The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of inhaled fluticasone furoate and vilanterol trifenatate in healthy subjects.

AIM To investigate the effects of the cytochrome P450 3A4 (CYP3A4) inhibitor ketoconazole on the pharmacokinetics (PK) and pharmacodynamics of fluticasone furoate (FF) and vilanterol trifenatate (VI). METHODS Two double-blind, randomized, placebo-controlled, two-way crossover studies in healthy subjects. In study 1, subjects received single doses of ketoconazole (400 mg) or placebo on days 1-6, with a single dose of inhaled VI (25 μg) on day 5. Pharmacodynamic and PK data were obtained up to 48 h following the VI dose. In study 2, subjects received once daily ketoconazole (400 mg) or placebo for 11 days, with FF/VI (200/25 μg) for the final 7 days. Pharmacodynamic and PK data were obtained up to 48 h following the day 11 dose. RESULTS In study 1, there was no effect of co-administration of ketoconazole and VI on pharmacodynamic or PK parameters. In study 2, co-administration of ketoconazole and FF/VI had no effect on 0-4 h maximal heart rate or minimal blood potassium {treatment difference [90% confidence interval (CI)] -0.6 beats min(-1) (-5.8, 4.5) and 0.04 mmol l(-1) (-0.03, 0.11), respectively}, whilst there was a 27% decrease in 24 h weighted mean serum cortisol [treatment ratio (90% CI) 0.73 (0.62, 0.86)]. Co-administration of ketoconazole increased [percentage change (90% CI)] FF area under the curve (0-24) and maximal plasma concentration by 36% (16, 59) and 33% (12, 58), respectively, and VI area under the curve (0-t') and maximal plasma concentration by 65% (38, 97) and 22% (8, 38), respectively. CONCLUSION Co-administration of FF/VI or VI with ketoconazole resulted in a less than twofold increase in systemic exposure to FF and VI. There was no increase in β-agonist systemic pharmacodynamic effects, while serum cortisol was decreased by 27%. Co-administration of FF/VI with strong CYP3A4 inhibitors has the potential to increase systemic exposure to both fluticasone furoate and vilanterol, which could lead to an increase in the potential for adverse reactions.

[1]  C. Crim,et al.  The efficacy and safety of the novel long-acting β2 agonist vilanterol in patients with COPD: a randomized placebo-controlled trial. , 2012, Chest.

[2]  D. Kelleher,et al.  Comparison Of Inhalation Profiles Through A Novel Dry Powder Inhaler (nDPI) And Lung Function Measurements For Healthy Subjects, Asthma And Chronic Obstructive Pulmonary Disease (COPD) Patients , 2012, ATS 2012.

[3]  L. Tombs,et al.  The absolute bioavailability of fluticasone furoate (FF) and vilanterol (VI) trifenatate following inhaled administration in combination in healthy subjects , 2011 .

[4]  D. Postma,et al.  Prolonged protection of the new inhaled corticosteroid fluticasone furoate against AMP hyperresponsiveness in patients with asthma , 2010, Allergy.

[5]  V. Norris,et al.  The Pharmacodynamics, Pharmacokinetics And Tolerability Of Repeat Doses Of The Novel Inhaled Long-acting Beta2 Adrenoceptor Agonist (LABA) GW642444 (25, 50 And 100mcg) In Healthy Subjects , 2010, ATS 2010.

[6]  Lei Zhang,et al.  Scientific and regulatory perspectives on metabolizing enzyme-transporter interplay and its role in drug interactions: challenges in predicting drug interactions. , 2009, Molecular pharmaceutics.

[7]  A. Valipour,et al.  Short-term effects of inhaled salbutamol on autonomic cardiovascular control in healthy subjects: a placebo-controlled study. , 2009, British journal of clinical pharmacology.

[8]  M. Pavesi,et al.  The Prokinetic Cinitapride Has No Clinically Relevant Pharmacokinetic Interaction and Effect on QT during Coadministration with Ketoconazole , 2007, Drug Metabolism and Disposition.

[9]  B. Smith,et al.  Development of an in vivo preclinical screen model to estimate absorption and first-pass hepatic extraction of xenobiotics. II. Use of ketoconazole to identify P-glycoprotein/CYP3A-limited bioavailability in the monkey. , 2004, Drug metabolism and disposition: the biological fate of chemicals.

[10]  Mark M. Roden,et al.  Interrelationship Between Substrates and Inhibitors of Human CYP3A and P-Glycoprotein , 1999, Pharmaceutical Research.

[11]  A. Woodcock,et al.  Pharmacokinetics and systemic effects of inhaled fluticasone propionate in chronic obstructive pulmonary disease. , 2003, British journal of clinical pharmacology.

[12]  S. Clarke,et al.  Human Cytochromes P450 and Their Role in Metabolism-Based Drug-Drug Interactions , 2001 .

[13]  Adnan Custovic,et al.  Comparison of pharmacokinetics and systemic effects of inhaled fluticasone propionate in patients with asthma and healthy volunteers: a randomised crossover study , 2000, The Lancet.

[14]  A. Bye,et al.  Absorption Kinetics after Inhalation of Fluticasone Propionate via the Diskhaler®, Diskus® and Metered-Dose Inhaler in Healthy Volunteers , 2000, Clinical pharmacokinetics.

[15]  D. Greenblatt,et al.  Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo probe: Effect of ketoconazole , 1999, Clinical pharmacology and therapeutics.

[16]  L. Benet,et al.  The effects of ketoconazole on the intestinal metabolism and bioavailability of cyclosporine , 1995, Clinical pharmacology and therapeutics.