Felodipine population dose-response and concentration-response relationships in patients with essential hypertension

To characterize the population dose-response and concentration-response relationships of felodipine and to investigate the influence of patient variables on these relationships.

We studied 239 evaluable patients with mild to moderate essential hypertension in a multicenter, randomized, double-blind dose-escalation trial, followed by an optional open-label maintenance phase for the remainder of 1 year. Extended-release felodipine (2.5 to 20 mg) monotherapy was given once daily. Felodipine plasma concentration and sitting diastolic blood pressure were measured at approximately 2 and 24 hours after drug administration. Analysis, performed with use of the population approach (NONMEM program), accounted for baseline and placebo effects.

A saturation (Emax) model best described both felodipine dose response (only 24-hour postdose data) and concentration response. The maximum effect (Emax) characterizing dose response was found to increase linearly with age and was estimated to be 20.6 mm Hg in the typical individual (60 years of age). The dose at which 50% of the maximum effect is achieved (D50) was estimated to be 11.1 mg. The Emax characterizing concentration response also increased linearly with age and was estimated to be 27.8 mm Hg for the typical individual. The concentration at which 50% of the maximum effect is achieved (C50) was related to plasma renin activity (PRA) by the following: (21.6.PRA)/(0.25 + PRA) nmol/L; its value in the typical individual was estimated to be about 16.9 nmol/L. Felodipine (oral) clearance decreased with increasing age, up to 60 years, and was larger in black patients.

The effects of age on felodipine pharmacokinetics and pharmacodynamics lead to a heightened antihypertensive response in the elderly. A starting dose of 2.5 mg daily is recommended, especially in elderly patients.