Pharmacokinetics and safety of imiquimod 5% cream in the treatment of actinic keratoses of the face, scalp, or hands and arms.

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.

Pharmacokinetic comparison of beclomethasone dipropionate extrafine aerosol from two inhaler devices in children with asthma.

OBJECTIVE: The primary objective was to test the comparability of the pharmacokinetics of beclomethasone dipropionate (BDP) delivered from a pressurized extrafine solution formulation in two inhalation devices in children with asthma. One inhaler was actuated using the press and breathe (P&B) technique and the other was breath-actuated (AH); both inhalers used HFA-134a as propellant. METHODS: Eighteen children aged between 9 years and 12 years entered and completed the study; written informed consent was obtained from all patients and their legal guardians. Each patient received, according to a randomized three-period crossover design, 200 microg BDP as four inhalations from 50 microg/actuation P&B, 200 microg BDP as four inhalations from 50 microg/actuation AH, and 400 microg BDP as four inhalations from 100 microg/actuation AH. Each patient was instructed on the proper use of each device once, at the screening visit. Patients self-administered all inhalations at the same time of day during the study without further coaching. Blood samples were collected for 24 h during each period to assay for the presence of BDP and metabolites. The log-transformed pharmacokinetic data were compared using a confidence-interval approach. RESULTS: Almost all the BDP-derived material in the plasma was the active metabolite beclomethasone 17-monopropionate; pharmacokinetic analyses were only performed for this metabolite. The ratios each of the pharmacokinetic parameters maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC), between the AH and P&B inhaler devices, were 0.94 and 1.1, respectively, and the corresponding 95% confidence intervals demonstrated comparability of the devices. Dose proportionality of C(max) and AUC between the 200-microg and 400-microg doses was similarly shown. About twice as many inhalation errors occurred during the P&B administration as during the AH periods, but the incidence was still low and did not result in any change in pharmacokinetics. CONCLUSION: The rate and extent of drug absorption was comparable from the P&B and AH inhaler devices in children with asthma. Dose proportionality was also observed.

Pharmacokinetics of beclomethasone 17-monopropionate from a beclomethasone dipropionate extrafine aerosol in adults with asthma.

OBJECTIVE: The objectives of this study were to test the dose and strength proportionalities of beclomethasone dipropionate (BDP) delivered from two strengths of a pressurized extrafine solution formulation. METHODS: Thirty adults with mild, stable asthma, aged between 18 years and 70 years, completed the study; written informed consent was obtained from all patients. Each patient received, according to a randomized four-period crossover design, 100 microg BDP as two inhalations from 50-microg/actuation strength, 100 microg BDP as one inhalation from 100-microg/actuation strength, 400 microg BDP as eight inhalations from the 50-microg/actuation strength, and 400 microg BDP as four inhalations from the 100-microg/actuation strength. Patients self-administered all inhalations at the same time of day during the study. Blood samples were collected for 12 h during each period to assay for the presence of BDP and metabolites. The log-transformed pharmacokinetic data were compared for proportionality equivalence using a confidence-interval approach. RESULTS: Almost all the BDP-derived material in the plasma was the active metabolite beclomethasone 17-monopropionate (17-BMP). Due to low levels, neither elimination half-life ( t(1/2)) nor the area under the plasma concentration-time curve (AUC) for 17-BMP could be calculated for the 100-microg BDP doses. Dose proportionality of the 100-microg and 400-microg BDP doses, using 17-BMP maximum plasma concentration (C(max)) was demonstrated for each strength. Strength proportionality of the 50-microg and 100-microg/actuation strengths was observed for C(max) at both dose levels and for AUC at the higher dose level. The t(1/2) of 17-BMP was found to be approximately 2.8 h. CONCLUSION: This study demonstrated both the strength and dose proportionalities of the BDP extrafine aerosol. This important information will allow physicians maximum flexibility in prescribing this aerosol product.