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.