Dental procedures in 24 patients with chronic immune thrombocytopenia in prospective clinical studies of eltrombopag.

Primary immune thrombocytopenia (ITP) is an autoimmune disease characterized by chronically low peripheral blood platelet counts. Eltrombopag is an oral, non-peptide, thrombopoietin-receptor agonist that increases platelet production. This report examines peri-procedural platelet counts and bleeding complications among chronic ITP patients requiring dental procedures while participating in clinical studies with eltrombopag. A total of 494 patients participated in five clinical studies of eltrombopag in chronic ITP. Information about dental procedures was collected prospectively in four studies and retrospectively in one study. Twenty-four patients (22 eltrombopag, 2 placebo) underwent 32 dental procedures (dental cleaning, tooth repair, artificial crown, dental prosthesis, tooth extraction, dental or wisdom teeth extraction, dental root extraction, and endodontic procedures, among others) during study treatment or up to 10 days later. Supplemental ITP therapy (e.g., corticosteroids, platelet transfusions) was given before the dental procedure to increase platelet counts in three eltrombopag-treated patients and both placebo-treated patients. The mean pre-procedure platelet count ± standard deviation for all procedures in the overall population of patients, eltrombopag group, and placebo group prior to undergoing dental procedures was 96 000 ± 81 069/µl,103 517 ± 81 522/µl, and 23 333 ± 9291/µl, respectively. Two patients in each group had platelet counts below 30 000/µl before the procedure. No patient who had a dental procedure experienced a bleeding adverse event. Among patients with chronic ITP who required a dental procedure during clinical studies of eltrombopag, supplemental ITP treatment was required for both patients who received placebo but was not required for most patients who received eltrombopag. No bleeding complications were reported. These data imply that patients with chronic ITP who receive eltrombopag and experience increases in platelet counts fulfill current pre-procedural platelet count recommendations to undergo invasive dental procedures, and may have a lower risk of bleeding complications and a reduced need for supplemental ITP treatment.

Dose response of umeclidinium administered once or twice daily in patients with COPD: a pooled analysis of two randomized, double-blind, placebo-controlled studies.

Umeclidinium (UMEC) is an inhaled long-acting muscarinic antagonist approved in the US and EU for the once-daily (QD) treatment of chronic obstructive pulmonary disease (COPD); it is not indicated for the treatment of asthma. To fully characterize the dose-response relationship of UMEC in patients with COPD, a pooled analysis of data from two randomized, placebo-controlled, cross-over, dose-ranging studies was performed, evaluating UMEC at doses of 15.6-1000 mcg QD and 15.6-250 mcg twice daily (BID). The primary endpoint was trough forced expiratory volume in one second (FEV(1)) at the end of each study's treatment period (Day 8/Day 15). A population model-based analysis using total daily UMEC dose was used for the primary analysis comparing QD and BID dosing. A physiological effect (E(max)) model was optimal in defining the relationship between UMEC dose and the primary endpoint, demonstrating a clear monotonic dose response over QD and BID dosing regimens. UMEC doses ≥62.5 mcg QD were differentiated from lower doses and BID dosing did not provide benefit over QD dosing. The potency (ED(50)) estimate was 33 mcg with QD dosing. These data indicate that UMEC 62.5 mcg and 125 mcg QD provide lung function benefits that warrant further investigation for the treatment of COPD.

Dose response of umeclidinium administered once or twice daily in patients with COPD: a randomised cross-over study.

BACKGROUND: Umeclidinium bromide (UMEC) is an inhaled long-acting muscarinic antagonist in development for chronic obstructive pulmonary disease (COPD). METHODS: This was a multicentre, randomised, double-blind, placebo-controlled, three-way cross-over, incomplete block study to evaluate UMEC 15.6, 31.25, 62.5, and 125 µg administered once daily (QD), and UMEC 15.6 µg and 31.25 µg administered twice daily (BID), over 7 days in patients with COPD. Tiotropium was included as an open-label treatment arm. The primary efficacy endpoint was trough forced expiratory volume in 1 second (FEV1) on Day 8. Secondary efficacy endpoints included weighted mean FEV1 over 0-24 hours after morning dosing on Day 7, and serial FEV1 at each time point over 24 hours after morning dosing on Day 7. Safety and pharmacokinetics were also examined. RESULTS: One hundred and sixty-three patients (mean age 59.5 years, 52% female) were randomised. Based on the population dose-response model of trough FEV1 data, the geometric mean potency (ED50) of UMEC was 37 µg (95% confidence interval [CI]: 18, 57) with a predicted maximum intrinsic efficacy (Emax) at trough of 0.185 L (95% CI: 0.153, 0.218) after QD dosing. UMEC 125 µg QD demonstrated the greatest improvements in measure of lung function compared with doses of 62.5 µg and below. UMEC 125 µg QD exhibited more consistent increases in FEV1 from baseline across serial time points over 24 hours compared with other UMEC doses and tiotropium. Increases in FEV1 over 0-12 hours were similar to those observed over 12-24 hours after the second dose of UMEC was administered. UMEC was rapidly absorbed following inhaled dosing and eliminated from plasma. Adverse events, generally mild, were highest with UMEC 125 µg QD (18%) compared with placebo (8%), tiotropium (4%) and other UMEC doses (5-12%). CONCLUSIONS: UMEC is a potent QD bronchodilator with geometric mean ED50 of 37 µg. A dose ordering over the range of UMEC 15.6-125 µg QD doses was observed, with UMEC 125 µg showing the greatest improvement in trough FEV1.