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Pharmacology: Pharmacodynamics: In vitro and in vivo studies have shown that diacerein inhibits the production of interleukin 1 and decreases collagenolytic activity.
The anti-osteoarthritis properties of diacerein are due to its capacity to inhibit the pro-inflammatory, pro-catabolic cytokines such as interleukin 1 which plays an important role in the degradation of articular cartilage, for example, it inhibits cartilage production and stimulates the liberation of cartilage degrading enzymes (collagenase and stromelysin).
Clinical studies of 2 to 6 months duration demonstrate that diacerein is effective in improving the signs and symptoms of osteoarthritis (pain and joint function). These studies show that the drug has a slow onset of action which becomes significant after 30-45 days and which is maintained once treatment is interrupted. Diacerein has a good gastric tolerance.
Pharmacokinetics: After oral administration, diacerein is hydrolysed before entering the systemic circulation and is absorbed, metabolised and excreted as rhein and its conjugates. All the pharmacokinetic data that follow refer to this active principle.
Absorption: After oral administration, diacerein undergoes a first hepatic passage and is totally deacetylated to rhein. After the intake of a single dose of 100 mg, the peak plasma levels (Cmax) were 8-10 μg/ml of free rhein. The values for Tmax were 1.8-2.0 hours after administration to fasting healthy volunteers.
The simultaneous intake of a standard meal induces a delay in the absorption process and prolongs the Tmax together which results in a higher bioavailability (increase of about 25% in the AUC). Given this behaviour, it is advisable to take the drug with meals.
Distribution: Nearly all the non-conjugated rhein (more than 99%) is bound to plasma proteins, mainly albumin, and is not displaced by the usual drugs at their therapeutic concentrations. The mean distribution volume in steady state, Vss/F, was approximately 17.1 litres.
Metabolism: Diacerein is very rapidly metabolised (mainly pre-systematically) to rhein and this is conjugated to different extents in different species.
Elimination: The elimination half-life of plasma (t½) is about 5-7 hours. Excretion is mainly renal as rhein and as conjugates of rhein (glucuronide and sulphate). Following oral administration of doses of 50-100 mg, about 50% of the total dose of diacerein is recovered in the urine as rhein, mainly (more than 90%) as the sulpho- and gluco-conjugated forms of rhein.
Linearity: In linearity studies using doses between 50 and 200 mg diacerein, the Cmax and AUC of free and total rhein were proportional to the doses administered.
Pharmacokinetics in special groups of patients: A comparison between healthy subjects and patients with renal insufficiency shows that there is a highly significant increase in the AUC and terminal half-life (t½) with a simultaneous decline in renal clearance of rhein in subjects with severe renal insufficiency (creatinine clearance less than 30 ml/min). Consequently diacerein is contraindicated in this type of patients. In patients with moderate renal insufficiency, a 50% reduction in the daily dose is recommended (see Dosage & Administration and Contraindications).
Finally, when elderly patients are compared to a control group of younger healthy volunteers, an increase in the AUC proportional to age and a prolongation of the terminal plasma half-life of free rhein are observed. However, these findings did not reach the necessary significance to require a modification of the dose in these patients. Therefore, the dose for elderly patients is the same as that for younger adults (see Dosage & Administration).
Toxicology: Pre-Clinical Safety: In acute toxicology studies following oral administration of the drug in rodents, the LD50 was greater than 2,000 mg/kg. The main clinical symptom was diarrhoea. The laxative action, proportional to the dose administered, was also the most frequently observed adverse effect after repeated administration to rats and dogs.
Diacerein had no effects on reproduction and was not teratogenic in the species studied. Both the drug and its metabolite rhein showed an absence of genotoxicity under the conditions of in vitro and in vivo studies. In longer-term studies carried out in rats and mice, there was no evidence of a carcinogenic potential.
Therefore, the results of the pre-clinical studies do not reveal any particular risks to humans if we consider the results of the safety pharmacology studies, repeated dose toxicity studies, genotoxicity, carcinogenicity and reproduction studies.
