title: Pharmacokinetic-pharmacodynamic model for fantofarone cardiac and brachial haemodynamic effects in healthy volunteers.
abstract: OBJECTIVE
  To investigate the pharmacokinetics of SR 33671, the main active metabolite of the calcium antagonist fantofarone, and the relationships between its concentrations and pharmacodynamic effects after a single oral administration of two doses (100 and 300 mg) of fantofarone.
  
  
  METHODS
  A placebo-controlled, randomized, double-blind and crossover study was performed in six healthy volunteers. SR 33671 plasma concentrations (C, ng ml-1 ) and effects (E) on heart rate (HR, beats min-1 ), PR interval duration (ms), brachial artery flow (BAF, ml min-1 ) and brachial vascular resistance (BVR, mmHg s ml-1 ) were determined repeatedly after drug intake. Haemodynamic effects were expressed as percent changes from initial values. Bi-exponential (pharmacokinetics), and linear [E=S.C+E0, for cardiac effects] or sigmoid [E=Emax.Cgamma/(CEgamma50+Cgamma ), for haemodynamic effects] models were fitted to individual data.
  
  
  RESULTS
  Peak plasma concentrations and areas under the curve up to 24 h were (mean+/-s.d.) 16+/-10 ng ml-1 and 157.50+/-89.13 ng ml-1 h, and 63+/-11 ng ml-1 and 535.50+/-135.11 ng ml-1 h, after 100 and 300 mg, respectively. Terminal half-life was approximately 4 h. For pharmacodynamics, we obtained: S=-0.201+/-0.057 beats min-1/ng ml-1 for HR, S=0.526+/-0.114 ms/ng ml-1 for PR interval duration, Emax=42+/-6%, CE50=8.8+/-7.2 ng ml-1 and gamma=2.2+/-1.5 for BAF, and Emax=-28+/-4%, CE50=5.8+/-5.1 ng ml-1 and gamma=3.4+/-1.8 for BVR. At a SR 33671 concentration of 15 ng ml-1, BVR is decreased by 27% whereas HR is reduced by less than 3 beats min-1 and PR interval duration is increased by less than 8 ms.
  
  
  CONCLUSIONS
  Fantofarone is able to induce submaximal peripheral vasodilating effects at doses that are devoid of any clinically significant cardiac effect.
authors.affiliation: Service de Pharmacologie Clinique, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France.
authors.forename: E
authors.initials: E
authors.lastname: Bellissant
authors.forename: J F
authors.initials: JF
authors.lastname: Giudicelli
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001916:Brachial Artery; D002121:Calcium Channel Blockers / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D007212:Indolizines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008954:Models, Biological; D010627:Phenethylamines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects; D014665:Vasodilator Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D002121:Calcium Channel Blockers; D007212:Indolizines; D010627:Phenethylamines; D014665:Vasodilator Agents; C059901:fantofarone