title: A Phase I study to determine the pharmacokinetic profile, safety and tolerability of sildenafil (Revatio®) in cardiac surgery: the REVAKI-1 study.
abstract: Acute kidney injury (AKI) is a common and severe complication of cardiac surgery. There is no effective prevention or treatment. Sildenafil citrate (Revatio®, Pfizer Inc.), a phosphodiesterase type 5 inhibitor, prevents post cardiac surgery AKI in pre-clinical studies, however its use is contraindicated in patients with symptomatic cardiovascular disease. The aim of this study is to assess the safety and pharmacokinetics of intravenous sildenafil in cardiac surgery patients.
  
  
  
  We conducted an open label, dose escalation study with six patients per dose level. The six doses were 2.5 mg, 5 mg or 10 mg as a bolus, either alone or followed by an additional 2 h infusion of 2.5 mg sildenafil.
  
  
  
  Thirty-six patients entered the trial, of which 33 completed it. The mean age was 69.9 years. One patient died during surgery, two others were removed from the trial before dosing (all at dose level 5 mg + 2.5 mg). The pharmacokinetic profile of sildenafil was similar to previously published studies. For a dose of 10 mg administered as a bolus followed by 2.5 mg administered over 2 h the results were AUC∞537 ng h ml-1, Cmax189.4 ng ml-1and t1/210.5 h. The drug was well tolerated with no serious adverse events related to drug administration. Higher sildenafil doses stabilized post-surgery nitric oxide bioavailability.
  
  
  
  Pharmacokinetics of sildenafil during cardiopulmonary bypass were comparable to those of other patient groups. The drug was well tolerated at therapeutic plasma levels. These results support the further evaluation of sildenafil for the prevention of AKI in cardiac surgery.
authors: University of the Free State, Bloemfontein, South Africa.|medac GmbH, Wedel, Germany.|Leicester Clinical Trials Unit, Leicester General Hospital, Leicester, UK.
authors: Arne
authors: 0000-0002-4324-5820
authors: A
authors: Ring
authors: Leicester Clinical Trials Unit, Leicester General Hospital, Leicester, UK.
authors: Tom
authors: T
authors: Morris
authors: University of Leicester, Cardiovascular Sciences and NIHR Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
authors: Marcin
authors: M
authors: Wozniak
authors: University of Leicester, Cardiovascular Sciences and NIHR Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
authors: Nikol
authors: N
authors: Sullo
authors: University of Leicester, Cardiovascular Sciences and NIHR Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
authors: William
authors: W
authors: Dott
authors: University of Leicester, Cardiovascular Sciences and NIHR Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
authors: Veerle
authors: V
authors: Verheyden
authors: University of Leicester, Cardiovascular Sciences and NIHR Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
authors: Tracy
authors: T
authors: Kumar
authors: University Hospitals Leicester NHS Trust, Leicester, UK.
authors: Nigel
authors: N
authors: Brunskill
authors: University Hospitals Leicester NHS Trust, Leicester, UK.
authors: Rakesh
authors: R
authors: Vaja
authors: University of Leicester, Cardiovascular Sciences and NIHR Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
authors: Gavin J
authors: GJ
authors: Murphy
mesh_terms: D058186:Acute Kidney Injury / Q000517:prevention & control; D061605:Administration, Intravenous; D000368:Aged; D006348:Cardiac Surgical Procedures / Q000379:methods*; D002315:Cardiopulmonary Bypass / Q000379:methods; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D058986:Phosphodiesterase 5 Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011183:Postoperative Complications / Q000517:prevention & control; D000068677:Sildenafil Citrate / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D009569:Nitric Oxide; D000068677:Sildenafil Citrate
keywords: cardiac surgery; clinical pharmacology; dose proportionality; nitrite oxide; pharmacokinetics; sildenafil