Is acitretin contraindicated in patients with renal failure on haemodialysis? If not, what dosage i

Fråga: Is acitretin contraindicated in patients with renal failure on haemodialysis? If not, what dosage is recommended?

Neotigason (acitretin) for skin cancer is being considered in a 38-year-old woman with renal failure on haemodialysis.

Sammanfattning: Only limited data is available on the pharmacokinetics of acitretin in patients with renal failure. Neither acitretin nor 13-cis-acitretin is removed by haemodialysis. Following extensive metabolism, about 50% of a given dose of acitretin is excreted as metabolites in the urine. Available data does not indicate accumulation of the parent drug or the main metabolite in patients with renal failure on haemodialysis. Information on other metabolites is lacking, as is information on whether the metabolites are pharmacologically active. Dosage of acitretin in patients with renal failure on haemodialysis is assumed to be as in patients with normal renal function. If the bioavailiability of acitretin is lower in patients with renal failure ordinary doses of acitretin might not be sufficient. Considering the safety aspect, initiating therapy with ordinary doses and then adjust the dose according to the individual response seems prudent.

Svar: Acitretin is an active metabolite of etretinate (1). It is a second generation retinoid, one of a group of natural and synthetic analogues of vitamin A that control cell differentiation and proliferation in a number of epithelial tissues (1). Acitretin is eliminated almost entirely by metabolism (2). The main metabolite is 13-cis-acitretin, but other metabolites have also been identified (2). No information has been found concerning whether these metabolites are active or not. Up to 50% of a dose is excreted in the urine and up to 60% in the feces, with no unchanged acitretin or 13-cis-acitretin detectable in the urine (2). Acitretin is extensively bound (>99%) to plasma proteins, in particular albumin (1). Acitretin is not appreciably bound to fat-storing tissue and there are no indications of any "deep" storage compartment for acitretin (1).

Only limited data is available on the pharmacokinetics of acitretin in patients with renal failure. Following oral administration of single doses of acitretin to patients (n=6) with chronic renal failure on haemodialysis, the peak plasma concentration and area under the concentration-time curve (AUC 0-24) of acitretin were lower as compared to healthy volunteers (3). The mechanisms behind these findings are unclear. No acitretin or 13-cis acitretin was detected in the dialysates, indicating that dialysis treatment cannot account for the lower AUCs of the retinoids in patients with renal failure compared with those in controls. The lower peak plasma concentrations might be explained by reduced absorption in patients with renal failure or by increased apparent volume of distribution. Many drugs are less well-bound to plasma proteins in patients with renal dysfunction, resulting in an increased fraction of unbound drug, increased apparent volume of distribution and increased total drug clearance. This could explain the observed lower AUCs. The amount of unbound, active, drug would not be expected to be altered.

Since acitretin undergoes extensive metabolism and the excretion of the individual metabolites is not fully elucidated, accumulation of metabolites other than 13-cis-acitretin in patients with renal failure cannot be excluded.

Adverse effects of acitretin are usually dose-related (1). Mucocutaneous reactions are most common. Elevated levels of serum triglycerides and, to a lesser extent, cholesterol and liver transaminase levels are also frequently observed.