Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
ATC-Code: D11AX18
Other Dermatologicals
Mechanisms of action: Diclofenac is a non-steroidal anti-inflammatory drug.
The mechanism of action of diclofenac in AK may be related to the inhibition of the cyclooxygenase pathway leading to reduced prostaglandin E2 (PGE2) synthesis. In addition, immunohistochemistry (IHC) from skin biopsies ac revealed that the clinical effects of diclofenac in AK are primarily due to anti-inflammatory, anti-angiogenic and possibly anti-proliferative effects and apoptosis-inducing mechanisms.
Pharmacodynamic Effects: Sunactic has been shown to clear AK lesions with maximum therapeutic effect seen 30 days after cessation of drug therapy.
Clinical efficacy and safety: Data from 3 company-sponsored, randomised, double- blind clinical trials in which diclofenac sodium was used as a comparator arm (Studies 0908, 1004 and 0702) provide further evidence on the efficacy of diclofenac sodium in the treatment of AK lesions (including hyperkeratotic lesions) across a number of endpoints. Specifically, the diclofenac sodium arm showed histological clearance rates between 47.6% and 54.1% while these were between 33,9% and 42.7% for vehicle. Complete clinical clearance of AK lesions was achieved in 37.9% and 23.4% of patients at 30 (n=11/29) and 60 days post-treatment (n= 76/380).
In a three arm study comparing 0.5% 5-FU, diclofenac sodium and vehicle, both active arms were superior to vehicle in histological and complete cure rates, whereas 0.5% 5-FU was not inferior to diclofenac sodium and showed higher histological clearance compared to it (70.1% vs 54.1%).
Moderate-to-significant improvements were reported using investigator and patient Global Improvement Index following diclofenac sodium treatment.
Observational 1-year follow-up data indicate that following treatment with diclofenac sodium, complete clearance was achieved by 28.8% and 36.8% at 6 and 12 months post treatment respectively (18.9% and 25.0% with placebo at similar time points).
The efficacy of diclofenac sodium has been investigated in 32 patients (24 on diclofenac sodium, 8 on placebo) who had previously undergone organ transplantation, and now had a currently stable graft. diclofenac sodium was superior to vehicle in both complete clearance of AK lesions (41% vs 0%) and lesion count reduction (53% vs 17%).

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Absorption: Mean absorption through the skin varies between <1-12% with large inter-individual variability. Absorption is dependent on the amount of the topical dose applied and the site of application.
Distribution: Diclofenac binds highly to serum albumin.
Biotransformation: Biotransformation of diclofenac involves partly conjugation of the intact molecule, but mainly single and multiple hydroxylations resulting in several phenolic metabolites, most of which are converted to glucuronide conjugates. Two of these phenolic metabolites are biologically active, however to a much lesser extent than diclofenac. Metabolism of diclofenac following percutaneous and oral administration is similar.
Elimination: Diclofenac and its metabolites are excreted mainly in the urine. Systemic clearance of diclofenac from plasma is 263 ± 56 ml/min (mean value ±standard deviation) following oral administration. Terminal plasma half-life is short (1-2 hours).
For the metabolites also have short terminal half-lives of 1-3 hours.
Pharmacokinetics in special patient populations: After topical application, the absorption of diclofenac in normal and compromised epidermis are comparable although there is a large inter-individual variation. Systemic absorption of diclofenac is approximately 12% of the administered dose for compromised skin and 9% for intact skin.