Effect of verapamil on systemic exposure and safety of umeclidinium and vilanterol: a randomized and open-label study

Rashmi Mehta, Dennis Kelleher, Andrew Preece, Stephen Hughes, Glenn Crater, Rashmi Mehta, Dennis Kelleher, Andrew Preece, Stephen Hughes, Glenn Crater

Abstract

Background: The combination of umeclidinium (UMEC), a long-acting muscarinic receptor antagonist, and vilanterol (VI), a selective long-acting β₂ agonist, is in development for the treatment of chronic obstructive pulmonary disease (COPD). This study evaluated the pharmacokinetics, safety and tolerability, and pharmacodynamics of once-daily, inhaled UMEC and UMEC/VI when co-administered with oral verapamil, a moderate P-glycoprotein transporter and moderate cytochrome P450 3A4 (CYP3A4) inhibitor frequently used by patients with COPD and cardiovascular comorbidities.

Methods: Subjects were randomized to one of two 13-day treatment regimens: UMEC 500 μg or UMEC 500 μg/VI 25 μg. All subjects received a single tablet containing 240 mg verapamil on each of days 9-13.

Results: Repeat doses of UMEC and UMEC/VI in combination with and without verapamil were safe and well tolerated. There was no increase in systemic exposure of UMEC when administered in combination with VI compared to UMEC alone. UMEC maximum concentration was similar with or without verapamil; a moderate increase in UMEC area under the curve (approximately 1.4-fold) was observed with verapamil. Verapamil did not increase systemic exposure to VI following administration of the UMEC/VI combination.

Conclusion: Administration of UMEC and UMEC/VI combination was well tolerated and did not show clinically relevant increases in systemic exposure for either drug. The UMEC/VI combination is unlikely to have a clinically meaningful drug-drug interaction with moderate P-glycoprotein transporter and CYP3A4 inhibitor drugs.

Keywords: long-acting muscarinic antagonist; long-acting β2 agonist; umeclidinium; verapamil; vilanterol.

Figures

Figure 1
Figure 1
Median plasma umeclidinium concentration-time semi-log plot at Day 8 (without verapamil) and Day 13 (with verapamil). (A) Umeclidinium treatment group; (B) Umeclidinium/vilanterol treatment group. Abbreviations: LLQ, lower limit of quantification; UMEC, umeclidinium; V, verapamil; VI, vilanterol.
Figure 2
Figure 2
Plot of individual maximum (0–4 hours) heart rate versus log Cmax (by treatment). (A) Umeclidinium log Cmax; (B) Vilanterol log Cmax. Abbreviations: bpm, beats per minute; Cmax, maximum observed plasma concentration; HR, heart rate; UMEC, umeclidinium; V, verapamil; VI, vilanterol.

References

    1. Fletcher MJ, Upton J, Taylor-Fishwick J, et al. COPD uncovered: an international survey on the impact of chronic obstructive pulmonary disease [COPD] on a working age population. BMC Public Health. 2011;11:612.
    1. Mannino DM, Braman S. The epidemiology and economics of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2007;4(7):502–506.
    1. Halbert RJ, Natoli JL, Gano A, Badamgarav E, Buist AS, Mannino DM. Global burden of COPD: systematic review and meta-analysis. Eur Respir J. 2006;28(3):523–532.
    1. Ng TP, Niti M, Fones C, Yap KB, Tan WC. Co-morbid association of depression and COPD: a population-based study. Respir Med. 2009;103(6):895–901.
    1. Foster TS, Miller JD, Marton JP, Caloyeras JP, Russell MW, Menzin J. Assessment of the economic burden of COPD in the US: a review and synthesis of the literature. COPD. 2006;3(4):211–218.
    1. GOLD: Global initiative for chronic obstructive lung disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. 2011. [Accessed November 23, 2012]. Available from: .
    1. Gruffydd-Jones K, Loveridge C. The 2010 NICE COPD Guidelines: how do they compare with the GOLD guidelines? Prim Care Respir J. 2011;20(2):199–204.
    1. Fromer L, Cooper CB. A review of the GOLD guidelines for the diagnosis and treatment of patients with COPD. Int J Clin Pract. 2008;62(8):1219–1236.
    1. Tashkin DP, Fabbri LM. Long-acting beta-agonists in the management of chronic obstructive pulmonary disease: current and future agents. Respir Res. 2010;11:149.
    1. Cazzola M, Calzetta L, Matera MG. ß(2) -adrenoceptor agonists: current and future direction. Br J Pharmacol. 2011;163(1):4–17.
    1. Mehta R, Hardes K, Cahn A, et al. Safety, tolerability and pharmacokinetics (PK) of repeated doses of GSK573719 Inhalation Powder, a new long-acting muscarinic antagonist, in healthy adults [abstract] Eur Respir J. 2011a;38(Suppl 5):723s.
    1. Cahn A, Lovick R, Newlands A, et al. Safety, tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of GSK573719 inhalation powder in healthy subjects [abstract] Eur Resp J. 2011;38(Suppl 55):723s.
    1. Mehta R, Newlands A, Kelleher D, Preece A, Cahn A, Crater G. Safety, pharmacokinetics (PK) and pharmacodynamics (PD) of single doses of GSK573719 inhalation powder, a new long-acting muscarinic antagonist (LAMA), in patients with COPD. Eur Respir J. 2011;38(Suppl 55):138s.
    1. Donohue J, Anzueto A, Brooks J, Mehta R, Kalberg C, Crater G. A randomized, double-blind, dose-ranging study of the novel LAMA GSK573719 in patients with COPD. Respir Med. 2012;106(7):970–979.
    1. Decramer M, Maltais F, Feldman G, et al. Bronchodilation of umeclidinium, a new long-acting muscarinic antagonist, in COPD patients. Respir Physiol Neurobiol. 2013;185(2):393–399.
    1. Kempsford R, Norris V, Siederer S. Vilanterol trifenatate, a novel inhaled long-acting beta2 adrenoceptor agonist, is well tolerated in healthy subjects and demonstrates prolonged bronchodilation in subjects with asthma and COPD. Pulm Pharmacol Ther. 2013;26(2):256–264.
    1. Procopiou PA, Barrett VJ, Bevan NJ, et al. Synthesis and structure-activity relationships of long-acting beta2 adrenergic receptor agonists incorporating metabolic inactivation: an antedrug approach. J Med Chem. 2010;53(11):4522–4530.
    1. Feldman G, Walker RR, Brooks J, Mehta R, Crater G. 28-day safety and tolerability of umeclidinium in combination with vilanterol in COPD: a randomized placebo-controlled trial. Pulm Pharmacol Ther. 2012;25(6):465–471.
    1. Kelleher DL, Mehta RS, Jean-Francois BM, et al. Safety, tolerability, pharmacodynamics and pharmacokinetics of umeclidinium and vilanterol alone and in combination: a randomized crossover trial. PLoS ONE. 2012;7(12):e50716.
    1. US Food and Drug Administration. Guidance for Industry Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations Draft Guidance. Silver Spring: US Food and Drug Administration; 2012. [Accessed November 23, 2012]. Available from: .
    1. World Medical Association. World Medical Association Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects. Seoul: 59th WMA General Assembly; 2008. [Accessed November 23, 2012]. Available from: .
    1. GD Searle LLC. Calan (verapamil hydrochloride) [Package insert] New York: GD Searle LLC, Division of Pfizer Inc; 2010. [Accessed November 23, 2012]. Available from: .
    1. Salpeter SR. Cardiovascular safety of beta(2)-andrenoceptor agonist use in patients with obstructive airway disease: a systematic review. Drugs Aging. 2004;21(6):405–414.
    1. Sovani MP, Whale CI, Tattersfield AE. A benefit-risk assessment of inhaled long-acting beta2-agonists in the management of obstructive pulmonary disease. Drug Saf. 2004;27(10):689–715.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe