Soriatane (Acitretin) - Clinical Pharmacology

Clinical Pharmacology:

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).

Etretinate has a much longer elimination half-life compared to that of acitretin. In one study the apparent mean terminal half-life after 6 months of therapy was approximately 120 days (range 84 to 168 days). In another study of 47 patients treated chronically with etretinate, 5 had detectable serum drug levels (in the range of 0.5 to 12 ng/mL) 2.1 to 2.9 years after therapy was discontinued. The long half-life appears to be due to storage of etretinate in adipose tissue.

Progestin-only Contraceptives:

It has not been established if there is a pharmacokinetic interaction between acitretin and combined oral contraceptives. However, it has been established that acitretin interferes with the contraceptive effect of microdosed progestin preparations.¹ Microdosed “minipill” progestin preparations are not recommended for use with Soriatane. It is not known whether other progestational contraceptives, such as implants and injectables, are adequate methods of contraception during acitretin therapy.

Clinical Studies:

In two double-blind placebo controlled studies, Soriatane was administered once daily to patients with severe psoriasis (ie, covering at least 10% to 20% of the body surface area). At 8 weeks (see Table 1) patients treated in Study A with 50 mg Soriatane per day showed significant improvements (p ≤ 0.05) relative to baseline and to placebo in the physician’s global evaluation and in the mean ratings of severity of psoriasis (scaling, thickness, and erythema). In study B, differences from baseline and from placebo were statistically significant (p ≤ 0.05) for all variables at both the 25 mg and 50 mg doses; it should be noted for Study B that no statistical adjustment for multiplicity was carried out.

Table 1. Summary of the Soriatane Efficacy Results of the 8-Week Double-Blind Phase of Studies A and B

Efficacy Variables	Study A		Study B
	Total daily dose		Total daily dose
	Placebo (N=29)	50 mg (N=29)	Placebo (N=72)	25 mg (N=74)	50 mg (N=71)
Physician’s Global Evaluation
Baseline	4.62	4.55	4.43	4.37	4.49
Mean Change
After 8 Weeks		−2.00Values were statistically significantly different from placebo and from baseline (p ≤ 0.05). No adjustment for multiplicity was done for Study B. The efficacy variables consisted of: the mean severity rating of scale, lesion thickness, erythema, and the physician’s global evaluation of the current status of the disease. Ratings of scaling, erythema, and lesion thickness, and the ratings of the global assessments were made using a seven-point scale (0=none, 1=trace, 2=mild, 3=mild-moderate, 4=moderate, 5=moderate-severe, 6=severe).	−0.06	−1.06	−1.57
Scaling
Baseline	4.10	3.76	3.97	4.11	4.10
Mean Change
After 8 Weeks	−0.22	−1.62	−0.21	−1.50	−1.78
Thickness
Baseline	4.10	4.10	4.03	4.11	4.20
Mean Change
After 8 Weeks	−0.39	−2.10	−0.18	−1.43	−2.11
Erythema
Baseline	4.21	4.59	4.42	4.24	4.45
Mean Change
After 8 Weeks	−0.33	−2.10	−0.37	−1.12	−1.65

A subset of 141 patients from both pivotal studies A and B continued to receive Soriatane in an open fashion for up to 24 weeks. At the end of the treatment period, all efficacy variables, as indicated in Table 2, were significantly improved (p≤0.01) from baseline, including extent of psoriasis, mean ratings of psoriasis severity and physician’s global evaluation.

Table 2. Summary of the First Course of Soriatane Therapy (24 Weeks)

Variables	Study A	Study B
Mean Total Daily Soriatane Dose (mg)	42.8	43.1
Mean Duration of Therapy (Weeks)	21.1	22.6
Physician’s Global Evaluation	N=39	N=98
Baseline	4.51	4.43
Mean Change From Baseline	−2.26Indicates that the difference from baseline was statistically significant (p ≤ 0.01). The efficacy variables consisted of: the mean severity rating of scale, lesion thickness, erythema, and the physician’s global evaluation of the current status of the disease. Ratings of scaling, erythema, and lesion thickness, and the ratings of the global assessments were made using a seven-point scale (0=none, 1=trace, 2=mild, 3=mild-moderate, 4=moderate, 5=moderate-severe, 6=severe).	−2.60
Scaling	N=59	N=132
Baseline	3.97	4.07
Mean Change From Baseline	−2.15	−2.42
Thickness	N=59	N=132
Baseline	4.00	4.12
Mean Change From Baseline	−2.44	−2.66
Erythema	N=59	N=132
Baseline	4.35	4.33
Mean Change From Baseline	−2.31	−2.29

All efficacy variables improved significantly in a subset of 55 patients from Study A treated for a second, 6-month maintenance course of therapy (for a total of 12 months of treatment); a small subset of patients (n=4) from Study A continued to improve after a third 6-month course of therapy (for a total of 18 months of treatment).