The mechanism of action of Soriatane is unknown.

Pharmacokinetics

Absorption:Oral absorption of acitretin is optimal when given with food. For this reason, acitretin was given with food in all of the following studies. After administration of a single 50 mg oral dose of acitretin to 18 healthy subjects, maximum plasma concentrations ranged from 196 to 728 ng/mL (mean 416 ng/mL) and were achieved in 2 to 5 hours (mean 2.7 hours). The oral absorption of acitretin is linear and proportional with increasing doses from 25 to 100 mg. Approximately 72% (range 47% to 109%) of the administered dose was absorbed after a single 50 mg dose of acitretin was given to 12 healthy subjects.

Distribution: Acitretin is more than 99.9% bound to plasma proteins, primarily albumin.

Metabolism : (see Pharmacokinetic Drug Interactions: Ethanol): Following oral absorption, acitretin undergoes extensive metabolism and interconversion by simple isomerization to its 13-cis form (cis-acitretin). The formation of cis-acitretin relative to parent compound is not altered by dose or fed/fast conditions of oral administration of acitretin. Both parent compound and isomer are further metabolized into chain-shortened breakdown products and conjugates, which are excreted. Following multiple-dose administration of acitretin, steady-state concentrations of acitretin and cis-acitretin in plasma are achieved within approximately 3 weeks.

Elimination: The chain-shortened metabolites and conjugates of acitretin and cis-acitretin are ultimately excreted in the feces (34% to 54%) and urine (16% to 53%). The terminal elimination half-life of acitretin following multiple-dose administration is 49 hours (range 33 to 96 hours), and that of cis-acitretin under the same conditions is 63 hours (range 28 to 157 hours). The accumulation ratio of the parent compound is 1.2; that of cis-acitretin is 6.6.

Special Populations

Psoriasis: In an 8-week study of acitretin pharmacokinetics in patients with psoriasis, mean steady-state trough concentrations of acitretin increased in a dose proportional manner with dosages ranging from 10 to 50 mg daily. Acitretin plasma concentrations were nonmeasurable ( < 4 ng/mL) in all patients 3 weeks after cessation of therapy.

Elderly: In a multiple-dose study in healthy young (n=6) and elderly (n=8) subjects, a two-fold increase in acitretin plasma concentrations were seen in elderly subjects, although the elimination half-life did not change.

Renal Failure: Plasma concentrations of acitretin were significantly (59.3%) lower in end-stage renal failure subjects (n=6) when compared to age-matched controls, following single 50 mg oral doses. Acitretin was not removed by hemodialysis in these subjects.

Pharmacokinetic Drug Interactions (see also boxed CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS: DRUG INTERACTIONS): In studies of in vivo pharmacokinetic drug interactions, no interaction was seen between acitretin and cimetidine, digoxin, phenprocoumon or glyburide.

Ethanol: Clinical evidence has shown that etretinate (a retinoid with a much longer half-life, see below) can be formed with concurrent ingestion of acitretin and ethanol. In a two-way crossover study, all 10 subjects formed etretinate with concurrent ingestion of a single 100 mg oral dose of acitretin during a 3-hour period of ethanol ingestion (total ethanol, approximately 1.4 g/kg body weight). A mean peak etretinate concentration of 59 ng/mL (range 22 to 105 ng/mL) was observed, and extrapolation of AUC values indicated that the formation of etretinate in this study was comparable to a single 5 mg oral dose of etretinate. There was no detectable formation of etretinate when a single 100 mg oral dose of acitretin was administered without concurrent ethanol ingestion, although the formation of etretinate without concurrent ethanol ingestion cannot be excluded (see boxed CONTRAINDICATIONS AND WARNINGS). Of 93 evaluable psoriatic patients on acitretin therapy in several foreign studies (10 to 80 mg/day), 16% had measurable etretinate levels ( > 5 ng/mL).