Imiquimod

Pharmacological Actions
Imiquimod is classified as an immune response modifier, specifically acting as a Toll-like receptor 7 (TLR7) agonist. This action stimulates the innate immune system by activating immune cells, leading to the production of cytokines such as interferons, interleukins, and tumor necrosis factors. This immune activation is crucial for its therapeutic effects in treating conditions like external genital and perianal warts (EGW), actinic keratoses (AK), and superficial basal cell carcinoma. While the exact mechanism for AK and EGW is not fully elucidated, it is associated with increased markers of cytokines and immune cells upon topical application, with no direct antiviral activity observed in cell culture for EGW. The immune response is thought to help eliminate abnormal skin cells and viral infections, making it effective for these dermatological conditions.
The time course of these pharmacological actions is influenced by the drug's pharmacokinetics, particularly its prolonged retention in the skin when applied topically. This sustained presence, with an apparent half-life of 24-29 hours, suggests a gradual release and prolonged immune activation, which is beneficial for local treatment but may contribute to local skin reactions over time.
Pharmacokinetics and Bioavailability
The pharmacokinetics of Imiquimod vary significantly between topical and oral routes, reflecting its primary use as a topical agent.

Absorption: Systemic absorption is minimal, with mean peak serum concentrations ranging from 0.1 ng/mL to 3.5 ng/mL depending on the dose and application area (e.g., face, scalp, hands/arms). Urinary recovery data indicate systemic absorption is less than 1%, with recovery rates of 0.08% to 2.41% of the applied dose, suggesting very low bioavailability into the bloodstream.
Half-life: The apparent half-life is approximately 24-29 hours, significantly longer than subcutaneous dosing (2 hours), due to prolonged retention in the skin. This prolonged half-life supports its efficacy for local immune activation over extended periods.
Steady-state: Achieved by Day 7 with once-daily dosing, indicating a build-up effect over the initial treatment phase.

Bioavailability: Research from a clinical study indicates an oral bioavailability of 47% relative to subcutaneous administration, with no significant effect from food intake on absorption rate or extent. This suggests it can be administered orally in fasted or non-fasted states, though this is not a standard route.
Absorption Half-life: Approximately 1 hour, with Tmax around 2.6 hours in fasted states and 3.6 hours in non-fasted states, showing a slight delay with food.
Elimination Half-life: About 2.5 hours, with total body clearance around 970 ml/h×kg, indicating rapid systemic clearance compared to topical use.
Dose and Study Context: The study involved a 100 mg oral dose, significantly higher than typical topical doses, highlighting its experimental nature for oral use.

The difference in bioavailability and half-life between routes underscores Imiquimod's design for topical application, where local effects are prioritized over systemic exposure.
Dosage and Administration
Imiquimod is available as a 3.75% cream for topical use, with specific dosing regimens based on the condition:

Apply a thin layer (0.5 grams, equivalent to 18.75 mg Imiquimod) once daily at bedtime to the affected area (face or balding scalp) for two 2-week treatment cycles, separated by a 2-week no-treatment period. Leave on for about 8 hours, then remove with mild soap and water. Dosage interruption may be necessary for local skin reactions, but cycles should not be extended.

Apply a thin layer (0.25 grams, equivalent to 9.375 mg Imiquimod) once daily at bedtime until total clearance or for up to 8 weeks, leave on for about 8 hours, then remove. Dosage interruption may be needed for local skin reactions.

General Notes: Not for oral, ophthalmic, intra-anal, or intravaginal use. Prescribe no more than 2 boxes (56 packets) or two 7.5 g bottle pumps per treatment course to limit exposure.

Safety Profile and Toxicity
The safety range is defined by adherence to prescribed doses, with exceeding these increasing the risk of adverse reactions. The minimum effective dose aligns with the prescribed regimens, as lower doses may not achieve therapeutic efficacy. The maximum dose without high risks is the prescribed amount, as higher doses can lead to severe local skin reactions and potential systemic effects.

Adverse Reactions: Common side effects include local skin reactions (erythema, scabbing, flaking, edema, erosion, exudate), headache, application site pain, irritation, pruritus, fatigue, influenza-like illness, and nausea, reported in ≥4% of patients. Postmarketing reports include application site tingling, angioedema, cardiovascular events, endocrine disorders, hematological decreases, hepatic issues, infections, musculoskeletal pain, neuropsychiatric events, respiratory issues, urinary retention, skin changes, and vascular events.
Overdosage: Topical overdosage can increase severe local skin reactions. Oral ingestion of doses >200 mg has been associated with hypotension in clinical trials, indicating a threshold for systemic toxicity. For management, contact the Poison Help line at 1-800-222-1222.
LD50 (Lethal Dose 50%): From animal toxicity studies, the following LD50 values were observed:

Oral: 1665 mg/kg in rats, 200 mg/kg in Cynomolgus monkeys.
Intravenous: 6-8 mg/kg.
Intraperitoneal: 763 mg/kg in rats, 879 mg/kg in mice.
Subcutaneous: 20 mg/kg in rats. These values are from preclinical studies and not directly applicable to humans, but they provide insight into potential toxicity thresholds, especially for accidental ingestion.

When It Becomes Too Dangerous: For topical use, exceeding recommended doses can lead to severe local skin reactions, potentially requiring dosage interruption. For oral ingestion, doses above 200 mg are concerning, with hypotension reported, suggesting a point where systemic effects become significant.