Abstract
Aim: This study has been designed to assess the bioequivalence
of the newly developed delayed-release oral tablets (test) 30 mg
nifedipine compared to its marketed counterpart (30 mg; reference) in
healthy adult Chinese volunteers.
Methods: We conducted randomized, open-label, four-period,
crossover trials, including a fasting trial and a fed trial. The
subjects were administered the test or reference products in a 1:1 ratio
at random throughout each period with 7 days washout period. Then, in
the next session, they got the alternate products. Liquid
chromatography-tandem mass spectrometry and WinNonlin software were used
to evaluate the bioequivalence of nifedipine peak blood concentration
(Cmax) and area under the concentration-time curve
(AUC).
Result: A total of 46 subjects participated in the fasting
trial and 48 subjects in the postprandial trial. In both cases, the 90%
CI of the geometric mean ratios of Cmax,
AUC0-t and AUC0-∞ were in the
equivalence range (80-125%). When nifedipine was given concomitantly
with a high-fat meal, tmax was approximately twofold
earlier, absorption was approximately 4.8% less, and
Cmax changed little compared to fasting conditions. In
addition, no serious adverse events were observed in the subjects.
Conclusion: This study confirms the bioequivalence of the test
and reference formulations of nifedipine extended-release tablets under
fasting and postprandial conditions. Food giving leads to a much earlier
Tmax, which is different from the results of other
studies. The effect of food effect on the pharmacokinetics of nifedipine
needs to be further explored.
Introduction
Nifedipine (NFP) is a short-acting dihydropyridine calcium channel
blocker1. Nifedipine can selectively block L-type
calcium channels on cardiac and smooth muscle cells, organize the inward
flow of extracellular calcium ions, reduce the intracellular calcium ion
concentration, relieve the effect of vascular smooth muscle spasm,
reduce peripheral vascular resistance, reduce myocardial oxygen
consumption, and lower diastolic and systolic blood pressure in
hypertensive patients2. At the same time, nifedipine
can diastole the coronary arteries, and its application in small doses
can have a very good anti-anginal effect. It is currently used
clinically for the prevention and treatment of various types of coronary
artery disease and angina pectoris, is also indicated for various types
of hypertension, and has good efficacy in persistent and severe
hypertension3,4.
Nifedipine is almost completely absorbed from the gastrointestinal tract
after oral administration and undergoes first-pass metabolism in the
liver and intestinal wall, and its oral bioavailability reaches
43%-77%. Nifedipine is highly bound to plasma proteins, metabolized by
the liver, and excreted primarily in the urine, with only less than 1%
of the dose being excreted in its original form5.
Regular nifedipine tablets have low and irregular bioavailability, and
short-acting calcium antagonists cause increased sympathetic tone and
reflex tachycardia, along with adverse effects such as headache,
palpitations, flushing, and dizziness6-78. In
contrast, nifedipine extended-release and controlled-release
formulations do not have the ”sudden release” phenomenon of ordinary
tablets, which can reduce the gastrointestinal stimulation of the drug
and avoid the adverse reactions caused by high peak blood
concentrations, making the onset of nifedipine smooth and blood pressure
control more stable9. Nifedipine extended-release
tablets III, in the size of 30 mg, are capable of releasing nifedipine
at a near-constant rate for 24 hours, similar to controlled-release
tablets. Nifedipine extended-release tablets I and II are generally
taken on an empty stomach, whereas nifedipine extended-release tablets
III are not restricted by meal times because they are not affected by
gastrointestinal motility or pH10. Therefore, the
objective of this study was to investigate the pharmacokinetic
properties of nifedipine extended-release formulation in the Chinese
population and to evaluate the bioequivalence of the test formulation
nifedipine extended-release tablets (Hunan Dino Pharmaceutical Co.,
Ltd.) and the reference formulation nifedipine controlled-release
tablets (trade name: Baysinto®, size: 30 mg/tablet Bayer AG) to obtain
regulatory approval for the test formulation.