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.