Randomized study of the safety, pharmacokinetics, and bronchodilatory efficacy of a proprietary glycopyrronium metered-dose inhaler in study patients with chronic obstructive pulmonary disease

BACKGROUND: Bronchodilator medications are central to the symptomatic management of chronic obstructive pulmonary disease (COPD). Metered-dose inhalers (MDIs) are the most commonly used devices to deliver treatment to patients with COPD and asthma, comprising approximately 70% of bronchodilator prescriptions. Proprietary porous-particle technology permits the formulation of long-acting muscarinic antagonists, long-acting β(2)-agonists, and a combination of both in hydrofluoroalkane (HFA) MDIs, providing a solution to formulation challenges inherent to the development of HFA MDIs, which have contributed to the development of dry-powder inhalers. METHODS: In this randomized, double-blind, 4-period, 6-treatment, placebo- and active-controlled, multicenter, crossover study, 4 ascending single doses of a proprietary glycopyrronium (GP) MDI were evaluated compared with Placebo MDI and open-label tiotropium (TIO) in study patients with COPD. Thirty-three study patients were enrolled and received single-dose administration of 4 of the 6 treatments (Placebo MDI, TIO 18 μg, or GP MDI at 14.4, 28.8, 57.6, and 115.2 μg ex-actuator) with an interval of 1 to 3 weeks between doses. The primary efficacy endpoint was peak change in forced expiratory volume in 1 second (FEV(1)). RESULTS: All 4 doses of GP MDI showed statistically superior efficacy compared with Placebo MDI for peak FEV(1) (differences of 146 to 248 mL; P < .001), with a clear dose ordering of the response. Statistically significant differences compared with Placebo MDI were noted at almost all doses for the secondary FEV(1) parameters (P ≤ .049) except 24-hour trough FEV(1) at 28.8 μg. All doses were safe and well tolerated in this study; the most frequently reported adverse event was dry mouth (0–14.3% across doses; 9.5% for Placebo MDI, and 9.1% for TIO). CONCLUSIONS: This study demonstrated superior bronchodilatory efficacy of GP MDI compared with Placebo MDI at all doses tested, and no serious adverse events were reported. This study supports the further evaluation of GP MDI in study patients with COPD. In addition, these findings indicate that the correct dosage of glycopyrronium is no more than 115.2 μg total daily dose, or 57.6 μg twice daily based on comparisons with the active comparator. TRIAL REGISTRATION: This clinical trial was registered on ClinicalTrials.gov, Identifier: NCT00871182

Absence of an effect of a single-dose deferasirox on the steady-state pharmacokinetics of digoxin.

Deferasirox (Exjade, ICL670) is a potent iron chelator, recently approved as first-line therapy for the treatment of blood-transfusion-related iron overload. Iron deposition in the heart may lead to cardiac dysfunction in patients with iron overload. Thus, the combination of cardiac glycosides and deferasirox is likely to be used in clinical practice

Sinistrin clearance for determination of glomerular filtration rate: a reappraisal of various approaches using a new analytical method

Several approaches are available to estimate the glomerular filtration rate (GFR) from the sinistrin clearance. To compare such approaches, GFR was estimated in six healthy volunteers, both after a bolus injection and a bolus dose followed by a 6-hour infusion. A recently developed high-performance liquid chromatography method was used for the determination of sinistrin levels, enabling precise measurements in plasma and urine samples with high sensitivity. Blood and urine were sampled up to 6 hours. Four calculation methods for estimating GFR were applied: 1) classical ratio of urinary excretion rate over plasma concentration (UV/P); 2) two-point (log-linear regression slope times monocompartmental volume of distribution) after bolus; 3) ratio of dose over area under the curve (D/AUC) after bolus; and 4) ratio of infusion rate over steady-state concentration during infusion (Rinf/P). The results obtained by fitting a pharmacokinetic model to all the plasma and urine data served as the standard against which the performance of the respective calculation methods were examined. The UV/P method performed poorly on bolus data, mainly by underestimating GFR at late times; on both bolus and infusion data, it suffered from important imprecisions on the urinary volume. The two-point method appeared applicable only between 2 and 4 hours after the bolus dose. The D/AUC method with extrapolation to infinity was highly reliable when integrating the concentrations up to 3 hours or more after the bolus dose. The Rinf/P method was satisfactory if applied later than 2 to 3 hours after the loading dose. The advantages and drawbacks of each method have to be evaluated in relation to the particular clinical setting in which GFR is to be estimated