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      Effect of severe renal impairment on umeclidinium and umeclidinium/vilanterol pharmacokinetics and safety: a single-blind, nonrandomized study

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          Abstract

          Background

          Umeclidinium and vilanterol, long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease, are primarily eliminated via the hepatic route; however, severe renal impairment may adversely affect some elimination pathways other than the kidney.

          Objectives

          To evaluate the effect of severe renal impairment on the pharmacokinetics of umeclidinium and umeclidinium/vilanterol.

          Methods

          Nine patients with severe renal impairment (creatinine clearance <30 mL/min) and nine matched healthy volunteers received a single dose of umeclidinium 125 μg; and after a 7- to 14-day washout, a single dose of umeclidinium/vilanterol 125/25 μg.

          Results

          No clinically relevant increases in plasma umeclidinium or vilanterol systemic exposure (area under the curve or maximum observed plasma concentration) were observed following umeclidinium 125 μg or umeclidinium/vilanterol 125/25 μg administration. On average, the amount of umeclidinium excreted in 24 hours in urine (90% confidence interval) was 88% (81%–93%) and 89% (81%–93%) lower in patients with severe renal impairment compared with healthy volunteers following umeclidinium 125 μg and umeclidinium/vilanterol 125/25 μg administration, respectively. Treatments were well tolerated in both populations.

          Conclusion

          Umeclidinium 125 μg or umeclidinium/vilanterol 125/25 μg administration to patients with severe renal impairment did not demonstrate clinically relevant increases in systemic exposure compared with healthy volunteers. No dose adjustment for umeclidinium and umeclidinium/vilanterol is warranted in patients with severe renal impairment.

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          Most cited references 26

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          Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring.

          Cytochrome P450 (CYP) 3A4 is the most abundant enzyme of CYPs in the liver and gut that metabolizes approximately 50% currently available drugs. A number of important drugs have been identified as substrates, inducers, and/or inhibitors of CYP3A4. The substrates of CYP3A4 considerably overlap with those of P-glycoprotein. Both CYP3A4 and P-glycoprotein are subject to inhibition and induction by a number of factors. Mechanism-based inhibition of CYP3A4 is characterized by NADPH-, time-, and concentration-dependent enzyme inactivation occurring when some xenobiotics or drugs are converted by CYPs to reactive metabolites. Such an inhibition of CYP3A4 is caused by chemical modification of the heme, the protein, or both as a result of covalent binding of modified heme to the protein. To date, the identified clinically important mechanism-based CYP3A4 inhibitors mainly include macrolide antibiotics (eg, clarithromycin and erythromycin), anti-HIV agents (eg, ritonavir and delavirdine), antidepressants (eg, fluoxetine and fluvoxamine), calcium channel blockers (eg, verapamil and diltiazem), steroids and their modulators (eg, gestodene and mifepristone), and several herbal and dietary components. The inactivation of CYP3A4 by drugs often causes unfavorable and long-lasting drug-drug interactions and probably fatal toxicity, depending on many factors associated with the enzyme, drugs, and the patients. Clinicians are encouraged to have a sound knowledge of drug-induced, mechanism-based CYP3A4 inhibition; take proper cautions, and perform close monitoring for possible drug interactions when using drugs that are mechanism-based CYP3A4 inhibitors. To minimize drug-drug interactions involving mechanism-based CYP3A4 inhibition, it is necessary to choose safe drug combination regimens, adjust drug dosages appropriately, and conduct therapeutic drug monitoring for drugs with narrow therapeutic indices.
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            Human drug metabolising cytochrome P450 enzymes: properties and polymorphisms.

            The cytochrome P450s are responsible for about 75% of phase I dependent drug metabolism and for the metabolism of a huge amount of dietary constituents and endogenous chemicals. The human has 59 active genes, and 6 of those encode important drug metabolising enzymes. About 40% of cytochrome P450 dependent drug metabolism is catalysed by polymorphic enzymes and such drug P450 interactions are frequently seen in adverse drug reaction reports. In this contribution an update of human cytochrome P450 enzymology and pharmacogenetics is given with particular emphasis on CYP1B1, CYP2B6, CYP2E1 and CYP3As.
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              A randomized, double-blind dose-ranging study of the novel LAMA GSK573719 in patients with COPD.

              This study evaluated the dose-response and dosing interval of the novel long-acting muscarinic receptor antagonist (LAMA) GSK573719 in patients with COPD. This randomized, double-blind, placebo-controlled, 3-way cross-over, incomplete block study evaluated 5 once-daily doses of GSK573719 (62.5-1000 μg), 3 twice-daily doses (62.5-250 μg), and open-label tiotropium for 14 days in patients (N = 176) with COPD (FEV(1) of 35-70% predicted). The primary endpoint was morning trough FEV(1) at Day 15. Secondary endpoints included 0-24 h weighted mean FEV(1) and serial FEV(1) values over 28 h. Safety measures and pharmacokinetics were assessed. All once-daily doses of GSK573719 significantly increased trough FEV(1) at Day 15 with improvements ranging from 95 to 186 mL over placebo (p ≤ 0.006), from 79 to 172 mL with twice-daily dosing (p ≤ 0.03), and 105 mL with tiotropium (p = 0.003). No clear dose ordering was observed. Once-daily doses significantly (p < 0.001) increased 0-24 h weighted mean FEV(1) at Day 14 by 131-143 mL over placebo, comparable to increases with the twice-daily doses (120-142 mL) and tiotropium (127 mL). Significant reductions in rescue albuterol use and improvements in FVC were also observed with once-daily dosing. Plasma C(max) occurred within 5-15 min of dosing after which the drug was rapidly cleared and eliminated. GSK573719 was well tolerated, with no apparent treatment-related changes in vital signs, ECG and Holter assessments, or clinical laboratory parameters. Once-daily dosing with GSK573719 in COPD provides clinically significant and sustained improvement in lung function over 24 h with similar efficacy to twice-daily dosing. Copyright © 2012 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of COPD
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove Medical Press
                1176-9106
                1178-2005
                2015
                18 December 2014
                : 10
                : 15-23
                Affiliations
                [1 ]Respiratory Medicines Development Center, GSK, Research Triangle Park, NC, USA
                [2 ]Clinical Pharmacology Science and Study Operations, GSK, Stockley Park, UK
                [3 ]Respiratory Medicines Development Centre, GSK, Stockley Park, UK
                [4 ]Statistics and Programming, Synergy, Slough, Berkshire, UK
                Author notes
                Correspondence: Rashmi Mehta, GSK, 5 Moore Drive, Research Triangle Park, NC, USA 27709, Tel +1 919 483 5356, Fax +1 919 483 6380, Email rashmi.s.mehta@ 123456gsk.com
                Article
                copd-10-015
                10.2147/COPD.S68094
                4279609
                © 2015 Mehta et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Original Research

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