Pharmacokinetics and tolerability of oral sildenafil in adults with cystic fibrosis lung disease

• Published in: Journal of cystic fibrosis Vol. 14; no. 2; pp. 228 - 236
• Main Authors: Taylor-Cousar, J.L, Wiley, C, Felton, L.A, St. Clair, C, Jones, M, Curran-Everett, D, Poch, K, Nichols, D.P, Solomon, G.M, Saavedra, M.T, Accurso, F.J, Nick, J.A
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2015
• Subjects: Adult; Biomarkers; Biomarkers - metabolism; Cystic fibrosis; Cystic Fibrosis - drug therapy; Cystic Fibrosis - metabolism; Cystic Fibrosis - physiopathology; Drug Monitoring - methods; Female; Humans; Inflammation; Inflammation - drug therapy; Leukocyte Elastase - metabolism; Lung - metabolism; Lung - physiopathology; Male; Pharmacokinetics; Phosphodiesterase 5 Inhibitors - administration & dosage; Phosphodiesterase 5 Inhibitors - adverse effects; Phosphodiesterase 5 Inhibitors - pharmacokinetics; Phosphodiesterase inhibitors; Pulmonary/Respiratory; Severity of Illness Index; Sildenafil; Sildenafil Citrate - administration & dosage; Sildenafil Citrate - adverse effects; Sildenafil Citrate - pharmacokinetics; Sputum - drug effects; Sputum - metabolism; Treatment Outcome; ATS; time to maximum concentration; DIOS; interleukin-8; PRO; AUC; colony forming units; PDEi; CF TDN; Cystic Fibrosis Questionnaire–Revised; ventilation/perfusion; T 1/2; IL-8; half-life; FEV 1; PASS; NCI; Cystic Fibrosis Foundation; phosphodiesterase inhibitor; T max; Biomarkers; Federal Drug Administration; maximum concentration; distal intestinal obstruction syndrome; CFTR; power analysis and sample size; CFF; CFQ-R; FDA; therapeutics development network; EBC; C max; CTEAE; CFU; standard operating protocol; exhaled breath condensate; National Cancer Institute; V/Q; elimination rate constant; TDN; computed tomography; forced expiratory volume in 1 s; Cystic Fibrosis Therapeutics Development Network; Cystic fibrosis; Inflammation; area under the curve; BAL; American Thoracic Society; CT; k e; common terminology criteria for adverse events; patient reported outcome; SOP; cystic fibrosis transmembrane conductance regulator; Sildenafil; Pharmacokinetics; bronchoalveolar lavage; Phosphodiesterase inhibitors; ke; Cmax; T1/2; Tmax; FEV1
• ISSN: 1569-1993; 1873-5010
• DOI: 10.1016/j.jcf.2014.10.006

Abstract Rationale Airway inflammation is central to cystic fibrosis (CF) pathophysiology. Pre-clinical models have shown that phosphodiesterase inhibitors (PDEi) like sildenafil have anti-inflammatory activity. PDEi have not been studied in CF subjects. Objectives We evaluated the pharmacokinetics, tolerability, and safety of sildenafil in subjects with CF. Sputum biomarkers were used to explore efficacy. Methods An open-label pilot study of oral sildenafil administration was conducted in adults with mild to moderate CF lung disease. Subjects received oral sildenafil 20 or 40 mg p.o. t.i.d. for 6 weeks. Measurements and main results Twenty subjects completed the study. Estimated elimination rate constants were statistically different in subjects with CF compared to previously published non-CF subjects. Side effects were generally mild. There were no drug-related serious adverse events. Sputum neutrophil elastase activity decreased. Conclusions Subjects with CF may eliminate sildenafil at a faster rate than non-CF subjects. Sildenafil administration was safe in subjects with CF and decreased sputum elastase activity. Sildenafil warrants further study as an anti-inflammatory in CF.