrin derivative-based formulations of acitretin in Sprague-Dawley rats.

Acitretin, an active metabolite of etretinate, is as effective as etretinate in the treatment of psoriasis. Recently, we developed some water-soluble formulations of acitretin with 2-hydroxypropyl-beta-cyclodextrin (HPBCD)/randomly substituted methyl-beta-cyclodextrin (RMBCD). In this study, the biopharmaceutic properties of these formulations were tested in Sprague-Dawley rats. After single intravenous dosing (2.5, 5, or 10 mg/kg) with the HPBCD-based formulation, the area under the plasma concentration-time curve of acitretin increased proportionally with the dose and its clearance remained unchanged within the tested dose range. We also found that the RMBCD-based formulation of acitretin improved its bioavailability and decreased the variations in various pharmacokinetic parameters. The improved biopharmaceutic properties of RMBCD-based acitretin might be attributed to its enhanced aqueous solubility. The elimination of acitretin through bile excretion was also studied. Our results indicated that the major fraction of acitretin (approximately 40%) was excreted in the bile as beta-glucuronide conjugate and only trace amounts were excreted as unconjugated acitretin (approximately 0.5%). This finding further confirmed the importance of conjugated metabolism and biliary excretion in the elimination of this drug.

Retinoides en dermatología / Retinoids in Dermatology

Desde su introducción en la Dermatología hace 60 años, los retinoides han adquirido la condición de fármaco indispensable en nuestra especialidad. Este hecho se debe tanto a la observación de resultados efectivos en un alto número de procesos cutáneos como por las innovaciones que se han realizado tanto en su estructura como en su formulación. En la actualidad su efectividad y seguridad está bien establecida, tanto en formulaciones tópicas como sistémicas, en acné, psoriasis y fotoenvejecimiento. En los últimos años se han descrito nuevas indicaciones de los retinoides en dermatología entre las que caben destacar su uso en el tratamiento del cáncer cutáneo, o con fines cosméticos con buenos resultados en cicatrización de las heridas, estrías cutáneas en fases iniciales o alopecia androgenética. Los avances farmacológicos han permitido derivados de la vitamina A más efectivos y con menos efectos adversos. Tretinoina, aún con una mayor actividad irritante, sigue siendo el fármaco más efectivo por vía tópica en fotoenvejecimiento y cáncer cutáneo. Isotretinoina por vía oral es el fármaco de elección en el acné crónico y severo, adapaleno es la formulación tópica mejor tolerada en el acné, tazaroteno es el primer retinoide tópico con efectividad en psoriasis, etretinato y acitretino se consideran de elección en el tratamiento sistémico del psoriasis. Por último, se han descrito de forma reciente nuevas moléculas que han ampliado las indicaciones de los retinoides en dermatología, son alitretinoina para el sarcoma de Kaposi asociado a SIDA y bexaroteno para el linfoma cutáneo de células T (AU)

Efficacy of acitretin in severe psoriasis.

Acitretin (Soriatane, Roche Pharmaceuticals) is an aromatic retinoid, effective in the treatment of severe psoriasis. This study highlights data from two existing clinical trials to capture PASI 50 and PASI 75 responder rates which represent a common metric used in current psoriasis clinical trials. A review of pharmacokinetics, safety and a discussion of relapse rate establish acitretin as an efficacious, convenient, oral treatment for initial and maintenance therapy of severe psoriasis.

[Acitretine]. / Acitrétine.

Acitretin (Soriatane(R)) is an aromatic retinoïd (carboxylic acid metabolite of etretinate). Acitretin has a terminal elimination half-life of about 55 to 60 hours. However, concomitant intake of alcohol induces transformation to etretinate (lipophilic ester) which has a longer terminal elimination half life (84 to 168 days). Due to the teratogenic effect of acitretin, contraception should be used during therapy and 2 years afterwards. Acitretin monotherapy is effective in pustular psoriasis and psoriatic palmo-plantar keratoderma. In the other forms of psoriasis, combination with phototherapy (PUVA, UVB) or topical therapy is necessary (calcipotriol, corticosteroids). Acitretin is effective in cutaneous disorders of keratinization (ichtyosis, palmo-plantar keratoderma, Darier's disease). Severe cutaneous forms of lichen planus were recently recognized as indications of acitretin treatment; 35 to 40 mg daily is the mean effective dosage in adults (0.5 mg/kg/j in children). Acitretin was shown effective in preventing the development of new skin carcinomas in predisposed patients (Xeroderma pigmentosum, immunosupression). Acitretin is a potent teratogen. Mucocutaneous side effects are varied (cheilitis, dry mucosae, xerosis, palmo-plantar peeling, hair loss.), dose-dependent and reversible. Biological side-effects consist principally in elevations of transaminases (5 to 8% of patients). Acute hepatotoxic reactions are rare. Hyperlipidemia is another side-effect commonly observed. Bony changes (ligament calcifications, osteoporosis) have been reported with various incidence. In children, growth and development have to be monitored. Combination of acitretin with potentially hepatotoxic molecules (methotrexate) is contraindicated, as is combination with cyclines (risk of intracranial hypertension).