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\begin{document}

\title{A Randomized, Open, Crossover bioequivalence study and Food Effect
Assessment of Two fixed-dose combination of Lisinopril /
Amlodipinebesylatein Healthy Chinese Subjects}



\author[1]{Ting Li}%
\author[1]{Yanping Liu}%
\author[1]{Shu-qin Liu}%
\author[1]{Ping Shi}%
\author[2]{Xin Jiang}%
\author[2]{Ye Tao}%
\author[1]{Xiao-meng Gao}%
\author[1]{Ya-ping Ma}%
\author[2]{Yu Cao}%
\affil[1]{Affiliation not available}%
\affil[2]{The Affiliated Hospital of Qingdao University}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background:This study was conducted to compare the PK characteristics,
food effect and evaluate the bioequivalence between two fixed-dose
combinations of lisinopril /amlodipine besylate in healthy Chinese
subjects. Methods: A single center, randomized, open-label, single-dose,
crossover bioequivalence study was designed in healthy Chinese subjects
under both fasting and fed conditions. Cmax and AUC were used to
evaluate bioequivalence. Adverse events were recorded. Results: 75
healthy subjects completed the study. The 90\% confidence intervals of
the ratio of geometric means of Cmax and AUC0-[?] of lisinopril and
amlodipine fell within 0.80-1.25. A fat-high breakfast produced
significant alteration in the Cmax and AUC of lisinopril after a dose of
either reference or test drug. No severe adverse events were observed.
Conclusion: The trial demonstrated that the test and the reference drug
of fixed-dose combinations of lisinopril /amlodipine besylate were
bioequivalent and well tolerated under fasting and fed condition%
\end{abstract}%



\sloppy


\textbf{Introduction}

Hypertension is an independent and major risk factor for cardiovascular
diseases, and a lowering blood pressure (BP) substantially reduces
prematuremorbidity and mortality{[}1{]}.The 2019annual report on
cardiovascular health and diseases in China indicated that, the number
of Chinese residents withhypertensionhas reached 245 million{[}2{]}.
However, only 45.8\% of the patients are treated, and the control of
hypertension was 16.8\%{[}3{]}. According to Chinese Guidelines for
Prevention and Treatment of Hypertension,five classes of
anti-hypertensive drugs, including calcium channel blockers (CCB),
angiotensin-converting enzyme inhibitors (ACEI), angiotensinreceptor
blockers (ARB), diuretics, \selectlanguage{greek}β-\selectlanguage{english}blockers, and fixed-ratio preparations
composed of the above drugs, are recommended.Highriskgroup of patients
with BP [?] 160/100 mmHg and 20/10mmHg higher than that of the target BP,
or patientswhoreceive mono-therapy and do not achieve the goal BPshould
be treated with combinationtherapy{[}4{]}. It is well known that,
compared to free-dose combinations, fixed-dose combinations (FDCs) of
two or more antihypertensive agents in a single pill can improve
medication compliance, an importantconsideration when requiring patients
to self-administermultiple medications. One of the preferred specific
drug regimens is ACEI/CCB,as the most common adverse effects of CCBs,
peripheral edema and tachycardia, are partially neutralized by RAAS
inhibitors{[}5{]}.

Lisinopril, an ACEI, can decreaseperipheral vascular resistance and
reduce blood pressure, preload, and afterload, without changes in heart
rate{[}6{]}. Lisinopril is the only ACE inhibitor that exhibits a linear
dose-response curve{[}7{]}. The antihypertensive effect of lisinopril
usually appears within 1 h after oral administration, and peaks at about
6h. Bioavailability of lisinopril is about 20-28 \%, and its
cumulativeeffective half-lifeafter multiple administration is about 12
h. Lisinopril does not bind to other plasma proteins other thanACE, and
it is excreted from the urine in its original form without
undergoingmetabolic transformation{[}8{]}.

Amlodipine, a dihydropyridine-based CCB, inhibits the transmembrane
influx of calciumions into vascular smooth muscle and is indicated for
the management of stable angina and hypertension. Amlodipine is almost
completely absorbed and is converted to inactive metabolites by CYP3A4
in liver{[}9{]}.After single oral administration, amlodipine reaches at
C\textsubscript{max} within 6.0--8.0 hours and has a terminal
elimination half-life of40--50 hours, with high oral bioavailability of
60\%--65\%{[}10{]}.

The combination of lisinopril and amlodipine, two classes of long acting
drugs, has a marked additional effect on blood pressure and fewer side
effects than individual monotherapy{[}11, 12{]}. Though many
pharmacokinetics studies forlisinoprilandamlodipine as a single pill
have been reported, very few were focused on an FDC.The FDC of
Lisinopril 10mg/ Amlodipine besylate 5mg (Lisonorm\selectlanguage{ngerman}®) has been developed
by Gedeon Richter Ltd and approvedin multiple countriesin the European
Union, but not yet in China.The aim of this study was to compare the PK
characteristics and evaluate the bioequivalence and food effect
betweenLisonorm and the newly developed lisinopril/amlodipine besylate
FDC productin Healthy Chinese Subjects.

\textbf{Materials and Methods}

\textbf{Formulations}

The test product of lisinopril 10mg /amlodipinebesylate 5mg (batch
no.:180101;expiration date: December 2019)was produced by Sichuan
MEIDAKANG Pharmaceutical Co. Ltd(SichuanProvince,China), and developed
by Sichuan Sunrise Biopharm Co. Ltd (Sichuan Province, China).

The reference product of Lisonorm®(batch no.:T79030A;expiration date:
September 2019) was produced by Gedeon Richter Ltd (Hungary).

\textbf{Subjects}

Healthy volunteers that meet the inclusion criteria and not the
exclusion criteria were enrolled in the study after the clinical and
laboratory examinations. The inclusion criteria included as
follows:1)healthy male and female aged over 18years;2)the Body Mass
Index is in the range of19.0 to 26.0 kg/m\textsuperscript{2} (both
inclusive), and males with minimum of 50 kg weight, females with minimum
of 45kg weight; 3)subjects have no clinically significant abnormalities,
including vital signs, physical examinations, laboratory tests, and ECG
as determined by clinical examination; 4)agree to follow approved birth
control methods.

Subjects were excluded if any of the following conditions were present:
1)allergic diathesis or hypersensitivity toinvestigational products;
2)history or presence of significant cardiovascular, urogenital,
pulmonary, hepatic, renal, gastrointestinal, endocrine, immunological,
dermatological, neurological or psychiatric disease or disorder, or
other medical history affecting drug absorption; 3)use of any drugs or
herbal medicinewithin 14 days; 4)smoking more than five cigarettes a
day, abuse of alcohol or drugs, drinking too much tea, coffee or
caffeinated drinks (more than 8 cups a day, 250ml/cup); 5)donation or
loss of blood or plasma \textgreater{}400mL in the past 3 months;
6)consumption of any beverages or food containing caffeine or products
rich in grapefruit, such as coffee, tea and chocolate, etc,within 48
hours prior toreceiving study drug.

\textbf{Ethic}

The bioequivalence study has been registered on ClinicalTrials.gov
(No.:NCT04885660, retrospectively registered in May 2021) and been
approved bythe Medical Ethics Committeeof the Affiliated Hospital of
Qingdao University (No.: QYFYEC 2018--055-01). The study was conducted
in accordance with the Declaration of Helsinki, Good Clinical Practice
(GCP) and applicable lawsand regulationsof China National Medical
Products Administration(NMPA).Writteninformed consent wasobtained from
all subjects before their participation in the study.

\textbf{Study design}

This was a single center, randomized, open-label, single-dose,
two-period crossover bioequivalence study in both fasting and fed
conditions. According to pre-test and previous studies, the coefficient
of individual variation of lisinopril/amlodipinebesylate FDC product
arranged from 20\%-30\%{[}13-15{]}. Under the condition that \selectlanguage{greek}α\selectlanguage{english}=0.05,
statistical test efficiency 1-\selectlanguage{greek}β\selectlanguage{english}= 0.9, coefficient of variationwas 0.28,
equivalent lower limitwas 0.80, upper limit was1.25 and actual
ratiowas1, 35 samples were needed, using the ''equivalence tests for the
ratio of two means in a 2x2 cross over design'' process insoftwarePower
Analysis and Sample Size (PASS,version 15.0).Considering the possibility
of shedding, 40 subjects were planned to be selectedin each fasting and
fed bioequivalence study. All eligible subjects were randomly
assignedaccording to the random table generated by the statistical
professionals in the Department of Shanghai Second Military Medical
University using SAS9.4. The subjects took the test(T) and
reference(R)drugsrespectivelywith 240ml water after an overnight fast of
at least 10 hours (fasting study) or after the high-fat breakfast within
half an hour before dosing(fed study).The high-fat breakfast contained
929 kcal calories, and consisted of three pork buns with cabbage,
spinach mixed with Yuba, and millet gruel. Breakfast composition and
energy distribution was showed in Table1. Subjects were forbidden to
drink water within 1h before and after taking the drug, and the lunch
and dinner were provided at 4 h and 8 h respectively post-drug
administration. No other food and beverage intake was permitted except
the normal diets provided by the clinical trial center during the study.
A washout of 14 days was set between the two administrations, according
to the half-life recorded inoriginal drug instructions. 4ml venous blood
samples were collected before drug administration and
at1,2,3,4,5,6,7,8,9,10,11,12,13,24,36,48,72,96,144,168h after
administration. The samples were centrifuged at 1700gear per minute for
10min at 4 to separate the plasma, which was divided into two
aliquots(drug monitoring at least 800ul and backup) and stored at
-80until analysis.The study flow chart is presented in Figure 1.

\textbf{Bioanalytical Assay}

Plasma concentrations of lisinopril and amlodipine were measured by an
established and validated liquid chromatography-tandem mass spectrometry
(LC-MS/MS) method at Suzhou Haike Pharmaceutical Technology Co., Ltd
(Suzhou, Jiangsu Province, China). For the analysis of lisinopril,
plasma samples were pretreated by liquid liquid extraction with
isopropanol: ethyl acetate(1:2,V/V); LSN-d5 was used as internal
standard; 5mM ammoniumacetate aqueous solution, 0.01\% formic acid and
methanol were used as mobile phase; chromatographic separation was
performed on Atlantis-dC18 column(Waters, Massachusetts, USA) and the
analytes were detected using Triple Quad TM 5500 tandem mass
spectrometer(Sciex, Canada) in positive ion mode, with ion sprayin
multiple reaction monitoring mode.The lower limit of quantification was
0.500ng/mL and the assay dynamic range was 0.500-100ng/mL. The analytes
in matrix were stable when stored at -20 for 26 days, at -80 for 169
days and after four freeze-thaw cycles.

Amlodipine plasma concentrations were determinedusing a liquid
chromatography unit(Shimadzu,LC-30AD,Japan) and a mass
spectrometer(Sciex, Triple Quad TM 6500 plus, Canada). Under multiple
reaction monitoring, LC-MS/MS system adopts positive ionization
mode.Forthe analysis of amlodipine, the lower limit of quantification
was 0.050ng/mL and the assay dynamic range was 0.050-10.0ng/mL.The
analytes in matrix were stable when stored at -20 for 91days, at -80
for 207 days and after four freeze-thaw cycles.

Data collection and analysis was performed with Analyst 1.6.3 software
(Sciex, Canada) and Watson LIMS(Thermo, USA). Calibration curves were
constructed using linear regression equation obtained by the weighted
(W=1/X\textsuperscript{2}) least square method fitting for both
analytes.Quantitation of qualitycontrol and clinical samples were also
performed by theAnalyst software using the same mathematical algorithm
asthat used in the calibration of standard curves.

\textbf{Pharmacokinetic Analysis}

Pharmacokinetic (PK) parameters for lisinopril and amlodipine in plasma
were estimated by a non-compartmental model (NCA) using Phoenix
WinNonlin version 7.0 software (Pharsight Corporation, St Louis, MO,
USA). For the purpose of bioequivalence analysis, the maximum observed
concentration (C\textsubscript{max}), the area under the plasma
concentration-time curve from time 0 to the last measured time point
(AUC\textsubscript{0-t}), and the area under the plasma
concentration-time curve from time 0 to infinity
(AUC\textsubscript{0-[?]})were considered as primary PK parameters. The
secondary PK parameters were the observed time to
C\textsubscript{max}(T\textsubscript{max}) and the apparent terminal
half-life (T\textsubscript{1/2}). C\textsubscript{max} and
T\textsubscript{max}were the factually measured data
andAUC\textsubscript{0-t} was calculated using the linear and
logarithmic trapezoidal methods. AUC\textsubscript{0-[?]} was calculated
according to the following formula: AUC\textsubscript{0-[?]}=
AUC\textsubscript{0-t}+C\textsubscript{last}/\selectlanguage{greek}λ\selectlanguage{english}\textsubscript{z}(C\textsubscript{last}is
the last measurable concentration and is the first order rate constant
of terminal elimination determined from a linear regression line after
logarithmic transformation at the end of concentration time curve.
\selectlanguage{greek}λ\selectlanguage{english}\textsubscript{z}is the slope calculated by linear regression after
logarithmic conversion at the end of the concentration-time curve).
T\textsubscript{1/2} was calculated to be ln2/\selectlanguage{greek}λ.

\selectlanguage{english}\textbf{Safety assessment}

The safety was evaluated by monitoring vital signs, physical
examination, laboratory tests, electrocardiogram(ECG) and adverse events
(AEs) collected after dosing throughout the study. Vital signs,
including body temperature, blood pressure (BP) and heart rate, were
measured at screening, before drug administration and at 2, 4, 6, 8, 12,
24, 36, 48, 72, 96, 144, 168h after administration. Routine laboratory
tests (hematology, urinalysis, serum chemistry and pregnancy test for
females) and 12-lead ECG were conducted at screening and before removal
from the study. The AEs, including all subjective symptoms reported by
subjects and objective signs observed by clinical investigators, were
recorded and assessed for their severity and the correlation with
research drugs.

\textbf{Statistical analysis}

Statistical analysis was performed by SAS 9.4. All data were tested by
two-side test and the probability value (P) less than 0.05 was
considered statistically significant.AUC and C\textsubscript{max} were
logarithmically transformed and analyzed by linear mixed effect model.
Sequence, period and formulation were fixed effects, and subject within
sequence was included as a random effect. Analysis of variance (ANOVA)
of cross-over design was performed on the log-transformed variables. The
geometric mean ratios (GMRs) of the primary pharmacokinetic parameters
and their 90\% confidence intervals (CIs) were calculated, and the test
formulation was judged as bioequivalence if it fell within the
equivalent range (80-125\%). Bioequivalence was assessed separately in
both the fasting and fed groups.

\textbf{Results}

\textbf{Subject characteristics}

A total of 181 subjects were screened for inclusion; 92 healthy subjects
(40 fasting group and 52 fedgroup) were randomized into each of the
study group, and 75 subjects (39 of fasting group and 36 of fed group)
completed the study. 1 subject in fasting group withdrew because of
pregnancy before admission in second period. 12 subjects in fed group
fell off as a result of failing to finish the high-fat breakfast within
30 minutes, and replaced by the other subjects from the waiting list;
besides, another 4 subjects dropped out due to poor compliance,
voluntary withdrawal and AE of tonsillitis.

Data from the subjects who received a study drug at least once were used
for safety assessment and subjects who completed the study were included
in the PK analysis. The baseline demographic characteristics of subjects
showed no statistical difference between the sequence groups (Table2).

\textbf{Pharmacokinetics}

The mean plasma concentration versus time profiles of lisinopril and
amlodipine following a single dose of the test or reference products
under fasting and fed conditions are illustrated in Figure2, the PK
parameters are summarized in Table3.

The intra individual variation ofAUC\textsubscript{0-72} and
AUC\textsubscript{0-t} of lisinopril were 21.2\%, 19.3\% and 14.5\%,
13.3\% respectively under fasting and fed condition, indicating that
lisinopril has low variability. Therefore, the bioequivalence evaluation
results ofAUC\textsubscript{0-72} were added.

Regarding theC\textsubscript{max}, AUC\textsubscript{0-t},
AUC\textsubscript{0-72} (only lisinopril) and AUC\textsubscript{0-[?]} of
lisinopril and amlodipine respectively,the 90\% CIs for the GMRs fell
within the predefined acceptance range of 80-125\%, and provided
supportive evidence for bioequivalence (Table4). Accordingly, lisinopril
had a relatively long terminal elimination half-life of about 90 hours,
which may be related to the binding saturation of the drug and ACE. In
the fasting study, although the sample collected at 168 h after
administration did not reach 3-5 half-lives, the last detectable
concentration of all subjects was lower than 1/20 of the corresponding
peak concentration and only 2.5\% (2/79) of
AUC\textsubscript{\_\%Extrap}was more than 20\%. Therefore, the plasma
concentration from 0-168h can completely describe the pharmacokinetic
behavior of lisinopril. Compared with the fasting study, the
C\textsubscript{max} and AUC of lisinopril under fed condition were
significantly reduced. Although 54.5\% (40/74) of
AUC\textsubscript{\_\%Extrap} was higher than 20\%, 89.2\% (66/74) of
the final concentration at 168h were lower than 1/10 of the
corresponding peak concentration, which could basically describe the
pharmacokinetic behavior of lisinopril. After eliminating the data with
AUC\textsubscript{\_\%Extrap} greater than 20\% for sensitivity
analysis, the 90\% CI for the GMRs of AUC\textsubscript{0-[?]} of the test
and reference preparation was 96.2\% (86.7-106.7\%).

A fat-high breakfast produced significant alteration in the
C\textsubscript{max} and AUC of lisinopril after a dose of either
reference or test drug in Chinese healthy subjects.Compared with fasting
study, after high -fat postprandial administration, lisinopril
C\textsubscript{max}, AUC\textsubscript{0-t}, AUC\textsubscript{0-72}and
AUC\textsubscript{0-[?]} under fed condition were greatly decreased by
74\%, 59\%, 66\%, 53\% for test products (P\textless{}0.001), and 73\%,
57\%, 64\%, 51\% for reference products (P\textless{}0.001). In
addition, there was a nearly 1.5-hour delay in median
T\textsubscript{max} under fed conditions for the test products.
However, no changes were observed in T\textsubscript{max}for reference
products and in T\textsubscript{1/2} for both the test and reference
products between the two fasting and fed studies.

\textbf{Safety assessment}

The test and reference drug of lisinopril/amlodipinebesylate FDC product
showed good tolerance in all subjects. During the study, the vital signs
of subjects were stable except that some subjects had signs of blood
pressure reduction due to the expected effect of the study drug, and
there was no clinically significant change in the follow-up laboratory
examination after the administration compared with the baseline value.In
the study of fasting condition, a total of 33 treatment emergent adverse
events (TEAEs) were recorded in 20 subjects (50\% of 40 subjects) after
T treatment, and 25 TEAEs were recorded in 16 subjects (40\% of 40
subjects) after R treatment. In the fed study, 13 TEAEs were recorded in
10 subjects (22.7\% of 44 subjects) after T treatment, and 12 TEAEs were
recorded in 9 subjects (20.5\% of 44 subjects) after R treatment.All AEs
were light and spontaneously recovered without specific intervention
except for one instance of tonsillitis, which may be irrelevant to the
study drugs, and a case ofatopic dermatitis.No subjects withdrew from
the study due to AEs except for one case of tonsillitis and no severe
adverse events (SAE) occurred. There was no significant difference in
the incidence of AEs between the two treatments. All TEAEs were
summarized according to system organ classification (SOC) and preferred
term (PT), and were presented in Table5.Hypotension was the most common
AE, and Figure 3 illustrates the changes in mean systolic blood pressure
(SBP) and diastolic blood pressure (DBP) from baseline to 24 hours.The
results showed that the blood pressure decreased maximally from pre-dose
values by 6 h after one dose of lisinopril/amlodipinebesylate FDC
product and the suppression lasted up to 12 h. There was no significant
difference in mean SBP between the fasting and fed groups, except at 8 h
after administration of test product (P=0.038). However, the DBP
decreasedmore than SBP in healthy Chinese subjects, and compared to fed
study, the DBPdecreased obviously more at 4 h, 6 h, 8 h following the
dosing with both regimens in the fasting state (P\textless{}0.05).

\textbf{Discussion}

The purpose of thisstudy was to compare the PK properties to examine
whether the new lisinopril/amlodipinebesylate FDC product was equivalent
to the reference for a new drug application to the NMPA.In this study,
the GMR and its 90\% CI for the C\textsubscript{max},
AUC\textsubscript{0-t}, AUC\textsubscript{0-72} (only lisinopril) and
AUC\textsubscript{0-[?]} of lisinopril and amlodipinerespectively, under
both fasting and fed conditions, fell within the conventional
bioequivalence criteria of 0.80-1.25.In addition, compared with the
reference drug, the incidence of AEs of the test drug had no difference,
and showedsimilar safety and tolerance. These results indicated that the
two lisinopril/amlodipinebesylate FDC preparations were bioequivalent
and exchangeable in clinical practice.

In this study, food appeared to greatly decrease the extent of
lisinopril absorption by more than half and affect the antihypertensive
effect for both the reference and test products. These results are
inconsistent with the instructions of the original lisinopril tablet
(Zestril\selectlanguage{ngerman}® produced by AstraZeneca UK limited) and the reference
Lisonorm(produced by Gedeon Richter Ltd). The instructions say the
gastrointestinal absorption of lisinopril is not affected by food.A
previous study investing the influence of food consumption on the rate
or extent of absorption of orally administered lisinopril in healthy
volunteers observed that, a breakfast (524kcal, consisting of one fried
egg, two pieces of toast or bread, 20g of orange marmalade or jelly, two
stripes of bacon, 150ml of skimmed milk and 100ml of orange juice)did
not affect the bioavailability of lisinopril{[}16{]}. This inconsistency
may probably be due to the fact that (i) high-caloric and high-fat foods
have a more obvious impact on the physiology of the gastrointestinal
tract and lead to more significant changes in the bioavailability of
pharmaceuticals{[}17{]}; (ii)spinach in breakfast is rich in oxalic
acid, which may change gastrointestinal PH and gastrointestinal
peristalsis {[}18{]}; and (iii) the participants of this study were all
young Chinese adults, and there may be ethnic differences in the
pharmacokinetics of lisinopril. Among ACE inhibitors, lisinopril has a
unique property that does not require hydrolysis to exert ACE
inhibition, and only lisinopril and captopril are not ester prodrugs and
less lipophilic{[}19{]}. Food has been shown to reduce the
bioavailability of captopril by 35\% to 50\% after a single oral
administration, but not the bioavailability of inhibitors administered
as ester prodrugs{[}20{]}.With high solubility, low membrane
permeability and poor metabolism, the pharmacokinetic of lisinopril may
be dominated by absorptive transporter effects{[}21{]}.Only about a
quarter of the administered dose is absorbed and the low bioavailability
is due to poor gastrointestinal absorption rather than first-pass
hepatic metabolism, as demonstrated by the factthat mean fecal recovery
of lisinopril was 69\% of intact drug{[}22{]}.

In order to better understand the possible reasons for the decrease of
lisinopril absorption in the fed study, we searched for various factors
that affect lisinopril bioavailability.Little is known about
pharmacokinetic interaction of lisinopril so far.Drugs that often used
with lisinopril,such as nifedipine, digoxin,hydrochlorothiazide, have no
substantial effect on the pharmacokinetics of lisinopril{[}23-25{]}.No
drug-drug interactions (DDIs) were found between the active components
amlodipine and lisinopril. One of the factors that has been reported to
affect the kinetic properties of lisinopril was age. Drug concentrations
of elderly patients (\textgreater{}65 years) have been reported to be
approximately double those of younger patients{[}26{]}. And a recent
study demonstrated that a concomitant ingestion of epigallocatechin
gallate(EGCG)-concentrated green tea extract significantly decreased
lisinopril C\textsubscript{max}, AUC0-24 and AUC0-\selectlanguage{english}[?]by 71\%,69\% and
67\%, without altering renal clearance of lisinopril{[}27{]}. However,
in the present study, the enrolled subjects was all between 18 and 50
years old, and those who have drink too much tea were excluded.
Moreover, it was forbidden to taketeawithin 48 hours before taking the
first administration and during the test.Therefore, larger studies are
needed to evaluate the effect of food on the pharmacokinetics of
lisinopril in Chinese.

\textbf{Conclusions}

In conclusion, the new lisinopril/amlodipinebesylate FDC
product(specification: lisinopril 10mg / amlodipine 5mg)developed by
Sichuan Sunrise Biopharm Co. Ltd (Sichuan Province, China)are equivalent
to the Lisonorm (specification: lisinopril 10mg / amlodipine 5mg)
produced by Gedeon Richter Ltd (Hungary). If the test formulation can be
approved by NMPA, it can be used in the treatment of hypertension in
Chinese adult patients. However, patients may need to avoid consumption
of high-fat, high-calorie diet during treatment.

\textbf{Acknowledgements}

The authors acknowledge the staff at Sichuan Sunrise Biopharm Co., Ltd
(Sichuan Province, China) for the study protocol, the staff at Suzhou
Haike Pharmaceutical Technology Co., Ltd (Jiangsu Province, China) for
sample assay and pharmacokinetics analysis and the staff at Shanghai
Second Military Medical University (Shanghai, China) for statistical
analysis. We are also grateful to the volunteers participating in the
study.

\textbf{Data Availability}

The datasets generated and analyzed during the current study are
available from the corresponding author on reasonable request.

\textbf{References}

1. Williams, B., et al., \emph{2018 ESC/ESH Guidelines for the
management of arterial hypertension.} Eur Heart J, 2018. \textbf{39}
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2. China, T.W.C.o.t.R.o.C.H.D.i.,\emph{Annual report on cardiovascular
health and diseases in China 2019.} Chinese Circulation Journal, 2020.
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3. Wang, Z., et al., \emph{Status of Hypertension in China: Results From
the China Hypertension Survey, 2012-2015.} Circulation, 2018.
\textbf{137} (22): p. 2344-2356.

4. Joint Committee for Guideline, R.,\emph{2018 Chinese Guidelines for
Prevention and Treatment of Hypertension-A report of the Revision
Committee of Chinese Guidelines for Prevention and Treatment of
Hypertension.} J Geriatr Cardiol, 2019.\textbf{16} (3): p. 182-241.

5. Canbakan, B., \emph{Rational approaches to the treatment of
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