Felodipine pharmacokinetics and plasma concentration vs effect relationships

Abstract

Felodipine was completely absorbed from an oral solution (OS), as well as from the conventional (CT) and extended release (ER) tablets. The time to peak plasma concentration increased in the order OS < CT < ER. Peak plasma felodipine concentrations were significantly lower and trough concentrations higher when felodipine was administered in the ER-tablet compared with CT and oral solution. The variability in plasma felodipine concentration during the dose interval, expressed as the fluctuation index, increased in the order ER o.d. < CT b.i.d. < CT o.d. The distribution of the AUC of plasma felodipine concentrations vs time determined in 140 individuals was unimodal, indicating that genetic factors are unlikely to influence the metabolism of felodipine to any clinically significant extent. With increasing age the plasma concentrations and the terminal half-life of felodipine increased, whereas the plasma clearance and the ratio of the AUC of the primary pyridine metabolite to that of unchanged drug decreased. The time to maximum plasma felodipine concentration, the bioavailability and the volume of distribution were not consistently influenced by age. Body weight, body mass index and concomitant intake of beta-blockers had negligible influence on the pharmacokinetics of felodipine. The pharmacokinetics in the limited number females did not differ substantially from that of the males in our investigation. No consistent effect on blood pressure was seen in healthy subjects after administration of felodipine. In hypertensive patients, however, there was a good relationship between plasma felodipine concentration and antihypertensive effect. There was no hysteresis for the reduction in blood pressure. The relationship between plasma felodipine concentration and antihypertensive effect could, in most patients, be described by a modified Emax model. The average Emax value was estimated to be approximately 30 mmHg. Placebo correction decreased the magnitude of the blood pressure reduction. The Emax estimates increased with increasing initial blood pressures whereas age had a negligible effect. Patients with high and low plasma felodipine concentrations had similar Emax values. The EC50 values were not influenced by any of these factors. The Emax model used was less suitable for patients with low initial blood pressure levels.

In conclusion: The plasma concentration vs time profile of felodipine is modified by using different pharmaceutical formulations, without loss of bioavailability. As a group, the elderly have higher total concentrations of unchanged felodipine in plasma compared with young individuals. The variation in plasma concentrations between individuals is, however, only partially explained by age. There is a good and direct relationship between felodipine plasma concentrations and antihypertensive effects in hypertensive patients.(ABSTRACT TRUNCATED AT 400 WORDS)