Purpose: Recent advances in the understanding of innate immunity suggest that an orchestrated sequence of events is required to elicit a productive immune response against cancer. We studied the systemic administration of the Toll-like receptor 7 agonist 852A, a small-molecule imidazoquinoline, in patients with advanced cancer. Preclinical studies showed that 852A stimulates plasmacytoid dendritic cells to produce multiple cytokines, such as IFN-a, interleukin-1 receptor antagonist, and IFN-inducible protein-10. Our goal was to define the tolerated dose, pharmacokinetics, pharmacodynamics, and immunologic effects of 852A in humans. Experimental Design: Eligible adult patients with refractory solid organ tumors received i.v. 852A thrice weekly for 2 weeks. Patients who had responses or stable disease were eligible for additional cycles. Results: Twenty-five patients (median age, 55.0 years; 72% male) were enrolled in six cohorts at dose levels of 0.15 to 2.0 mg/m 2 . Serum drug levels showed dose proportionality and no evidence of drug accumulation. The maximum tolerated dose was 1.2 mg/m 2 ; higher doses were limited by fatigue and constitutional symptoms. Increases in IFN-a, interleukin-1 receptor antagonist, and IFN-inducible protein-10, immunologic activity, and clinical symptoms were observed in all patients receiving dose levels z0.6 mg/m 2 . Significant correlations were found between pharmacodynamic biomarkers and pharmacokinetic variables, and an objective clinical response was seen. Conclusions: 852A was safely administered i.v. at doses up to 1.2 mg/m 2 thrice weekly for 2 weeks with transient or reversible adverse effects. This novel Toll-like receptor 7 agonist is biologically active and holds promise for stimulating innate immune responses. Future trials are warranted to assess its therapeutic role in patients with cancer.
852A is an imidazoquinoline Toll-like receptor 7 agonist undergoing evaluation for the systemic treatment of cancer. 852A was administered to 6 healthy subjects as 3 rising subcutaneous doses (0.5 to 1.0 to 2.0 mg), to 6 subjects as 3 oral doses (10.0 to 20.0 to 15.0 mg, the third dose being a de-escalation), and to 6 subjects as a 2.0-mg dose by the subcutaneous, intravenous, and oral routes in crossover fashion. The subcutaneous and intravenous doses were well tolerated. One subject withdrew following the 20.0-mg oral dose because of hypotension. The 2.0-mg subcutaneous dose had 80.5% +/- 12.8% (mean +/- SD) bioavailability and gave serum concentrations comparable to intravenous administration by 30 minutes. Linear kinetics and an interferon-alpha dose response were observed for the 3 subcutaneous doses. Serum concentrations following the 2.0-mg oral dose were always lower than those following the same intravenous dose, and the oral route had a bioavailability of 26.5% +/- 7.84%. Concentrations appeared to increase with oral dose; however, large variabilities in both the rate and extent of absorption were seen between individuals. Approximately 40% of an absorbed dose was excreted unchanged in the urine. Overall, the study suggests that subcutaneous administration may be an acceptable method to deliver 852A for systemic applications.
The safety and efficacy of imiquimod 5% cream is being evaluated for the treatment of dysplastic lesions of the epidermis (actinic keratoses, AK). The objective of this clinical study was to describe the pharmacokinetics and safety of topical imiquimod during multiple dosing of AK subjects. A total of 58 adult subjects with 5 to 20 AK lesions at the treatment site applied imiquimod cream three times per week for up to 16 weeks as follows: 12 males and 11 females applied 12.5 mg imiquimod to the face; 11 males applied 25 mg to the entire balding area of the scalp; and 12 males and 12 females applied 75 mg to both hands and forearms. Pharmacokinetics and safety were assessed after the first and last doses, as well as biweekly. Imiquimod and its metabolites were measured in the serum and urine using sensitive liquid chromatography/mass spectrometry methods. Less than 0.6% of the applied doses was recovered in the urine of all subjects. Serum imiquimod levels were low, reflecting minimal dermal absorption, and increased with dose, although not proportionally. Peak levels at the end of dosing were 0.1, 0.2, and 1.6 ng/ml for the face, scalp, and hands/arms groups, respectively. A two- to fourfold accumulation was seen at the end of dosing. Local application site reactions were the most common adverse event, reported by approximately 50% of the subjects in each treatment group. The small number of systemic adverse events, including 'flu-like symptoms, were mostly mild and did not show a dose response. Thus, minimal systemic absorption and good safety margins for topical imiquimod were seen in AK subjects with doses as high as 75 mg three times per week for 16 weeks.
We set out to evaluate lung deposition, systemic availability, and basic pharmacokinetic parameters of beclomethasone dipropionate (BDP) in children with chronic asthma. Plasma levels of BDP, 17 and 21 beclomethasone monopropionate (17-BMP and 21-BMP), and beclomethasone were measured after an intravenous infusion of 60 microg BDP and after inhalation of A) 100 microg HFA-BDP, B) 200 microg HFA-BDP, C) 200 microg HFA-BDP after ingestion of charcoal to block gastrointestinal (GI) absorption of drug, and D) 400 microg CFC-BDP. A breath-actuated pMDI (Autohaler) was used for HFA inhalations, and a pMDI with a large volume spacer (Volumatic) for CFC inhalations. Treatments A-D were given in a randomized, cross-over design. Fourteen patients aged 10-14 years completed all 5 study days. The mean systemic bioavailabilities in percent of dose leaving the canister valve (ex-valve) were 70% (100 HFA), 74% (200 HFA), 60% (200 HFA + charcoal), and 27% (400 microg CFC). After HFA treatment, 82% of the systemically available dose was absorbed through the lungs, and 18% from the gastrointestinal tract. The estimated bioavailability of BDP from the GI tract was 68%. BDP was metabolized to 17-BMP within minutes. Mean steady-state volume of distribution of 17-BMP was 84 L, and the mean terminal half-life (T((1/2))) after the four inhalations was 2.7 hr (range, 2.2-3.7 hr). Mean T((1/2)) and clearance after i.v. administration were 1.7 hr and 0.9 L/min, respectively. The HFA Autohaler delivers approximately three times as much BDP to the intrapulmonary airways as a CFC-pMDI with a large volume spacer.
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