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Titolo:
Pharmacokinetic-pharmacodynamic model for fantofarone cardiac and brachialhaemodynamic effects in healthy volunteers
Autore:
Bellissant, E; Giudicelli, JF;
Indirizzi:
Hop Bicetre, Serv Pharmacol Clin, Le Kremlin Bicetre, France Hop Bicetre Le Kremlin Bicetre France Clin, Le Kremlin Bicetre, France Fac Med, Lab Pharmacol Clin, Rennes, France Fac Med Rennes FranceFac Med, Lab Pharmacol Clin, Rennes, France
Titolo Testata:
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
fascicolo: 6, volume: 48, anno: 1999,
pagine: 801 - 810
SICI:
0306-5251(1999)48:6<801:PMFFCA>2.0.ZU;2-9
Fonte:
ISI
Lingua:
ENG
Soggetto:
PLASMA-CONCENTRATIONS; ANTAGONIST; NIFEDIPINE; SR-33557;
Keywords:
concentration-effect relationship; effect compartment; fantofarone; haemodynamics; healthy volunteers; PK-PD modelling; sigmoid model;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
22
Recensione:
Indirizzi per estratti:
Indirizzo: Giudicelli, JF Ctr Hosp Bicetre, Serv Pharmacol Clin, 78 Rue Gen Leclerc, F-94275 Le Kremlin Bicetre, France Ctr Hosp Bicetre 78 Rue Gen Leclerc Le Kremlin Bicetre France F-94275
Citazione:
E. Bellissant e J.F. Giudicelli, "Pharmacokinetic-pharmacodynamic model for fantofarone cardiac and brachialhaemodynamic effects in healthy volunteers", BR J CL PH, 48(6), 1999, pp. 801-810

Abstract

Aims To investigate the pharmacokinetics of SR 33671, the main active metabolite of the calcium antagonist fantofarone, and the relationships betweenits 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 studywas 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 drugintake. Haemodynamic effects were expressed as percent changes from initial values. Bi-exponential (pharmacokinetics), and linear [E = S.C + E-0, forcardiac effects] or sigmoid [E = Emax .Cgamma/(CE50gamma + C-gamma ), 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%,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% whereasHR 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 27/10/20 alle ore 10:04:44