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Pharmacokinetic‐pharmacodynamic model for fantofarone cardiac and brachial haemodynamic effects in healthy volunteers
Author(s) -
Bellissant Eric,
Giudicelli JeanFrançois
Publication year - 1999
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.1999.00091.x
Subject(s) - pharmacokinetics , pharmacodynamics , crossover study , hemodynamics , heart rate , medicine , metabolite , brachial artery , pharmacology , placebo , anesthesia , chemistry , blood pressure , pathology , alternative medicine
Aims 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+E 0 , for cardiac effects] or sigmoid [E=E max .C γ /( C Eγ50+C γ ), 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, E max =42±6%, CE 50 =8.8±7.2 ng ml −1 and γ=2.2±1.5 for BAF, and E max =−28±4%, CE 50 =5.8±5.1 ng ml −1 and γ=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.