Discussion
This study compared the newly developed nifedipine extended-release tablets (test formulation, Qingdao Baiyang Pharmaceutical Co., Ltd.) with the marketed nifedipine extended-release tablets (reference formulation, Bayer AG) for bioequivalence assessment under fasting and postprandial conditions in healthy Chinese volunteers. The controlled-release formulation of nifedipine was also found to provide a constant release of 16-18 hours in the healthy Chinese population, resulting in stable maintenance of blood levels for more than 24 hours. This is very helpful for nifedipine to control hypertension, which requires stable control.
In a domestic survey of drug utilization in the cardiovascular system published in 2007, nifedipine was one of the most frequently selected clinical species11. The metabolism of nifedipine as a substrate drug for CYP3A4 is highly variable in the population, and its different metabolic distribution in patients makes the adverse effects more severe in some patients. Of particular note is that nifedipine can cause some serious adverse reactions, such as severe hypotension due to sublingual nifedipine12, severe exfoliative dermatitis, triggering cerebral ischemic attacks, cerebral infarction, and myocardial ischemia.
Therefore, the appropriate formulation can affect the metabolism and distribution of nifedipine in the patient’s body, thus enabling nifedipine to exert a gentle dilating effect on the peripheral arterial vessels and lower blood pressure, as well as reducing the occurrence of adverse effects. Nifedipine controlled-release tablets need to be taken only once a day, and by reducing the number of doses and maintaining a stable blood concentration, the drug can reduce the irritation of the gastrointestinal tract and avoid the adverse reactions caused by high blood concentration13.
Two separate studies were involved in the current study, including a fasting trial and a postprandial trial. Subjects were screened separately, with 48 subjects in the fasting group and 48 subjects in the postprandial group without crossover to each other, and after subjects were included in each of these two groups, they would undergo hospitalization, drug administration, blood collection, and discharge phases. It is necessary for subjects in both groups to be informed of the specific differences in the protocol and to obtain informed consent. The postprandial group will begin eating a high-fat, high-heat meal 30 min before dosing on the day of administration, and subjects will self-assess the menu provided by the investigator to determine that it can be consumed within 30 min. The fasting group, on the other hand, will remain fasted until the dose is administered.
The coefficient of variation for subjects was 19.37% in the fasting trial and 18.44% in the post-meal trial. The t1/2 for nifedipine was 7.12±2.65h in the fasting trial and 6.57±2.12h in the postprandial trial. comparing the pharmacokinetic parameters after a single fasting dose of the same dose as the subject formulation in the postprandial trial, the AUC curve area was reduced by approximately 4.8%, Cmax was not significantly changed, but Tmax was advanced by nearly twofold. the pharmacokinetic parameters reported in the literature for the postprandial period, absorption The postprandial pharmacokinetic parameters reported in the literature, the absorption amount was not changed significantly, and the Cmax was also not changed significantly, but the time to peak was earlier than in the fasting state. These results indicate that food does not affect the peak plasma concentration of nifedipine extended-release tablets and has no effect on drug absorption. The pharmacokinetic data from this study showed no significant differences in PK parameters (including Cmax and AUC0-∞) between the test formulation and the reference formulation under fasting and postprandial conditions. Based on the 90% confidence interval of the PK parameters obtained from the PK analysis in the range of 80%-125%, we can conclude that these data meet the regulatory requirements and that there is bioequivalence between the test formulation and the reference formulation.
In the present study, in contrast to previous findings, the effect of food factors on the pharmacokinetics of nifedipine was mainly the change in fasting and postprandial Tmax. In our study, the Tmax was 24h under fasting conditions and 6 h under postprandial conditions. the postprandial Tmax in the present study was nearly twofold earlier, which is completely different from the changes in Tmax in several previous studies on the pharmacokinetics of nifedipine extended-release tablets. In other people’s studies, the value of Tmax increases after meals, that is, eating makes the Tmax of nifedipine sustained-release tablets push back14; Or there is little difference in Tmax between fasting and postprandial15. Our results, on the other hand, suggest that feeding pushes forward the Tmax of nifedipine, and the reasons for this result are complex and may be related to factors such as gastrointestinal peristalsis, visceral blood flow, altered gastrointestinal PH, and possibly population factors. The effect of food on the pharmacokinetics of nifedipine extended-release tablets is of interest in this study, and more in-depth studies could be conducted in the future to elucidate the significance of food on nifedipine PK.
In recruiting subjects for this study, strict selection criteria were applied primarily for alcohol intake, smoking status, and other drugs that affect the nifedipine metabolizing enzyme CYP3A, as these factors may contribute to variability in nifedipine pharmacokinetic parameters.
In the safety assessment, no significant differences in the incidence of adverse reactions were observed between the tested and reference formulations, and no clinically meaningful changes were found in the physical examination, electrocardiogram, or laboratory tests.
This study has the limitation that because this trial was an open-label trial, psychological effects between subjects receiving the test and reference formulations were not completely excluded. The pharmacokinetic parameters in this study were derived from healthy Chinese subjects only, so there are limitations for other ethnicities, as well as other target populations for reference. It is hoped that more in-depth studies can be conducted to address these issues.