Page 1/18

Bioequivalence Study of Domperidone DrySuspension in Chinese Healthy Subjects UnderFasted and Fed Conditions: An Open-label,Randomized, Single-dose, Crossover Triallihua Wu  ( wlh_xu@zju.edu.cn )

Shulan (Hangzhou) Hospital A�liated to Zhejiang Shuren University, Shulan International MedicalCollegelQian Huang 

The First A�liated Hospital, College of Medicine, Zhejiang UniversityMeihua Lin 

First Hospital of Zhejiang Province: Zhejiang University School of Medicine First A�liated HospitalJiejing Kai 

The First A�liated Hospital, College of Medicine, Zhejiang UniversityYujie Huang 

The First A�liated Hospital, College of Medicine, Zhejiang UniversityYou Zhai 

The First A�liated Hospital, College of Medicine, Zhejiang UniversityJian Liu 

The First A�liated Hospital, College of Medicine, Zhejiang UniversityJianzhong Shentu 

The First A�liated Hospital, College of Medicine, Zhejiang University

Research Article

Keywords: bioequivalence, domperidone, dry suspension, pharmacokinetics

Posted Date: April 12th, 2022

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

License: This work is licensed under a Creative Commons Attribution 4.0 International License.  Read Full License

Page 2/18

AbstractBackground Domperidone, a selective antagonist of dopamine D2 receptors, has long been used as aprokinetic agents in the treatment of epigastric distress symptoms. This study aimed to provide adequateevidence for registration approval of a new genetic dry suspension formulation of domperidone bycomparing the safety and pharmacokinetic pro�les between the test and branded reference formulationin the context of fasted and fed condition.

Methods It was designed as a randomized, open-label, single-dose, two-period, two-treatment crossoverstudy. 32 and 28 eligible healthy subjects were enrolled in the fasted and fed study, respectively. Eachsubject was randomly assigned to receive either the test or reference formulation in the �rst period,followed by a 1-week washout period and dosing of the alternate formulation in the second period. Aseries of blood samples were collected at scheduled timepoints within 48 hours after administrationduring each treatment period. Plasma concentrations of domperidone were determined by validatedHPLC-MS/MS. Pharmacokinetic parameters, including Cmax, Tmax, AUC0–t, AUC0–∞, and t1/2, wereacquired based on the concentration versus time pro�les by non-compartmental analysis usingWinNonlin software. Then the geometric mean ratios (GMR) of Cmax, AUC0–t and AUC0–∞ between the twoformulations and corresponding 90% con�dence intervals (CIs) were calculated for bioequivalencedetermination. Safety was assessed as routine.

Results The two formulations showed similar pharmacokinetic pro�les. Under fasted condition, the GMRand corresponding 90% CIs of AUC0–t, AUC0-∞ and Cmax 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 andcorresponding 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 AUC0–t, AUC0-∞ and Cmax. All the values fell within the acceptedbioequivalence range of 80% to 125%. Both the test and the reference products were well toleratedwithout any serious or unexpected adverse reactions.

Conclusions Pharmacokinetic bioequivalence was established between the two dry suspensionformulations 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.

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

Page 3/18

After oral administration, domperidone is well absorbed and undergoes an extensive �rst-passmetabolism with the bioavailability being 13%~17%. Maxium concentration (Cmax) in plasma reacheswithin 2 hours, and the apparent elimination half-life (t1/2) is approximately 7h ~ 14h [5, 6]. The mainmetabolic pathway involves CYP3A-catalyzed N-dealkylation and aromatic hydroxylation. In addition, it’sreported 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 �rst 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 totablet, 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 ofdomperidone has been developed by Zhejiang Yatai Pharmaceutical Co., Ltd (Hangzhou, China).Consistent with National Medical Products Administration (NMPA) guidelines that call for comparing thebioavailability of the genetic product with the original agent for marketing, we carried out this study toassess the bioequivalence between the test and reference products under fasted or fed condition inhealthy adults. The Chinese Clinical Trials Registry identi�er was CTR1900023947.

Methods

Study drugsThe test domperidone dry suspension (10 mg, lot number S1180201, expiry date January, 2020) weremanufactured by Zhejiang Yatai Pharmaceutical Co., Ltd. (Hangzhou, China), and the referenceformulation is NAUZELIN®dry suspension (10 mg, lot number 071AFI; expiry date September, 2019), acommercially available original domperidone preparation from Kyowa Hakko Kirin, Tokyo, Japan.

SubjectsHealthy volunteers, male or female, aged between 18 and 45 years with a body mass index(BMI) between19 and 26 kg/m2, were recruited. After being well informed and fully understanding the risks and bene�tsof the study, all subjects provided written informed consent and underwent a comprehensive medicalexamination, 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 negativeserum pregnancy test at screening, and all the subjects agree to use routinely adequate contraception.Healthy subjects meeting the inclusion criteria were identi�ed. Exclusion criteria included a history ofallergy or atopic allergic disease; previous history of ECG with clinical signi�cance; any history of hepaticor renal impairment, digestive tract disease probably affecting drug absorption; clinically signi�cantabnormalities in laboratory tests. Subjects who used any drugs or food supplements within 2 weeksbefore screening were also excluded.

Study Design and Treatment

Page 4/18

This study consisted of two independent parts (fasted and fed studies). Each part was designed as arandomized, open-label, single-dose, two-period, two-treatment crossover study. It was carried out from 04June to 14 August 2019 in the Phase I Clinical Research Center of the First A�liated Hospital, ZhejiangUniversity School of Medicine, China, in accordance with the Declaration of Helsinki and the Good ClinicalPractice (GCP) guidelines. All documents including the protocol were reviewed and approved by the ethicscommittee of the First A�liated 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 an80% statistical power (β = 0.2) at a 5% level of signi�cance (α = 0.05). The intra-subject coe�cient ofvariation (CV) of 20.0% was selected as routine, the geometric mean ratio between the test and referenceformulations of Cmax was set to 0.92 (fasted) or 0.93 (fed), which was obtained from our previous pilotstudies. It was estimated that 27 (fasted) or 23 (fed) cases were required. Considering the dropout rate,we �nally determined to enroll 32 and 28 subjects in the fasted and fed study, respectively.

On the day of admission in the �rst 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 screeningsequence. The TR group received the test products in the �rst treatment period and the reference in thesecond, while the sequence of administration was reversed in the RT group. There was a 1-week washoutperiod between each administration. The random allocation table was prepared by statistician with blockrandomization using SAS (Version 9.4).

Participants in the fasted study received a single dose of the test or the reference product after overnightfasting 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. Bothformulations 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 anddinner were provided at 4 and 10 hours after administration, respectively. Besides, researchers releasedwater at �ve �xed timepoints with 240ml each time. Subjects were ambulatory, and quali�ed staff neededto pay close attention to them and take necessary measures in case of any individual situationthroughout the entire con�nement period. All subjects were required to avoid strenuous activity, smoking,juice and pharmaceutical/herbal products during the study period.

Blood sampling and analytical determinationsA series of blood samples were collected during each treatment period. In fasted study, 4 mL whole bloodsamples 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 sampleswere 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 afteradministration. Blood samples were centrifuged at 4 ℃ at 1700×g for 10 minutes. The supernatant wascollected as plasma samples and temporarily stored at -20°C within 2 hours of collection, and thentransferred to an ultra-low temperature refrigerator (− 70 ± 10°C) in 48 hours for storage until being usedfor analysis.

Page 5/18

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, thechromatographic 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 analysiswas performed using a Triple Quad 4500 (AB Sciex) mass spectrometer coupled with an electrosprayionization source in positive ion mode. The multiple reactions monitoring (MRM) transitions of m/z426.2→175.2 and m/z 432.2→181.2 were used to quantify domperidone and IS, respectively. Thevalidated linearity range for domperidone was 0.10 ~ 30.00 ng/mL. The intra-assay and inter-assaycoe�cients of variation for precision and accuracy of the lower limit of quantitation (LLOQ) were1.4%~11.8% and 10.4%, -17.6%~-4.2% and − 9.5%, respectively. The intra-assay and inter-assaycoe�cients of variation for precision and accuracy of other quality control samples (0.30 ng/mL, 2.50ng/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 AssessmentAccording to the protocol, safety was monitored by direct observations, laboratory tests, vital signs,physical examination results, and spontaneous reports from subjects. Any treatment emergent adverseevent (TEAE) would be collected and closely followed up to normal (or clinically insigni�cant) or beingclearly explained. Severity of adverse events (AEs) was de�ned according to Common TerminologyCriteria for Adverse Events (CTCAE) version 4.0, and the relationship with study treatment was alsodetermined.

Pharmacokinetic and Statistical AnalysisThe pharmacokinetic parameters of domperidone were calculated with WinNonlin software, version 7.0(Pharsight Corporation, Mountain View, California) by non-compartmental analysis. Individual plasmaconcentration–time curves were generated. Cmax and tmax were obtained directly from the observed data.AUC0 − t was calculated by the linear trapezoid rule. AUC0−∞ was calculated from AUC0 − t plus theextrapolated area from the last quanti�able concentration (Ct) divided by the elimination rate constant(λz). Elimination half-life (t1/2) was calculated as ln2/λz.

Statistical analyses were also performed with WinNonlin software. AUC0−∞, AUC 0−t, and Cmax wereconsidered as primary variables for bioequivalence determination. Analysis of variance (ANOVA) wasused to evaluate the effect of formulation, sequence, period, and subjects nested in sequence on naturallogarithm (ln)-transformed pharmacokinetic parameters. Parametric 90% con�dence intervals (CIs) forthe geometric mean ratio (GMR) between the two formulations (test-reference) were calculated using theSchuirmann method. If the difference between two compared parameters was found statisticallyinsigni�cant (p > 0.05) and 90% CIs for the GMR of AUC0−∞, AUC 0−t, and Cmax fell within the range of 80–125%, the two products were considered to be bioequivalent.

Page 6/18

Results

ParticipantsA total of 180 healthy volunteers were screened in June 2019. Finally, 32 subjects (20 males and 12females) 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 casescompleted the fasted and fed study, respectively. One participant withdrew from the second period of thefasted study due to chickenpox infection during washout period, whereas one subject discontinued thestudy before the �rst period dosing in the fed part.

Page 7/18

Table 1Demographic characteristics of subjects in the fasted or fed study.

Variable Fasted Fed

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 PropertiesAs described above, in the fasted study, 1 subject in TR group dropped out due to chickenpox infectionbefore the second treatment period dosing. Thus, 32 subjects were included in the pharmacokineticanalysis for the test formulation, and only 31 subjects for the reference product. In the fed study, 1 casewithdrew due to his vomiting during high-fat diet before the �rst period of administration. And, anothersubject who completed the fed study was found to be enrolled by mistaken on the day of discharge, ashis 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 �nally not to be used

Page 8/18

to determine the concentration of domperidone according to the protocol. Therefore, the pharmacokineticanalysis in the fed study included 26 subjects. The mean plasma concentration-time pro�les and semi-logarithmic concentration plots of domperidone obtained after single oral administration of the test andreference product under fasted and fed condition were shown in Figs. 1 and 2. Major pharmacokineticparameters of domperidone under fasted or fed conditions were listed in Table 2.

 

 

Table 2Pharmacokinetic parameters of domperidone after single oral administration of test and reference

domperidone dry suspension in the fasted or fed study.Parameter Fasted Fed

Test(n = 32) Reference (n = 31) Test(n = 26) Reference(n = 26)

Tmax (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)

Cmax (ng/mL)b 16.13 ± 6.97 15.00 ± 5.64 8.21 ± 2.35 7.40 ± 2.41

AUC0 − t (ng·h/mL)b 57.17 ± 17.09 56.26 ± 18.12 73.71 ± 14.08 71.37 ± 19.00

AUC0−∞ (ng·h/mL)b 60.16 ± 18.02 59.34 ± 19.27 78.70 ± 15.27 77.01 ± 20.07

t1/2 (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�nished the whole study were used in the fed study. The geometric mean ratios (GMRs) of Cmax, AUC0 − t

and AUC0−∞ were 104.61%, 101.48% and 101.17% in the fasted study, and 112.78%, 105.46% and104.21% 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.

   

Page 9/18

Table 3Geometric Mean Ratio (GMR) and the corresponding 90% con�dence intervals (CIs) for the primary

pharmacokinetic parameters in the fasted or fed study.Parameter Geometric mean GMR (T/R) 90% CI Power

Test (T) Reference (R)

Fasted          

Cmax (ng⋅ml− 1) 14.74 14.09 104.61 96.73 ~ 113.14% 98.32%

AUC0 − t (ng⋅ h⋅ ml− 1) 54.72 53.93 101.48 96.79 ~ 106.38% 100%

AUC0−∞ (ng⋅ h⋅ ml− 1) 57.59 56.92 101.17 96.66 ~ 105.90% 100%

Fed          

Cmax (ng⋅ml− 1) 7.89 7.00 112.78 103.64 ~ 122.73% 64.73%

AUC0 − t (ng⋅ h⋅ ml− 1) 72.38 68.63 105.46 99.19 ~ 112.12% 99.85%

AUC0−∞ (ng⋅ h⋅ ml− 1) 77.23 74.10 104.21 98.19 ~ 110.61% 99.97%

Safety and TolerabilityA 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 identi�ed through laboratory investigations. Six cases of sinus bradycardiaas grade 2 and one case of hyperkalemia as grade 2 were observed, which were spontaneously recoveredwithout intervention. Others were transient and considered mild. 1 subject dropped out before the secondtreatment period dosing because of chickenpox infection, which was considered to be unrelated to thetest formulation. Under the fed conditions, a total of 19 cases of TEAEs occurred in 15 subjects, with anoverall 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 �rst treatment period dosing because ofvomiting during high-fat breakfast. No serious adverse events or deaths occurred. The incidence ofTEAEs was summarized in Table 4.

  

Page 10/18

Table 4Total 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

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 alanineaminotransferase

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

DiscussionDry suspension has both the characteristics of solid preparation (such as easy to carry, convenienttransportation, good stability, etc.) and the advantages of liquid preparation (such as convenient

Page 11/18

administration, suitable for patients with di�culty in swallowing, etc.). It can be taken according to thespeci�c amount required for each dosing and usually has a good taste, so it is especially welcome andwell accepted by pediatric patients. In this study, we compared the pharmacokinetic characteristics of thetest domperidone dry suspension and the reference product under fasted or fed condition. Resultsshowed that the test/reference GMRs of Cmax, AUC0 − t and AUC0−∞ and their 90% CIs were all within therange of 80–125%, indicating that the speed and extent of domperidone absorption were similar betweenthe 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 thosepreviously reported in the literature demonstrated no critical variation, which enhanced the validity of thepresent results [5, 6]. It is well-known the absorption of domperidone is somewhat delayed if it is takenafter meals, as the speci�cations already has recommendations for dosing domperidone before meals.Consistent with this, we can see from Table 3, under fed condition, Tmax increased from 0.5h to 3h, Cmax

decreased by about half, while AUC0 − t and AUC0−∞ increased by about 30%, suggesting that a high-fatmeal markedly slowed down the rate of the absorption of domperidone, but enhanced the exposure ofdomperidone, regardless of the test or reference product. Similarly, a recent study of food effects ondomperidone pharmacokinetics by Wang et al. also reported that the absorption and elimination ofdomperidone was slowed down with the mean Tmax being 52% longer and t1/2 being 18% longer, whilethe exposure of domperidone was increased with the mean AUC being 25% more after giving the sameoral dose of domperidone tablet 30 minutes after a high-fat meal than after fasting [10]. However, t½ andTmax of domperidone from our fed study were much longer than the published data of Wang et al, whileCmax was much lower, which may be due to the difference between dry suspension and tabletpreparation.

As domperidone has been reported to affect cardiac repolarization by blockage of the rapid componentof the delayed recti�er potassium current (Ikr) [11], we monitored ECG changes. No QT intervalprolongation was noticed in the single-dose study. Sinus or nodal bradycardia was the only heart relevantAE 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 discomfortcomplaint were de�ned as grade 2 AE. All the ECG abnormal �ndings were transient and spontaneouslyrecovered without intervention. Almost all the other TEAEs were mild and collected from the laboratoryexaminations with low incidence. No serious adverse events were reported and no subject withdrew dueto TEAEs. Oral administration of domperidone appeared to be well tolerated.

ConclusionIn this study, the test and reference domperidone dry suspension were considered bioequivalent based onpharmacokinetic parameters for single dosing under fasting and fed conditions. All subjects showedgood tolerance for both products.

Page 12/18

AbbreviationsAEsAdverse eventsANOVAAnalysis of varianceAUC0 − t

Area under the concentration-time curve from time zero to the last quanti�able concentrationAUC0−∞

Area under the concentration-time curve from time zero to in�nityBMIBody mass indexCIsCon�dence intervalsCmax

Maximum concentrationCtthe last quanti�able concentrationCTCAECommon Terminology Criteria for Adverse EventsCVCoe�cient of variationCYPCytochrome P450ECGElectrocardiogramGCPGood Clinical PracticeGMRGeometric mean ratioHPLC-MS/MSHigh performance liquid chromatography-tandem mass spectrometryIkr

Recti�er potassium currentISInternal standardsLLOQlower limit of quantitationMHLWMinistry of Health, Labour and Welfare

Page 13/18

MRMMultiple reactions monitoringNMPANational Medical Products AdministrationSAESerious adverse eventSDStandard deviationT1/2

Elimination half-lifeTEAETreatment emergent adverse eventTmax

Time to Cmax

DeclarationsEthics approval and consent to participate

The protocol and relevant documents were reviewed and approved by the independent ethics committeeof the First A�liated Hospital, College of Medicine, Zhejiang University (approval No. 2019-EC-70). Thestudy 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 ofthe sponsor, Zhejiang Yatai Pharmaceutical Co., Ltd..

Competing interests

The authors declare that they have no con�ict of interest. 

Funding 

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

Author contributions

Page 14/18

LW was principal investigator and responsible for the study design, medical care, data analysis, as wellas writing and revising the article. JST contributed to study design and took responsibility for thepharmacokinetics 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 greatcontribution in the study execution and data acquisition. YZ contributed to the quality control through thestudy. All authors critically reviewed and approved the �nal version of the manuscript, and agreed to beaccountable for the study. 

Acknowledgments

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

 

References1. Reddymasu SC, Soykan I, McCallum RW. Domperidone: review of pharmacology and clinical

applications in gastroenterology. Am J Gastroenterol. 2007 Sep;102(9):2036–45.

2. Yüksel K, Tuğlular I. Critical review of European Medicines Agency (EMA) assessment report andrelated literature on domperidone. Int J Clin Pharm. 2019 Apr;41(2):387–90.

3. Leelakanok N, Holcombe A, Schweizer ML. Domperidone and Risk of Ventricular Arrhythmia andCardiac Death: A Systematic Review and Meta-analysis.Clin Drug Investig. 2016 Feb;36(2):97–107.

4. Fife D, Waller J, Kaplan S, Hu P, Phillips S, Oliveria SA, Richarz U. Awareness of, and Compliance with,Domperidone Revised Labeling After a Risk-Minimization Activity in Europe. Clin Drug Investig. 2019Nov;39(11):1057–66.

5. Hussein R, Lockyer M, Yusuf A, Al Gaai E, Abdelgaleel A, Hammami MM. Bioequivalence assessmentof two domperidone tablet formulations. Arzneimittelforschung. 2007;57(5):269–73.

�. Helmy SA, El Bedaiwy HM. Pharmacokinetics and comparative bioavailability of domperidonesuspension and tablet formulations in healthy adult subjects. Clin Pharmacol Drug Dev.2014;3(2):126–31.

7. Simard C, Michaud V, Gibbs B, Masse R, Lessard E, Turgeon J. Identi�cation of the cytochrome P450enzymes involved in the metabolism of domperidone. Xenobiotica. 2004;34(11–12):1013–23.

�. Yoshizato T, Kotegawa T, Imai H, Tsutsumi K, Imanaga J, Ohyama T, Ohashi K. Itraconazole anddomperidone: a placebo-controlled drug interaction study. Eur J Clin Pharmacol. 2012;68(9):1287–94.

9. Templeton I, Ravenstijn P, Sensenhauser C, Snoeys J. A physiologically based pharmacokineticmodeling approach to predict drug-drug interactions between domperidone and inhibitors ofCYP3A4. Biopharm Drug Dispos. 2016;37(1):15–27.

Page 15/18

10. Wang C, Qin Z, Ren G, Zhai Y, Fu K, Lu C, Chen X. Development of a sensitive UPLC-MS/MS assay fordomperidone and pharmacokinetics of domperidone tablet formulations in fasting and fed Chinesehealthy subjects. Int J Clin Pharmacol Ther. 2020;58(3):177–82.

11. Collins KK, Sondheimer JM. Domperidone-induced QT prolongation: add another drug to the list. JPediatr. 2008;153(5):596–8.

Figures

Page 16/18

Figure 1

Mean plasma concentration-time pro�les of domperidone after single oral administration of reference(n=31) and test (n=32) in the fasted study. (a) Linear scale;(b) Semilogarithmic scale. Data represent themean value, and error bars represent the SD.

Page 17/18

Figure 2

Mean plasma concentration-time pro�les of domperidone after single oral administration of reference(n=26) and test (n=26) in the fed study. (a) Linear scale;(b) Semilogarithmic scale. Data represent themean value, and error bars represent the SD.

Supplementary Files

Page 18/18

This is a list of supplementary �les associated with this preprint. Click to download.

CONSORT2010Checklist.doc