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Aldara

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Aldara

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism of action of Aldara (imiquimod) Cream in treating AK and sBCC lesions is unknown.

Pharmacodynamics

Actinic Keratosis

In a study of 18 subjects with AK comparing Aldara (imiquimod) Cream to vehicle, increases from baseline in week 2 biomarker levels were reported for CD3, CD4, CD8, CD11c, and CD68 for Aldara (imiquimod) Cream treated subjects; however, the clinical relevance of these findings is unknown.

Superficial Basal Cell Carcinoma

An open label study in six subjects with sBCC suggests that treatment with Aldara (imiquimod) Cream may increase the infiltration of lymphocytes, dendritic cells, and macrophages into the tumor lesion; however, the clinical significance of these findings is unknown.

External Genital Warts

Imiquimod has no direct antiviral activity in cell culture. A study in 22 subjects with genital/perianal warts comparing Aldara (imiquimod) Cream and vehicle shows that Aldara (imiquimod) Cream induces mRNA encoding cytokines including interferon-α at the treatment site. In addition HPVL1 mRNA and HPV DNA are significantly decreased following treatment. However, the clinical relevance of these findings is unknown.

Pharmacokinetics

Systemic absorption of imiquimod across the affected skin of 58 subjects with AK was observed with a dosing frequency of 3 applications per week for 16 weeks. Mean peak serum drug concentrations at the end of week 16 were approximately 0.1, 0.2, and 3.5 ng/mL for the applications to face (12.5 mg imiquimod, 1 single-use packet), scalp (25 mg, 2 packets) and hands/arms (75 mg, 6 packets), respectively.

Table 10: Mean Serum Imiquimod Concentration in Adults Following Administration of the Last Topical Dose During Week 16 (Actinic Keratosis)

Amount of Aldara Cream applied Mean peak serum imiquimod concentration [Cmax]
12.5 mg (1 packet) 0.1 ng/mL
25 mg (2 packets) 0.2 ng/mL
75 mg (6 packets) 3.5 ng/mL

The application surface area was not controlled when more than one packet was used. Dose proportionality was not observed. However it appears that systemic exposure may be more dependent on surface area of application than amount of applied dose. The apparent half-life was approximately 10 times greater with topical dosing than the 2 hour apparent half-life seen following subcutaneous dosing, suggesting prolonged retention of drug in the skin. Mean urinary recoveries of imiquimod and metabolites combined were 0.08 and 0.15% of the applied dose in the group using 75 mg (6 packets) for males and females, respectively following 3 applications per week for 16 weeks.

Systemic absorption of imiquimod was observed across the affected skin of 12 subjects with genital/perianal warts, with an average dose of 4.6 mg. Mean peak drug concentration of approximately 0.4 ng/mL was seen during the study. Mean urinary recoveries of imiquimod and metabolites combined over the whole course of treatment, expressed as percent of the estimated applied dose, were 0.11 and 2.41% in the males and females, respectively.

Clinical Studies

Actinic Keratosis

In two double-blind, vehicle-controlled clinical studies, 436 subjects with AK were randomized to treatment with either Aldara (imiquimod) Cream or vehicle cream 2 times per week for 16 weeks. The studies enrolled subjects with 4 to 8 clinically typical, visible, discrete, nonhyperkeratotic, nonhypertrophic AK lesions within a 25 cm²contiguous treatment area on either the face or scalp. The 25 cm² contiguous treatment area could be of any dimensions e.g., 5 cm x 5 cm, 3 cm by 8.3 cm, 2 cm by 12.5 cm. Study subjects ranged from 37 to 88 years of age (median 66 years) and 55% had Fitzpatrick skin type I or II. All Aldara (imiquimod) -treated subjects were Caucasians.

On a scheduled dosing day, the study cream was applied to the entire treatment area prior to normal sleeping hours and left on for approximately 8 hours. Twice weekly dosing was continued for a total of 16 weeks. The clinical response of each subject was evaluated 8 weeks after the last scheduled application of study cream. Efficacy was assessed by the complete clearance rate, defined as the proportion of subjects at the 8-week post-treatment visit with no (zero) clinically visible AK lesions in the treatment area. Complete clearance included clearance of all baseline lesions, as well as any new or sub-clinical AK lesions which appeared during therapy.

Complete and partial clearance rates are shown in the table below. The partial clearance rate was defined as the percentage of subjects in whom 75% or more baseline AK lesions were cleared.

Table 11: Clearance Rates (AK)

Complete Clearance Rates (100% AK Lesions Cleared)
Study Aldara Cream Vehicle
Study AK1 46% (49/107) 3% (3/110)
Study AK2 44% (48/108) 4% (4/111)
Partial and Complete Clearance Rates (75% or More Baseline AK
Lesions Cleared)
Study Aldara Cream Vehicle
Study AK1 60% (64/107) 10% (11/110)
Study AK2 58% (63/108) 14% (15/111)

Sub-clinical AK lesions may become apparent in the treatment area during treatment with Aldara (imiquimod) Cream. During the course of treatment, 48% (103/215) of subjects experienced an increase in AK lesions relative to the number present at baseline within the treatment area. Subjects with an increase in AK lesions had a similar response to those with no increase in AK lesions.

Superficial Basal Cell Carcinoma

In two double-blind, vehicle-controlled clinical studies, 364 subjects with primary sBCC were treated with Aldara (imiquimod) Cream or vehicle cream 5 times per week for 6 weeks. Target tumors were biopsy-confirmed sBCC and had a minimum area of 0.5 cm² and a maximum diameter of 2.0 cm (4.0 cm²). Target tumors were not to be located within 1.0 cm of the hairline, or on the anogenital area or on the hands or feet, or to have any atypical features. The population ranged from 31-89 years of age (median 60 years) and 65% had Fitzpatrick skin type I or II. On a scheduled dosing day, study cream was applied to the target tumor and approximately 1 cm (about 1/3 inch) beyond the target tumor prior to normal sleeping hours, and 5 times per week dosing was continued for a total of 6 weeks. The target tumor area was clinically assessed 12 weeks after the last scheduled application of study cream. The entire target tumor was then excised and examined histologically for the presence of tumor.

Efficacy was assessed by the complete response rate defined as the proportion of subjects with clinical (visual) and histological clearance of the sBCC lesion at 12 weeks post-treatment. Of Aldara (imiquimod) -treated subjects, 6% (11/178) who had both clinical and histological assessments posttreatment, and who appeared to be clinically clear had evidence of tumor on excision of the clinically-clear treatment area.

Data on composite clearance (defined as both clinical and histological clearance) are shown in the table below.

Table 12: Composite Clearance Rates at 12 Weeks Post-Treatment for Superficial Basal Cell Carcinoma

Study Aldara Cream Vehicle Cream
Study sBCC1 70% 2%
(66/94) (2/89)
Study sBCC2 80% 1%
(73/91) (1/90)
Total 75% 2%
(139/185) (3/179)

A separate 5-year, open-label study was conducted to assess the recurrence of sBCC treated with Aldara (imiquimod) Cream applied once daily 5 days per week for 6 weeks. Target tumor inclusion criteria were the same as for the studies described above. At 12-weeks post-treatment, subjects were clinically evaluated for evidence of persistent sBCC (no histological assessment). Subjects with no clinical evidence of sBCC entered the long-term follow-up period. At the 12 week Posttreatment assessment, 90% (163/182) of the subjects enrolled had no clinical evidence of sBCC at their target site and 162 subjects entered the long-term follow-up period for up to 5 years. Two year (24 month) follow-up data are available from this study and are presented in the table below:

Table 13: Estimated Clinical Clearance Rates for Superficial Basal Cell Carcinoma Follow-up Period

Follow-up visit after 12- week Post treatment assessment No. of Subjects who remained clinically clear No. of Subjects with sBCC recurrence No. of Subjects who discontinued at this visit with no sBCCa Estimated Rate of Subjects who Clinically Cleared and remained Clearb
Month 3 153 4 5 87%
Month 6 149 4 0 85%
Month 12 143 2 4 84%
Month 24 139 4 0 79%
a Reasons for discontinuation included death, non-compliance, entry criteria violations, personal reasons, and treatment of nearby sBCC tumor.
b Estimated rate of subjects who clinically cleared and remained clear are estimated based on the time to event analysis employing the life table method beginning with the rate of clinical clearance at 12 weeks post-treatment.

External Genital Warts

In a double-blind, placebo-controlled clinical study, 209 otherwise healthy subjects 18 years of age and older with genital/perianal warts were treated with Aldara (imiquimod) Cream or vehicle control 3 times per week for a maximum of 16 weeks. The median baseline wart area was 69 mm² (range 8 to 5525 mm²). Subject accountability is shown in the figure below.

Figure 1: Subject Accountability (External Genital Warts)

Subject Accountability - Illustration

Data on complete clearance are listed in the table below. The median time to complete wart clearance was 10 weeks.

Table 14: Complete Clearance Rates (External Genital Warts)- Study EGW1

Treatment Subjects with Complete Clearance of Warts Subjects Without Follow-up Subjects with Warts Remaining at Week 16
Overall
  Aldara Cream (n =109) 54 (50%) 19 (17%) 36 (33%)
  Vehicle (n = 100) 11 (11%) 27 (27%) 62 (62%)
Females
  Aldara Cream (n = 46) 33 (72%) 5 (11%) 8 (17%)
  Vehicle (n = 40) 8 (20%) 13 (33%) 19 (48%)
Males
  Aldara Cream (n = 63) 21 (33%) 14 (22%) 28 (44%)
  Vehicle (n = 60) 3 (5%) 14 (23%) 43 (72%)

Last reviewed on RxList: 11/12/2010
This monograph has been modified to include the generic and brand name in many instances.

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