The pharmacokinetics of an adenosine agonist, AMP 579, following intravenous administration were evaluated. Single AMP 579 doses of 20 to 150 micrograms/kg were infused intravenously over 6 hours using a constant-rate or two-step rate of infusion to healthy male volunteers. Plasma and urine samples were collected for measurement of AMP 579 concentration using a validated HPLC assay. An assessment of safety and tolerability was also performed. Based on a noncompartmental method of analysis, the pharmacokinetics of AMP 579 were characterized by rapid systemic clearance (0.77 to 0.85 L/h/kg), a moderate steady-state volume of distribution (0.80 to 0.94 L/kg), and a short terminal elimination half-life (0.84 to 1.13 h). AMP 579 exhibited dose (infusion rate)-proportional pharmacokinetics over the dose range. In addition, little or no unchanged AMP 579 was found in the urine. The primary cardiovascular pharmacodynamic response that was observed was a dose-related increase in mean ventricular heart rate. Fifteen minutes prior to the end of the infusion, volunteers administered the highest dose (150 micrograms/kg) exhibited a mean (range) 59% (36%-69%) increase in heart rate as compared to a mean (range) 18% (0%-73%) increase for the placebo group. No clinically relevant changes in the systolic or diastolic blood pressure were observed. The information obtained in this study should allow the design of AMP 579 dosage regimens that would maximize plasma AMP 579 concentrations and minimize the incidence of adverse events.
Triamcinolone acetonide is a glucocorticoid administered by oral inhalation in the management of asthma. With oral inhalation of glucocorticoids, systemic absorption can come from oropharyngeal, gastrointestinal, or airway deposition of the drug. The objectives of this study were to determine the absolute bioavailability of triamcinolone acetonide following inhalation administration and to delineate the airway contribution of triamcinolone acetonide absorption relative to the absolute bioavailability. All subjects received a 5-minute 400 mcg intravenous infusion of triamcinolone acetonide and a single 800 mcg dose of inhaled triamcinolone acetonide with and without oral charcoal administration in a randomized three-way crossover fashion. The oral charcoal allowed for isolating the pulmonary component of absorption by adsorbing the oropharyngeal and gastrointestinal deposited drug. The mean (+/- SD) absolute bioavailability value for inhaled triamcinolone acetonide was 25% (8.75%). Delineation of the airway contribution of triamcinolone acetonide absorption showed that 10.4% of an inhaled dose is absorbed as triamcinolone acetonide from the lungs. Mean (+/- SD) total body clearance was rapid at 0.57 (0.12) L/hr/kg. The mean (+/- SD) apparent volume of distribution following the intravenous dose was a low 1.96 (0.31) L/kg. No significant differences were noted in the apparent terminal elimination half-life of triamcinolone acetonide (approximately 2.4 hr) between treatments.
The impending phaseout of chlorofluorocarbons as propellants in pressurized metered-dose inhalers used in the treatment of asthma has resulted in the development of alternative devices to deliver drug to the pulmonary airways. These alternative devices include metered-dose inhalers using environmentally friendly hydroflurocarbon propellants and breath-actuated dry-powder inhalers. The purpose of this study was to compare the single- and multiple-dose pharmacokinetics, pharmacodynamics, and tolerability of a newly developed hydroflurocarbon formulation of triamcinolone acetonide (Azmacort HFA 225 mcg Inhalation Aerosol) to that of the dry-powder formulation of budesonide (Pulmicort Turbuhaler 200 mcg). This three-way crossover study used 18 normal healthy subjects each receiving a 675 mcg dose of triamcinolone acetonide, 600 mcg dose of budesonide, or placebo twice a day for 5 days. Serial plasma samples were collected after the first and last dose of test medication for pharmacokinetic analysis. Pharmacodynamics were assessed by changes in hypothalamic-pituitary-adrenal axis function as measured by 8 a.m. serum cortisol, 24-hour overnight serum cortisol AUC(0-24), and 24-hour urinary-free cortisol after the last evening dose of test drug. Tolerability was assessed through physical examinations, vital signs, 12-lead ECG, routine clinical labs, and adverse events recording. Both compounds were systemically absorbed. However, no significant drug accumulation was noted with chronic dosing. Chronic dosing did result in a statistically significant 20% reduction in basal 24-hour serum cortisol AUC(0-24) for both compounds. There were no clinically significant abnormalities in physical examination, vital signs, 12-lead ECG, or routine clinical labs noted during the study. Overall, the study drugs were well tolerated, with adverse events characterized as mild to moderate in severity.
A pharmacoscintigraphic study was conducted to compare the dose deposition of HMR 1031 from the existing nebulizer formulation and the new Ultrahaler device to help determine the doses for future phase 2 trials. This was a single-dose, open-label, randomized, two-way crossover study in which HMR 1031 (3 mg) was delivered by the Ultrahaler and the Pari LC Star nebulizer to 12 healthy male subjects. For both treatments, the formulations were radiolabeled with technetium-99m pertechnetate such that a maximum of 10 MBq was delivered on each study day. Scintigraphic images were acquired immediately after dosing to estimate the percentage of the dose delivered to the lungs and oropharynx. Serial plasma samples were collected up to 12 hours post-dose on each occasion and analyzed for HMR 1031 by a LC/MS/MS method with a lower limit of quantitation of 10 pg/mL (0.01 ng/mL). Pharmacokinetic parameters were calculated for HMR 1031 using noncompartmental methods. No serious adverse events were reported. The systemic absorption of HMR 1031 following inhalation administration was relatively rapid, with median T(max) values of 0.5 hours and 1.0 hours post-dose after administration via Ultrahaler and nebulizer, respectively. The mean plasma AUC(0-12) (Ultrahaler, 15.8 ng*h/mL; nebulizer, 11.1 ng*h/mL) and C(max) (Ultrahaler, 4.96 ng/mL; nebulizer, 2.28 ng/mL) values were approximately 42% and 118% higher for the Ultrahaler compared with the nebulizer. The mean terminal half-life of HMR 1031 was similar after administration from both devices (2.91 and 3.18 hours). Based on the scintigraphic data, the lung deposition of HMR 1031 after administration by Ultrahaler (24.6% of the administered dose) was approximately 37% higher compared with the lung deposition from the nebulizer (18.0% of the administered dose). This observation was in agreement with the relative difference in the plasma AUC values achieved after administration of the two formulations. The in vivo results based on the scintigraphic data were also comparable with those from in vitro studies for the Ultrahaler. Based on the ratio of the dose delivered by both the formulations, the required doses for the future Ultrahaler formulation can be predicted.
RPR749 and its methylated metabolite are orally active and selective adenosine A(1) agonists that can inhibit lipolysis and lower plasma triglyceride levels in a variety of animal models. RPR749 also appears to lower free fatty acid (FFA) and insulin levels and may have additional lipid-modifying effects. This double-blind, single increasing-dose, placebo-controlled, parallel group, randomized study, the first done in humans, evaluated the safety, pharmacokinetics, and pharmacodynamics (effect on FFA) after a single oral dose of up to 200 mg RPR749 or placebo. Six parallel groups of 8 healthy men (6 active and 2 placebo/group) were enrolled in the study. Plasma samples were collected for up to 72 hours post-dose. RPR749 and its metabolite RPR772 concentrations were measured by a validated LC/MS/MS method with a minimal quantifiable limit of 1 ng/mL. RPR749 was safe and well tolerated as a single oral dose up to 200 mg. The mean plasma concentrations of RPR749 were approximately 30-fold higher than the mean RPR772 plasma concentrations. The mean terminal half-life (t(1/2)) of RPR749 and RPR772 were similar (approximately 16.4 hours). Mean values for serum insulin, triglycerides, glycerol, and blood glucose remained within normal ranges. Mean FFA concentrations in serum decreased in all treatment groups with the maximal decrease in the 200-mg dose group. In conclusion, RPR749 has the ability to reduce circulating levels of FFA that can be related to plasma RPR749 concentrations and thus possesses pharmacological properties that may be beneficial in treating coronary artery diseases and hyperlipidemia.
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