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

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• 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. WHAT THIS STUDY ADDS• 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. AIMSThe 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. METHODSForty-four hypertensive patients aged 63 Ϯ 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. RESULTSSystolic BP decreased rapidly after the first dose of Coracten, achieving nadir at 5 h. HR rose by 1.2 Ϯ 8.8 beats min -1. After N-GITS HR fell by 2.4 Ϯ 7.7 beats min -1 (P = 0.159). Plasma NE was higher in the Coracten-(480 Ϯ 38.3 pg ml -1 ) than N-GITS-treated patients (343 Ϯ 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. CONCLUSIONSThis 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.

Looking back: editors' pick of 2008

“…A paper in January [18] suggests that standard tests of bioequivalence may tell only part of the relevant story. Another paper in May reinforces this message for another class of drug [19]. Patients may indeed be right.…”

A review of the gastrointestinal therapeutic system (GITS) formulation and its effectiveness in the delivery of antihypertensive drug treatment (focus on nifedipine GITS)

“…This postulate was evaluated in a randomized crossover study in 43 older hypertensive patients comparing “branded” nifedipine GITS and an alternative once-daily formulation (mini tablets in a capsule) 33. Peak nifedipine plasma concentrations were achieved at 4 hours after the first dose of the generic, modified-release formulation of nifedipine and at 6 hours after nifedipine GITS.…”

“…This study suggests that these two different formulations of once-daily nifedipine are not interchangeable since there were significantly different blood pressure and plasma noradrenaline responses. Furthermore, even at steady state, switching between formulations caused opposite effects on the activity of the sympathetic nervous system in response to a fall in blood pressure 33. It is important to appreciate that these significant differences were detected with repeated measurements over an 8-hour period and would not readily have been detected at conventional, single-time-point clinic visits.…”

Pharmacokinetic and Tolerability Comparison of Sustained and Immediate Release Oral Formulations of Nifedipine Tablet Formulations: A Single-Dose, Randomized, Open-Label, Two-Period, Two-Way Crossover Study in Healthy, Fasting Egyptian Male Volunteers

“…This short acting formulation has been demonstrated to produce reflex activation of the sympathetic nervous system (SNS) leading to flushing, tachycardia, worsening myocardial ischemia, and cerebrovascular ischemia, which may be disadvantageous in patients with cardiologic problems [10]. On the other hand, second-generation dihydropyridine (modified release nifedipine) has been developed with a delayed or modified release mechanism to improve patient adherence by reducing dose frequency, and to prolong therapeutic effect by minimizing peak to trough fluctuations of nifedipine plasma concentration and the SNS activation which these fluctuations cause [4,7,11,12].…”

“…The nifedipine sustained-release formulation provides a oncedaily dosing regimen compared to conventional immediate release nifedipine formulation administered three times daily, thus optimizing medication adherence especially in the elderly [11].…”