Pharmacokinetic-pharmacodynamic model for fantofarone cardiac and brachialhaemodynamic effects in healthy volunteers

Aims To investigate the pharmacokinetics of SR 33671, the main active metab olite of the calcium antagonist fantofarone, and the relationships between its concentrations and pharmacodynamic effects after a single oral administ ration 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 interva l duration (ms), brachial artery flow (BAF, ml min(-1) ) and brachial vascu lar 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 + E-0, for cardiac effects] or sigmoid [E = Emax .Cgamma/(CE50gamma + C-gamma ), for h aemodynamic effects] models were fitted to individual data. Results Peak plasma concentrations and areas under the curve up to 24 h wer e (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 m g, respectively. Terminal half-life was approximately 4 h. For pharmacodyna mics, 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, E-max = 42 +/- 6%, CE50 = 8.8 +/- 7.2 ng ml(-1) and gamma = 2.2 +/- 1.5 for BAF, and E-max = - 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 incr eased by less than 8 ms. Conclusions Fantofarone is able to induce submaximal peripheral vasodilatin g effects at doses that are devoid of any clinically significant cardiac ef fect.