Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Chemotherapeutics for topical use, antivirals: ATC Code: D06BB10.
Imiquimod is an immune response modifier. Saturable binding studies suggest a membrane receptor for imiquimod exists on responding immune cells. Imiquimod has no direct antiviral activity. In animal models imiquimod is effective against viral infections and acts as an antitumor agent principally by induction of alpha interferon and other cytokines. The induction of alpha interferon and other cytokines following imiquimod cream application to genital wart tissue has also been demonstrated in clinical studies.

Increases in systemic levels of alpha interferon and other cytokines following topical application of imiquimod were demonstrated in a pharmacokinetic study.

External genital warts:

Clinical Efficacy
The results of 3 phase III pivotal efficacy studies showed that treatment with imiquimod for sixteen weeks was significantly more effective than treatment with vehicle as measured by total clearance of treated warts.

In 119 imiquimod-treated female patients, the combined total clearance rate was 60% as compared to 20% in 105 vehicle-treated patients (95% CI for rate difference: 20% to 61% , p<0.001). In those imiquimod patients who achieved total clearance of their warts, the median time to clearance was 8 weeks.

In 157 imiquimod-treated male patients, the combined total clearance rate was 23% as compared to 5% in 161 vehicle-treated patients (95%CI for rate difference: 3% to 36%, p<0.001). In those imiquimod patients who achieved total clearance of their warts, the median time to clearance was 12 weeks.

Superficial basal cell carcinoma:

Clinical efficacy:
The efficacy of imiquimod 5 times per week for 6 weeks was studied in two double-blind vehicle controlled clinical trials. Target tumors were histologically confirmed single primary superficial basal cell carcinomas with a minimum size of 0.5 cm2 and a maximum diameter of 2 cm. Tumors located within 1 cm of the eyes, nose, mouth, ears or hairline were excluded. In a pooled analysis of these two studies, histological clearance was noted in 82% (152/185) of patients. When clinical assessment was also included, clearance judged by this composite endpoint was noted in 75% (139/185) of patients. These results were statistically significant (p<0.001) by comparison with the vehicle group, 3% (6/179) and 2% (3/179) respectively. There was a significant association between the intensity of local skin reactions (e.g. erythema) seen during the treatment period and complete clearance of the basal cell carcinoma.

Five -year data from a long-term open-label uncontrolled study indicate that an estimated 77.9% [95% CI (71.9%, 83.8%)] of all the subjects who initially received treatment became clinically clear and remained clear at 60 months.

Actinic keratosis:
Clinical efficacy:

The efficacy of imiquimod applied 3 times per week for one or two courses of 4 weeks, separated by a 4-week treatment-free period, was studied in two double-blind vehicle controlled clinical trials. Patients had clinically typical, visible, discrete, non-hyperkeratotic, non-hypertrophic AK lesions on the balding scalp or face within a contiguous 25 cm2 treatment area. 4-8 AK lesions were treated. The complete clearance rate (imiquimod minus placebo) for the combined trials was 46.1% (CI 39.0%, 53.1%).

One-year data from two combined observational studies indicate a recurrence rate of 27% (35/128 patients) in those patients who became clinically clear after one or two courses of treatment. The recurrence rate for individual lesions was 5.6% (41/737). Corresponding recurrence rates for vehicle were 47% (8/17 patients) and 7.5% (6/80 lesions).

Two open-label, randomised, controlled clinical trials compared the long-term effects of imiquimod with those of topical diclofenac in patients with actinic keratosis with respect to the risk of progression to in situ or invasive squamous cell carcinoma (SCC). Treatments were given as officially recommended. If the treated AK field was not completely cleared of lesions, additional treatment cycles could be started. All patients were followed-up until withdrawal or up to 3 years after randomisation. Results are emerged from a meta-analysis of both trials.
A total of 482 patients were included into the trials, of these 481 patients received study treatments, and of these 243 patients were treated with imiquimod and 238 patients with topical diclofenac. The treated AK field was located on the balding scalp or face with a contiguous area of about 40 cm² for both treatment groups presenting with a median number of 7 clinically typical AK lesions at baseline. There is clinical experience from 90 patients who got 3 or more imiquimod treatment cycles, 80 patients received 5 or more courses of imiquimod treatment over the 3-year study period.
Regarding the primary endpoint, histological progression, overall, 13 of 242 patients (5.4%) of the imiquimod group and 26 of 237 patients (11.0%) of the diclofenac group were found to have a histological progression to in situ or invasive SCC within 3 years, a difference of -5.6% (95% CI: -10.7% to -0.7%). Thereof 4 of 242 patients (1.7%) of the imiquimod and 7 of 237 patients (3.0%) of the diclofenac group were found to have a histological progression to invasive SCC within the 3-year period.
A total of 126 of 242 patients treated with imiquimod (52.1%) and 84 of 237 patients treated with topical diclofenac (35.4%) showed complete clinical clearance of the treated AK field at week 20 (i.e. about 8 weeks after the end of the initial treatment cycle); a difference of 16.6% (95% CI: 7.7%to 25.1%). For those patients with complete clinical clearance of the treated AK field recurrence of AK lesions was evaluated. A patient was counted as recurrent in these trials if at least one AK lesion was observed in the completely cleared field whereby a recurrent lesion could be a lesion which occurred at the same location as a formerly cleared lesion or a newly identified lesion anywhere in the treated AK field. The risk for recurrence of AK lesions in the treated field (as defined above) was 39.7% (50 of 126 patients) until month 12 for patients treated with imiquimod compared with 50.0% (42 of 84 patients) for patients treated with topical diclofenac, a difference of -10.3% (95% CI: -23.6% to 3.3%); and 66.7% (84 of 126 patients) for a treatment with imiquimod and 73.8% (62 of 84 patients) for topical diclofenac until month 36, a difference of -7.1% (95% CI: -19.0%to 5.7%).A patient with recurrent AK lesions (as defined above) in the completely cleared field had a chance of about 80% to become completely cleared again following an additional imiquimod treatment cycle compared with a chance of about 50% for a re-treatment with topical diclofenac.

Pediatric patients:
The approved indications genital warts, actinic keratosis and superficial basal cell carcinoma are conditions not generally seen within the pediatric population and were not studied.
Aldara Cream has been evaluated in four randomized, vehicle controlled, double-blind trials in children aged 2 to 15 years with molluscum contagiosum (imiquimod n = 576, vehicle n = 313).
These trials failed to demonstrate efficacy of imiquimod at any of the tested dosage regimens (3x/week for ≤16 weeks and 7x/week for ≤8 weeks).

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

External genital warts, superficial basal cell carcinoma and actinic keratosis: 
Less than 0.9% of a topically applied single dose of radiolabelled imiquimod was absorbed through the skin of human subjects. The small amount of drug which was absorbed into the systemic circulation was promptly excreted by both urinary and faecal routes at a mean ratio of approximately 3 to 1. No quantifiable levels (>5 ng/ml) of drug were detected in serum after single or multiple topical doses.

Systemic exposure (percutaneous penetration) was calculated from recovery of carbon-14 from [14C] imiquimod in urine and faeces.

Minimal systemic absorption of imiquimod 5% cream across the skin of 58 patients with actinic keratosis was observed with 3 times per week dosing for 16 weeks. The extent of percutaneous absorption did not change significantly between the first and last doses of this study. Peak serum drug concentrations at the end of week 16 were observed between 9 and 12 hours and were 0.1, 0.2, and 1.6 ng/mL for the applications to face (12.5 mg, 1 single-use sachet), scalp (25 mg, 2 sachets) and hands/arms (75 mg, 6 sachets), respectively. The application surface area was not controlled in the scalp and hands/ arms groups. Dose proportionality was not observed. An apparent half-life was calculated that was approximately 10 times greater than the 2 hour half-life seen following subcutaneous dosing in a previous study, suggesting prolonged retention of drug in the skin. Urinary recovery was less than 0.6% of the applied dose at week 16 in these patients.

Paediatric patients:
The pharmacokinetic properties of imiquimod following single and multiple topical application in paediatric patients with molluscum contagiosum (MC) have been investigated. The systemic exposure data demonstrated that the extent of absorption of imiquimod following topical application to the MC lesional skin of the paediatric patients aged 6-12 years was low and comparable to that observed in healthy adults and adults with actinic keratosis or superficial basal cell carcinoma. In younger patients aged 2-5 years absorption, based on Cmax values, was higher compared to adults.