Pharmacokinetics of felodipine after intravenous and chronic oral administration in patients with congestive heart failure.

Abstract

1 In a randomized, parallel, double-blind study felodipine was administered to 11 and placebo to 12 patients with congestive heart failure. The kinetics of felodipine were studied after acute intravenous administration and after chronic oral treatment for 8 weeks. The relationship between cardiac output and pharmacokinetics was analyzed. The pharmacokinetic data were compared with data from young healthy individuals and hypertensive patients.2 After oral therapy, significant correlations were found between cardiac output and AUC and systemic bioavailability (F). Furthermore, cardiac output before therapy was also significantly correlated with absorption characteristics. No relationship could be demonstrated between cardiac output and i.v. pharmacokinetics. A comparison of patients with heart failure and young healthy individuals revealed that the AUC was three times higher in heart failure patients, while V55 and the ratio of the AUC of the pyridine metabolite to that of felodipine were similar. Oral clearance was reduced by 50% and the terminal half-life was concomitantly increased. Pharmacokinetic data for felodipine are similar in patients with heart failure to published data from elderly hypertensive patients. 3 An increase in liver blood flow during chronic oral therapy, induced by felodipine itself, appears to explain an increase in bioavailability and thus to higher plasma drug concentrations. Thus, it is advisable to start felodipine treatment at a low dosage in patients with congestive heart failure.

Felodipine Clinical Pharmacokinetics

“…; it is therefore likely that the greater Cmax and AVC in patients with heart failure are also caused by the decrease in OR. However, when felodipine was administered as a conventional tablet blood flow increased and therefore the Cmax is probably increased further during the short term increase in OR (Dunselman et al 1989b). The large interindividual variation in plasma concentrations after an oral dose necessitates an individual dosage titration in patients with heart failure.…”

“…The effect of felbdipine in patients with heart failure is best described as massive arterial vasodilation without primary effects on myocardial filling pressures, resulting in an increase in flow and a reduction in vascular resistance without significant changes in arterial, pulmonary artery and atrial pressures (Dunselman et al 1989c;Kassis et al 1987). The same dosage of felodipine leads to higher Cmax and AVC in patients with congestive heart failure (table II) [Dunselman et al 1989b]. This cannot be explained by more rapid absorption, since tmax in patients with congestive heart failure is not significantly different from that in other patient groups.…”

Relationship of changes in felodipine pharmacokinetics to haemodynamics during chronic oral treatment of congestive heart failure patients

“…Relation between haemodynamics and felodipine pharmacokinetics in congestive heart failure patients during the intravenous study Our patients showed a three fold difference in clearance and a four fold difference in volume of distribution of felodipine between the patients at the start of the study [8]. These parameters appeared to be negatively correlated (sec "pharmacokinetic analysis" above).…”

“…On the other hand, pharmacokinetic studies with felodipine also resulted in large interpatient differences [5][6][7][8]. The aims of this analysis were to investigate a possible interrelationship between these findings in CHF patients and to look for an explanation in terms of differences in ANS activity.…”

“…With felodipine, a selective vasodilating dihydropyridine calcium antagonist, a three-to four-fold difference in both clearance and volume of distribution at equilibrium has been described with young male adults [5] and middle-aged [6], elderly hypertensive [7] congestive heart failure [8] patients. In the latter patients peak and trough concentrations after 8 weeks oral therapy with felodipine were predicted from the i.v.…”