Bioequivalence Study of Domperidone Dry Suspension in Chinese Healthy Subjects Under Fasted and Fed Conditions: An Open-label, Randomized, Single-dose, Crossover Trial

doi:10.21203/rs.3.rs-1400180/v1

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Bioequivalence Study of Domperidone Dry Suspension in Chinese Healthy Subjects Under Fasted and Fed Conditions: An Open-label, Randomized, Single-dose, Crossover Trial

https://doi.org/10.21203/rs.3.rs-1400180/v1

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Background Domperidone, a selective antagonist of dopamine D2 receptors, has long been used as a prokinetic agents in the treatment of epigastric distress symptoms. This study aimed to provide adequate evidence for registration approval of a new genetic dry suspension formulation of domperidone by comparing the safety and pharmacokinetic profiles between the test and branded reference formulation in the context of fasted and fed condition.

Methods It was designed as a randomized, open-label, single-dose, two-period, two-treatment crossover study. 32 and 28 eligible healthy subjects were enrolled in the fasted and fed study, respectively. Each subject was randomly assigned to receive either the test or reference formulation in the first period, followed by a 1-week washout period and dosing of the alternate formulation in the second period. A series of blood samples were collected at scheduled timepoints within 48 hours after administration during each treatment period. Plasma concentrations of domperidone were determined by validated HPLC-MS/MS. Pharmacokinetic parameters, including C_max, T_max, AUC_0–t, AUC_0–∞, and t_1/2, were acquired based on the concentration versus time profiles by non-compartmental analysis using WinNonlin software. Then the geometric mean ratios (GMR) of C_max, AUC_0–t and AUC_0–∞ between the two formulations and corresponding 90% confidence intervals (CIs) were calculated for bioequivalence determination. Safety was assessed as routine.

Results The two formulations showed similar pharmacokinetic profiles. Under fasted condition, the GMR and corresponding 90% CIs of AUC_0–t, AUC_0-∞ and C_max were 101.48% (96.79% to 106.38%), 101.17% (96.66% to 105.90%) and 104.61% (96.73% to 113.14%) , respectively. Under fed condition, the GMR and corresponding 90% CIs were 105.46% (99.19% to 112.12%), 104.21% (98.19% to 110.61%) and 112.78% (103.64% to 122.73%), respectively for AUC_0–t, AUC_0-∞ and C_max. All the values fell within the accepted bioequivalence range of 80% to 125%. Both the test and the reference products were well tolerated without any serious or unexpected adverse reactions.

Conclusions Pharmacokinetic bioequivalence was established between the two dry suspension formulations of domperidone in Chinese healthy subjects. Both products were safe and well tolerated.

Trial Registration ChiCTR, ChiCTR1900023947. Registered 19 June 2019- Retrospectively registered, http:// www.chictr.org.cn/ChiCTR1900023947.

bioequivalence

domperidone

dry suspension

pharmacokinetics

Domperidone is a selective antagonist of dopamine D2 receptors located outside of the blood–brain barrier. It has long been used as a prokinetic agents in the treatment of epigastric distress symptoms that triggered or aggravated by a meal since 1978 in Europe and Asia [1, 2]. Although controversy as regard to the cardiac risks of domperidone has been continuing over the years, the oral formulation as tablet or solution is still available in the market [3, 4].

After oral administration, domperidone is well absorbed and undergoes an extensive first-pass metabolism with the bioavailability being 13%~17%. Maxium concentration (C_max) in plasma reaches within 2 hours, and the apparent elimination half-life (t_1/2) is approximately 7h ~ 14h [5, 6]. The main metabolic pathway involves CYP3A-catalyzed N-dealkylation and aromatic hydroxylation. In addition, it’s reported that domperidone is a competitive and mechanism-based inhibitor of CYP3A in vitro. If co-administered with CYP3A inhibitors, the risk of adverse drug reactions will increase [7–9].

The first dry suspension formulation of domperidone (NAUZELIN^®) was developed by Kyowa Hakko Kirin, Tokyo, Japan, and approved by MHLW (Ministry of Health, Labour and Welfare) in 1982. Compared to tablet, the oral dry syrup is easy for being taken by critically ill patients with swallowing impairment, especially for children or old patients who need special care. Recently, a dry suspension formulation of domperidone has been developed by Zhejiang Yatai Pharmaceutical Co., Ltd (Hangzhou, China). Consistent with National Medical Products Administration (NMPA) guidelines that call for comparing the bioavailability of the genetic product with the original agent for marketing, we carried out this study to assess the bioequivalence between the test and reference products under fasted or fed condition in healthy adults. The Chinese Clinical Trials Registry identifier was CTR1900023947.

Study drugs

The test domperidone dry suspension (10 mg, lot number S1180201, expiry date January, 2020) were manufactured by Zhejiang Yatai Pharmaceutical Co., Ltd. (Hangzhou, China), and the reference formulation is NAUZELIN^®dry suspension (10 mg, lot number 071AFI; expiry date September, 2019), a commercially available original domperidone preparation from Kyowa Hakko Kirin, Tokyo, Japan.

Subjects

Healthy volunteers, male or female, aged between 18 and 45 years with a body mass index(BMI) between 19 and 26 kg/m², were recruited. After being well informed and fully understanding the risks and benefits of the study, all subjects provided written informed consent and underwent a comprehensive medical examination, including detailed medical history, physical examination, 12-lead electrocardiogram (ECG), chest X-ray and other laboratory tests. Female subject of childbearing potential must have a negative serum pregnancy test at screening, and all the subjects agree to use routinely adequate contraception. Healthy subjects meeting the inclusion criteria were identified. Exclusion criteria included a history of allergy or atopic allergic disease; previous history of ECG with clinical significance; any history of hepatic or renal impairment, digestive tract disease probably affecting drug absorption; clinically significant abnormalities in laboratory tests. Subjects who used any drugs or food supplements within 2 weeks before screening were also excluded.

Study Design and Treatment

This study consisted of two independent parts (fasted and fed studies). Each part was designed as a randomized, open-label, single-dose, two-period, two-treatment crossover study. It was carried out from 04 June to 14 August 2019 in the Phase I Clinical Research Center of the First Affiliated Hospital, Zhejiang University School of Medicine, China, in accordance with the Declaration of Helsinki and the Good Clinical Practice (GCP) guidelines. All documents including the protocol were reviewed and approved by the ethics committee of the First Affiliated Hospital, College of Medicine, Zhejiang University.

Sample size was calculated using PASS (Version 11.0.7) software. It was based on one-sided test with an 80% statistical power (β = 0.2) at a 5% level of significance (α = 0.05). The intra-subject coefficient of variation (CV) of 20.0% was selected as routine, the geometric mean ratio between the test and reference formulations of C_max was set to 0.92 (fasted) or 0.93 (fed), which was obtained from our previous pilot studies. It was estimated that 27 (fasted) or 23 (fed) cases were required. Considering the dropout rate, we finally determined to enroll 32 and 28 subjects in the fasted and fed study, respectively.

On the day of admission in the first treatment period, subjects were randomly assigned to Test-Reference (TR) or Reference-Test (RT) group at a 1:1 ratio by the principal investigator in the turn of screening sequence. The TR group received the test products in the first treatment period and the reference in the second, while the sequence of administration was reversed in the RT group. There was a 1-week washout period between each administration. The random allocation table was prepared by statistician with block randomization using SAS (Version 9.4).

Participants in the fasted study received a single dose of the test or the reference product after overnight fasting for at least 10 hours. Whereas the subjects in the fed study were required to have a standard high-fat breakfast (27.5% carbohydrate, 15.4% protein, and 57.1% fat) within 30 minutes before dosing. Both formulations were dissolved in 240ml warm water mixed evenly with glass rods before administration. Water intake was withheld within 1 hour before and at least 2 hours after dosing. Standardized lunch and dinner were provided at 4 and 10 hours after administration, respectively. Besides, researchers released water at five fixed timepoints with 240ml each time. Subjects were ambulatory, and qualified staff needed to pay close attention to them and take necessary measures in case of any individual situation throughout the entire confinement period. All subjects were required to avoid strenuous activity, smoking, juice and pharmaceutical/herbal products during the study period.

Blood sampling and analytical determinations

A series of blood samples were collected during each treatment period. In fasted study, 4 mL whole blood samples were collected into coded, K₂-EDTA anticoagulation tubes pre-dose (baseline) and at 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8,12, 24, 36, and 48 hours post-dose. In the fed study, whole blood samples were collected pre-dose and at 0.33, 0.67, 1, 1.33, 1.67, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, and 48 hours after administration. Blood samples were centrifuged at 4 ℃ at 1700×g for 10 minutes. The supernatant was collected as plasma samples and temporarily stored at -20°C within 2 hours of collection, and then transferred to an ultra-low temperature refrigerator (− 70 ± 10°C) in 48 hours for storage until being used for analysis.

Plasma concentrations of domperidone were determined by high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS) method validated previously by Wuhan Hongren bio-pharmaceutical Co., Ltd. (Wuhan, China). After liquid-liquid extraction using methyl tert-butyl ether, the chromatographic separation was performed on a LC-20AD XR (Shimadzu) Ultimate XB C18 (2.1×50 mm, 5 µm) with mobile phase A (100% acetonitrile) and mobile phase B (Water with 0.1% formic acid), gradient elution. Domperidone-d₆ was used as internal standards (IS). The mass spectrometric analysis was performed using a Triple Quad 4500 (AB Sciex) mass spectrometer coupled with an electrospray ionization source in positive ion mode. The multiple reactions monitoring (MRM) transitions of m/z 426.2→175.2 and m/z 432.2→181.2 were used to quantify domperidone and IS, respectively. The validated linearity range for domperidone was 0.10 ~ 30.00 ng/mL. The intra-assay and inter-assay coefficients of variation for precision and accuracy of the lower limit of quantitation (LLOQ) were 1.4%~11.8% and 10.4%, -17.6%~-4.2% and − 9.5%, respectively. The intra-assay and inter-assay coefficients of variation for precision and accuracy of other quality control samples (0.30 ng/mL, 2.50 ng/mL, 22.50 ng/mL) were 1.5%~5.6% and 2.5%~4.9%, -1.7%~5.9% and 0 ~ 3.4%, respectively.

Safety Assessment

According to the protocol, safety was monitored by direct observations, laboratory tests, vital signs, physical examination results, and spontaneous reports from subjects. Any treatment emergent adverse event (TEAE) would be collected and closely followed up to normal (or clinically insignificant) or being clearly explained. Severity of adverse events (AEs) was defined according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, and the relationship with study treatment was also determined.

Pharmacokinetic and Statistical Analysis

The pharmacokinetic parameters of domperidone were calculated with WinNonlin software, version 7.0 (Pharsight Corporation, Mountain View, California) by non-compartmental analysis. Individual plasma concentration–time curves were generated. C_max and t_max were obtained directly from the observed data. AUC_0 − t was calculated by the linear trapezoid rule. AUC_0−∞ was calculated from AUC_0 − t plus the extrapolated area from the last quantifiable concentration (Ct) divided by the elimination rate constant (λz). Elimination half-life (t_1/2) was calculated as ln2/λz.

Statistical analyses were also performed with WinNonlin software. AUC_0−∞, AUC _0−t, and C_max were considered as primary variables for bioequivalence determination. Analysis of variance (ANOVA) was used to evaluate the effect of formulation, sequence, period, and subjects nested in sequence on natural logarithm (ln)-transformed pharmacokinetic parameters. Parametric 90% confidence intervals (CIs) for the geometric mean ratio (GMR) between the two formulations (test-reference) were calculated using the Schuirmann method. If the difference between two compared parameters was found statistically insignificant (p > 0.05) and 90% CIs for the GMR of AUC_0−∞, AUC _0−t, and C_max fell within the range of 80–125%, the two products were considered to be bioequivalent.

Participants

A total of 180 healthy volunteers were screened in June 2019. Finally, 32 subjects (20 males and 12 females) were enrolled in the fasted study, and 28 subjects (12 males and 16 females) in the fed study. The demographic characteristics of these subjects were summarized in Table 1. 31 and 27 cases completed the fasted and fed study, respectively. One participant withdrew from the second period of the fasted study due to chickenpox infection during washout period, whereas one subject discontinued the study before the first period dosing in the fed part.

Table 1

Demographic characteristics of subjects in the fasted or fed study.
Variable	Fasted		Fed
Variable	RT(n = 16)	TR(n = 16)	RT(n = 14)	TR(n = 14)
Age, years
Mean (SD)	29.81 (7.67)	28.63 (6.62)	25.57 (6.81)	35.92 (5.82)
Median	28.50	28.00	23.00	35.00
Min, Max	22.00, 44.00	20.00, 42.00	18.00, 40.00	22.00, 43.00
Height, cm
Mean (SD)	168.06 (8.24)	162.81 (6.43)	164.71 (7.65)	159.62 (4.82)
Median	165.00	164.50	165.50	159.00
Min, Max	155.00, 185.00	148.00, 172.00	150.00, 177.00	153.00, 170.00
Weight, kg
Mean (SD)	64.44 (8.63)	61.02 (5.76)	62.37 (6.93)	58.74 (7.16)
Median	63.80	60.55	62.05	57.10
Min, Max	51.70, 81.10	50.00, 69.50	49.70, 74.50	49.10, 70.90
BMI(kg/m²)
Mean (SD)	22.74 (1.79)	22.98 (1.21)	22.94 (1.47)	22.99 (1.77)
Median	22.80	22.75	22.80	23.50
Min, Max	19.20, 25.30	20.40, 25.10	20.60, 26.00	20.50, 25.90
Gender
Male (%)	11 (68.75)	9 (56.25)	7 (50.00)	5(35.71)
Female (%)	5 (31.25)	7 (43.75)	7 (50.00)	9 (64.29)

Pharmacokinetic Properties

As described above, in the fasted study, 1 subject in TR group dropped out due to chickenpox infection before the second treatment period dosing. Thus, 32 subjects were included in the pharmacokinetic analysis for the test formulation, and only 31 subjects for the reference product. In the fed study, 1 case withdrew due to his vomiting during high-fat diet before the first period of administration. And, another subject who completed the fed study was found to be enrolled by mistaken on the day of discharge, as his abnormal liver function showed during the screening procedure was overlooked by the investigators, which met exclusion criteria. Consequently, the plasma samples of this subject were finally not to be used to determine the concentration of domperidone according to the protocol. Therefore, the pharmacokinetic analysis in the fed study included 26 subjects. The mean plasma concentration-time profiles and semi-logarithmic concentration plots of domperidone obtained after single oral administration of the test and reference product under fasted and fed condition were shown in Figs. 1 and 2. Major pharmacokinetic parameters of domperidone under fasted or fed conditions were listed in Table 2.

Table 2

Pharmacokinetic parameters of domperidone after single oral administration of test and reference domperidone dry suspension in the fasted or fed study.
Parameter	Fasted		Fed
Parameter	Test(n = 32)	Reference (n = 31)	Test(n = 26)	Reference(n = 26)
T_max (h)^a	0.50 (0.33, 1.00)	0.50 (0.33, 1.50)	3.00 (1.33, 4.00)	2.75 (0.67, 6.00)
C_max (ng/mL)^b	16.13 ± 6.97	15.00 ± 5.64	8.21 ± 2.35	7.40 ± 2.41
AUC_0 − t (ng·h/mL)^b	57.17 ± 17.09	56.26 ± 18.12	73.71 ± 14.08	71.37 ± 19.00
AUC_0−∞ (ng·h/mL)^b	60.16 ± 18.02	59.34 ± 19.27	78.70 ± 15.27	77.01 ± 20.07
t_1/2 (h)^b	11.89 ± 2.91	12.08 ± 2.65	13.45 ± 2.43	13.90 ± 4.73
Notes: ^aValues are presented as median (minimum, maximum). ^bValues are presented as mean ± SD.

As for bioequivalence evaluation, 32 individuals’ data were used in the fasted study, and 26 subjects who finished the whole study were used in the fed study. The geometric mean ratios (GMRs) of C_max, AUC_0 − t and AUC_0−∞ were 104.61%, 101.48% and 101.17% in the fasted study, and 112.78%, 105.46% and 104.21% under the fed condition (Table 3). 90% CIs for the GMRs were all within the range of 80–125% under fasted or fed conditions. Therefore, the two domperidone formulations were bioequivalent.

Table 3

Geometric Mean Ratio (GMR) and the corresponding 90% confidence intervals (CIs) for the primary pharmacokinetic parameters in the fasted or fed study.
Parameter	Geometric mean		GMR (T/R)	90% CI	Power
Parameter	Test (T)	Reference (R)	GMR (T/R)	90% CI	Power
Fasted
C_max (ng⋅ml^− 1)	14.74	14.09	104.61	96.73 ~ 113.14%	98.32%
AUC_0 − t (ng⋅ h⋅ ml^− 1)	54.72	53.93	101.48	96.79 ~ 106.38%	100%
AUC_0−∞ (ng⋅ h⋅ ml^− 1)	57.59	56.92	101.17	96.66 ~ 105.90%	100%
Fed
C_max (ng⋅ml^− 1)	7.89	7.00	112.78	103.64 ~ 122.73%	64.73%
AUC_0 − t (ng⋅ h⋅ ml^− 1)	72.38	68.63	105.46	99.19 ~ 112.12%	99.85%
AUC_0−∞ (ng⋅ h⋅ ml^− 1)	77.23	74.10	104.21	98.19 ~ 110.61%	99.97%

Safety and Tolerability

A total of 17 subjects reported 26 TEAEs in the fasted study, with an overall incidence of 53.13% (17/32). 25 of these AEs (96.2%) were identified through laboratory investigations. Six cases of sinus bradycardia as grade 2 and one case of hyperkalemia as grade 2 were observed, which were spontaneously recovered without intervention. Others were transient and considered mild. 1 subject dropped out before the second treatment period dosing because of chickenpox infection, which was considered to be unrelated to the test formulation. Under the fed conditions, a total of 19 cases of TEAEs occurred in 15 subjects, with an overall incidence of 55.56% (15/27). All AEs were mild except one case of sinus bradycardia as grade 2, which spontaneously recovered. One subject withdrew before the first treatment period dosing because of vomiting during high-fat breakfast. No serious adverse events or deaths occurred. The incidence of TEAEs was summarized in Table 4.

Table 4

Total number of treatment emergent adverse event (TEAE) and percentage of healthy subjects experiencing adverse events in the fasted or fed study. Values are given as no. (%).
Parameter	Fasted		Fed
Parameter	Reference(n = 31)	Test (n = 32)	Reference(n = 27)	Test (n = 27)
Death	0	0	0	0
SAE	0	0	0	0
TEAE	10 (32.26%)	12 (37.50%)	7 (25.93%)	9 (33.33%)
Elevated blood leucocyte	0	1 (3.13%)	0	0
Increased eosinophil counts	0	0	0	1 (3.70%)
Decreased hemoglobin	1 (3.23%)	0	0	0
Positive urine leukocyte	0	1 (3.13%)	1 (3.70%)	1 (3.70%)
Positive urine erythrocyte	0	2 (6.25%)	0	0
Positive urine protein	0	0	0	1 (3.70%)
Elevated alanine aminotransferase	0	0	0	1 (3.70%)
Elevated triglycerides	1 (3.23%)	1 (3.13%)	0	3 (11.11%)
Elevated blood uric acid	0	0	0	1 (3.70%)
Increased total bile acid	0	1 (3.13%)	0	0
Increased blood potassium	0	1 (3.13%)	0	0
Elevated blood pressure	1 (3.23%)	1 (3.13%)	0	0
Sinus bradycardia	7 (22.58%)	7 (21.88%)	5 (18.52%)	3 (11.11%)
Nodal tachycardia	0	0	0	1 (3.70%)
Chickenpox infection	0	1 (3.13%)	0	0
Throat foreign body sensation	0	0	1 (3.70%)	0

Dry suspension has both the characteristics of solid preparation (such as easy to carry, convenient transportation, good stability, etc.) and the advantages of liquid preparation (such as convenient administration, suitable for patients with difficulty in swallowing, etc.). It can be taken according to the specific amount required for each dosing and usually has a good taste, so it is especially welcome and well accepted by pediatric patients. In this study, we compared the pharmacokinetic characteristics of the test domperidone dry suspension and the reference product under fasted or fed condition. Results showed that the test/reference GMRs of C_max, AUC_0 − t and AUC_0−∞ and their 90% CIs were all within the range of 80–125%, indicating that the speed and extent of domperidone absorption were similar between the test and reference products. Bioequivalence was established regardless of fasted or fed condition.

Comparing the pharmacokinetic parameters of domperidone obtained in our fasted study with those previously reported in the literature demonstrated no critical variation, which enhanced the validity of the present results [5, 6]. It is well-known the absorption of domperidone is somewhat delayed if it is taken after meals, as the specifications already has recommendations for dosing domperidone before meals. Consistent with this, we can see from Table 3, under fed condition, T_max increased from 0.5h to 3h, C_max decreased by about half, while AUC_0 − t and AUC_0−∞ increased by about 30%, suggesting that a high-fat meal markedly slowed down the rate of the absorption of domperidone, but enhanced the exposure of domperidone, regardless of the test or reference product. Similarly, a recent study of food effects on domperidone pharmacokinetics by Wang et al. also reported that the absorption and elimination of domperidone was slowed down with the mean T_max being 52% longer and t_1/2 being 18% longer, while the exposure of domperidone was increased with the mean AUC being 25% more after giving the same oral dose of domperidone tablet 30 minutes after a high-fat meal than after fasting [10]. However, t½ and T_max of domperidone from our fed study were much longer than the published data of Wang et al, while C_max was much lower, which may be due to the difference between dry suspension and tablet preparation.

As domperidone has been reported to affect cardiac repolarization by blockage of the rapid component of the delayed rectifier potassium current (I_kr) [11], we monitored ECG changes. No QT interval prolongation was noticed in the single-dose study. Sinus or nodal bradycardia was the only heart relevant AE recorded in ECG, with an incidence of 22.22% (14/63) and 16.67% (9/54) in the fasted and fed study, respectively. Six cases of sinus bradycardia and one case of sinus bradycardia without any discomfort complaint were defined as grade 2 AE. All the ECG abnormal findings were transient and spontaneously recovered without intervention. Almost all the other TEAEs were mild and collected from the laboratory examinations with low incidence. No serious adverse events were reported and no subject withdrew due to TEAEs. Oral administration of domperidone appeared to be well tolerated.

In this study, the test and reference domperidone dry suspension were considered bioequivalent based on pharmacokinetic parameters for single dosing under fasting and fed conditions. All subjects showed good tolerance for both products.

AEs

Adverse events

ANOVA

Analysis of variance

AUC_0 − t

Area under the concentration-time curve from time zero to the last quantifiable concentration

AUC_0−∞

Area under the concentration-time curve from time zero to infinity

BMI

Body mass index

CIs

Confidence intervals

C_max

Maximum concentration

the last quantifiable concentration

CTCAE

Common Terminology Criteria for Adverse Events

Coefficient of variation

CYP

Cytochrome P450

ECG

Electrocardiogram

GCP

Good Clinical Practice

GMR

Geometric mean ratio

HPLC-MS/MS

High performance liquid chromatography-tandem mass spectrometry

I_kr

Rectifier potassium current

Internal standards

LLOQ

lower limit of quantitation

MHLW

Ministry of Health, Labour and Welfare

MRM

Multiple reactions monitoring

NMPA

National Medical Products Administration

SAE

Serious adverse event

Standard deviation

T_1/2

Elimination half-life

TEAE

Treatment emergent adverse event

T_max

Time to C_max

Ethics approval and consent to participate

The protocol and relevant documents were reviewed and approved by the independent ethics committee of the First Affiliated Hospital, College of Medicine, Zhejiang University (approval No. 2019-EC-70). The study was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice (GCP) guidelines. Written informed consent was obtained from all subjects included in the study.

Consent for publication

Not applicable.

Availability of data and material

Dataset is available from the corresponding author upon reasonable request and with the permission of the sponsor, Zhejiang Yatai Pharmaceutical Co., Ltd..

Competing interests

The authors declare that they have no conflict of interest.

Funding

This study was funded by Zhejiang Yatai Pharmaceutical Co., Ltd.

Author contributions

LW was principal investigator and responsible for the study design, medical care, data analysis, as well as writing and revising the article. JST contributed to study design and took responsibility for the pharmacokinetics analysis, statistical analysis, and data interpretation. ML and QH were sub-investigators and contributed to manuscript drafting. JK, YH and JL were investigators who made a great contribution in the study execution and data acquisition. YZ contributed to the quality control through the study. All authors critically reviewed and approved the final version of the manuscript, and agreed to be accountable for the study.

Acknowledgments

The authors would like to thank all the study participants, as well as clinical investigators including pharmacists, nurses, and study coordinators for their contribution.

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Bioequivalence Study of Domperidone Dry Suspension in Chinese Healthy Subjects Under Fasted and Fed Conditions: An Open-label, Randomized, Single-dose, Crossover Trial

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