Formulation of long-acting nifedipine tablets influences the heart rate and sympathetic nervous system response in hypertensive patients

Abstract

Pharmacokinetic and pharmacodynamics studies are usually carried out separately with theoretical linking or interpretations. The pharmacokinetics of short- vs. long-acting formulations of nifedipine is well known, but the pharmacokinetics of different once-a-day formulations of nifedipine is generally not well known by the practising physician. This study provides practical patient-based information linking pharmacokinetics to pharmacodynamics in one of the target populations of patients, those with hypertension, who might receive the two different drugs. AIMS The haemodynamic responses to nifedipine vary between short- and long-acting formulations. However, the latter have not been compared despite marked differences in their constitution. Our 1-month randomized, crossover study was designed to compare the 30-mg osmotic, constant-release nifedipine gastrointestinal therapeutic system (N-GITS) with an encapsulated mini-tablet Coracten XL. Forty-four hypertensive patients aged 63 +/- 7 years were studied. The formulation was changed on day 15 and (for a single dose) day 30. At days 0, 14, 15, 29 and 30, patients were monitored for 6 h after dosing, during which blood pressure (BP), heart rate (HR) and plasma levels of norepinephrine (NE) and nifedipine were measured. The primary outcome was the difference in plasma NE between formulations at the time of peak nifedipine level. Systolic BP decreased rapidly after the first dose of Coracten, achieving nadir at 5 h. HR rose by 1.2 +/- 8.8 beats min(-1). After N-GITS HR fell by 2.4 +/- 7.7 beats min(-1) (P = 0.159). Plasma NE was higher in the Coracten- (480 +/- 38.3 pg ml(-1)) than N-GITS-treated patients (343 +/- 75.0 pg ml(-1)) at the time of peak nifedipine concentrations (4 and 5 h, respectively) and their change from baseline was significantly (P = 0.0046) different. A similar difference between the drugs was seen again at days 15 and 30, at 5 h after switching formulations. This study suggests that two different formulations of once-daily nifedipine result in different BP and plasma NE responses, and that switching between formulations causes opposite effects upon the sympathetic nervous response to falling BP.