(Actinic Keratos is)
Amount of Imiquimod Cream
applied
Mean peak serum imiquimod
concentration [C ]
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.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenes is , Mutagenes is , Impairment of Fertility
In an oral (gavage) rat carcinogenicity study, imiquimod was administered to Wistar rats on a 2×/week
(up to 6 mg/kg/day) or daily (3 mg/kg/day) dosing schedule for 24 months. No treatment related tumors
were noted in the oral rat carcinogenicity study up to the highest doses tested in this study of 6 mg/kg
administered 2×/week in female rats (87× MRHD based on weekly AUC comparisons), 4 mg/kg
administered 2×/week in male rats (75× MRHD based on weekly AUC comparisons) or 3 mg/kg
administered 7×/week to male and female rats (153× MRHD based on weekly AUC comparisons). In a
dermal mouse carcinogenicity study, imiquimod cream (up to 5 mg/kg/application imiquimod or 0.3%
imiquimod cream) was applied to the backs of mice 3×/week for 24 months. A statistically significant
increase in the incidence of liver adenomas and carcinomas was noted in high dose male mice compared
to control male mice (251× MRHD based on weekly AUC comparisons). An increased number of skin
papillomas was observed in vehicle cream control group animals at the treated site only. The
quantitative composition of the vehicle cream used in the dermal mouse carcinogenicity study is the
same as the vehicle cream used for Imiquimod Cream, minus the active moiety (imiquimod).
In a 52-week dermal photoco-carcinogenicity study, the median time to onset of skin tumor formation
was decreased in hairless mice following chronic topical dosing (3×/week; 40 weeks of treatment
followed by 12 weeks of observation) with concurrent exposure to UV radiation (5 days per week) with
the Imiquimod Cream vehicle alone. No additional effect on tumor development beyond the vehicle
effect was noted with the addition of the active ingredient, imiquimod, to the vehicle cream.
Imiquimod revealed no evidence of mutagenic or clastogenic potential based on the results of five in
vitro genotoxicity tests (Ames assay, mouse lymphoma L5178Y assay, Chinese hamster ovary cell
chromosome aberration assay, human lymphocyte chromosome aberration assay and SHE cell
transformation assay) and three in vivo genotoxicity tests (rat and hamster bone marrow cytogenetics
assay and a mouse dominant lethal test).
Daily oral administration of imiquimod to rats, throughout mating, gestation, parturition and lactation,
demonstrated no effects on growth, fertility or reproduction, at doses up to 87× MRHD based on AUC
comparisons.
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