Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1. Pharmacodynamic properties
Anti-Osteoarthritic.
ATC Classification: M01AX21, Other Anti-inflammatory and Antirheumatic agents, Non- Steroids.
Diacerein is an anthraquinone derivative which has moderate anti-inflammatory activity. It is anti-inflammatory at high doses and devoid of any irritant effect on the stomach.
Action onset is slow, beginning towards day 30 of treatment and becoming significant after about 45 days. It has an additive effect in combination with NSAIDs.
In vitro, diacerein has the following properties:
- inhibition of phagocytosis and macrophage migration
- inhibition of interleukin-1 synthesis
- reduction of collagenolytic activity
In some models, diacerein stimulates production of proteoglycans, glycosaminoglycans and hyaluronic acid.
A positive effect on cartilage has been demonstrated in a number of animal models.
A multicentre, randomized, double-blind, placebo-controlled (ECHODIAH study) to evaluate the effect of diacerein on the progression of Joint Space narrowing (JSN) was preformed for a period of 3 years in 507 patients with hip osteoarthritis. Patients received either 50 mg of diacerein (n=255) or placebo (n=252) twice a day, i.e. in the morning and in the evening.

Efficacy was evaluated using the following two main criteria:
• Percentage of the patients with a radiological impairment (radiological joint space width decreased more than 0.5 mm).
• Annual rate of Joint Space Narrowing (JSN) rate per year (mm/year).

269 patients completed the trial.

At 3 years, the Intend-To-Treat (ITT) analysis shows that:
• The percentage of patients with a radiological impairment of more than 0.5 mm is significantly lower with diacerein group compared to placebo (50.7% versus 60.4 for placebo, p=0.036).
• JSN rate (0.39 mm/year) is not statistically different between the 2 groups.
The clinical significance of these results in terms of prognosis is unknown.

Pharmacokinetic Properties

5.2. Pharmacokinetic properties
• Orally administered diacerein undergoes a hepatic first-pass effect and is totally deacetylated to rhein, the sulphoconjugated metabolite.
• After a single 50 mg dose, plasma diacerein concentrations peak arises at a mean 2.5 hours and the maximal concentration (Cmax) is of the order of 3 mg/l.
• Diacerein 50 mg capsule intake with food increases the bioavailability (the area under the curve increases by nearly 25%) and delays absorption.
• For dose ranging from 50 to 200 mg of diacerin capsules in single dose, the pharmacokinetic parameters are dose-independent.
•   Protein binding is very strong (99%) and mainly consists in high-affinity binding to albumin.
•   The elimination half-life (t1/2) of rhein is approximately 4.5 hours. The total quantity excreted in the urine is around 30%. 80% of the rhein excreted in urine is in sulpho- and glucuroconjugated form and 20% is excreted in unchanged form.
•   Repeated administration of diacerein (50 mg twice daily) results in slight accumulation.
•   In patients with severe kidney failure (creatinine clearance less than 30 ml/min), the area under the curve and elimination half-life are doubled and urinary elimination halved.
•   In the elderly, given the good tolerance of the product, it is no necessary to change the dose, despite the slower elimination.