Evaluation of the pharmacokinetics, bioequivalence, and safety of two preparations of 20 mg trimetazidine

doi:10.21203/rs.3.rs-3964503/v1

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Evaluation of the pharmacokinetics, bioequivalence, and safety of two preparations of 20 mg trimetazidine

https://doi.org/10.21203/rs.3.rs-3964503/v1

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Purpose: Trimetazidine (TMZ) is effective for the treatment of angina. Herein, we assessed the pharmacokinetics, safety, and bioequivalence of TMZ hydrochloride tablets from two different manufacturers in healthy Chinese individuals under both fasting and fed conditions.

Methods: Twenty-eight participants were randomly assigned to either the fasting or fed arm in the single-center, randomized, open-label, crossover trial with a two-period, two-sequence design. TMZ levels in plasma were determined using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were determined using a non-atrioventricular model.

Results: The mean AUC0-t, AUC0-∞, and Cmax for the test and reference formulations were 461.1 and 488.6 h·ng/mL, 471.3 and 500.2 h·ng/mL, and 50.0 and 52.6 ng/mL in the fasting arm, respectively. Similarly, in the fed arm, the values were 439.6 and 453.8 h·ng/mL, 448.4 and 462.9 h·ng/mL, and 64.0 and 66.8 ng/mL. The bioequivalence of both fasting and fed states for all parameters fell within the acceptable limits in both TMZ preparations. All recorded adverse events were mild.

Conclusion: Overall, the test TMZ formulation was bioequivalent to the reference formulation and was safe for healthy Chinese subjects in both fasting and fed states.

Bioequivalence

Healthy Chinese volunteers

Trimetazidine

Safety

Cardiovascular disease (CVD) comprises several heart conditions that endanger human health and impose a substantial burden on society and the global healthcare system (Jaskuła et al., 2021). The prevalence of CVD in China has been steadily on the rise, with approximately 330 million individuals having CVD (National Center for Cardiovascular Diseases, China, 2023). In China, CVD emerged as the primary cause of mortality in 2020, surpassing cancer and other ailments (Wang et al., 2021).

CVD is linked to myocardial ischemia (Rezende et al., 2019), which in turn is closely related to myocardial energy metabolism (Ashrafian et al., 2007; Marzilli et al., 2019). Trimetazidine (TMZ) is a pharmacological agent with proven efficacy in managing various cardiovascular diseases, including stable angina pectoris, chronic heart failure, and myocardial infarction (Marzilli et al., 2019). TMZ (1-(2,3,4-trimethoxybenzyl) piperazine) (Slavov et al., 2004; Wisel et al., 2009) inhibits the oxidation of free fatty acids (Lionetti et al., 2011; Marzilli et al., 2019), and works at the cellular level to cause changes in energy metabolism within the heart muscle (Fragasso et al., 2006). After oral administration of TMZ hydrochloride 20 mg tablets, TMZ is quickly absorbed and achieves its peak concentration within 2 hours. Elimination of TMZ is predominantly renal, and most of the unchanged drug is excreted in urine (Jackson et al., 1996; Körnicke et al., 2020).

TMZ hydrochloride tablets were originally developed by Les Laboratoires Servier (France) under the name Vasorel. The drug was first approved in France in 1978 and listed in China in 2000. The objective of this study was to assess the pharmacokinetics (PKs), bioequivalence, and safety profile of TMZ hydrochloride tablets manufactured by Resun Pharmaceutical Co., Ltd. (test product, 20 mg) in comparison with Vasorel (reference product, 20 mg) among healthy Chinese volunteers under both fasting and fed conditions.

Study design and setting

This study aimed to evaluate the PKs, bioequivalence, and safety of two different formulations of TMZ hydrochloride tablets under fasting and postprandial conditions. The trial was conducted at a single center using a randomized, open-label, crossover design involving two preparations, two periods, and two sequences. The research incorporated a 7-day washout period between the distinct phases: the fasting study and the fed study. The study protocol received approval (PYZXYYEC [2018] P32) from the Independent Ethics Committee of the Affiliated Panyu Centra Hospital of Guangzhou Medical University on May 8, 2018. This clinical trial followed the guidelines of Good Clinical Practice, adhering to the principles outlined in the Declaration of Helsinki, and complying with all relevant regulations and guidelines. Informed consent was obtained from all trial participants. The research was conducted at the Affiliated Panyu Centra Hospital of Guangzhou Medical University's Phase I Clinical Trial Center.

Participants

All individuals participating in the study were required to fulfill the following conditions: (1) prior granting of informed consent preceding the commencement of the trial; (2) healthy Chinese adults with suitable body proportions; (3) normal or medically insignificant deviations in vital signs, findings from physical examinations, outcomes of laboratory tests, and electrocardiograms; (4) male and female participants to have a minimum body weight of 50 and 45 kg, respectively. Additionally, the body mass index of the participants was to fall within the range of 18.5 to 26.0 kg/m²; (5) reaching the end of the trial as per the study protocol.

The exclusion criteria were as follows: (1) history or presence of any significant clinical illness; (2) inability to communicate or collaborate with medical staff; (3) allergy to drugs or an allergic constitution; (4) clinically significant abnormal laboratory test results; (5) inability to follow a uniform diet; (6) participation in any clinical trial involving drugs within a period of 3 months prior to the start of the current study; (7) use of non-prescription drugs, health supplements, or Chinese herbs or medicines within 2 weeks before the trial, or use of prescription drugs within 1 month before the trial; (8) history of excessive consumption of tea, coffee, or caffeinated beverages, or consumption of any food and drink rich in xanthines or grapefruit juice within 48 hours before the test; (9) blood donation within 3 months before the test or blood donation or blood loss of > 400 mL (excluding menstrual blood loss) within 6 months before the trial; (10) history of alcohol or drug abuse; (11) smoking more than five cigarettes daily within the 3-month period prior to or throughout the duration of the trial; (12) difficulty in venous blood collection or dizziness on the sight of blood or needles; (13) pregnant or lactating; (14) use of oral contraceptives within 30 days before the trial; (15) positive blood pregnancy test; and (16) lactose intolerant.

Drugs

The test (T) formulation (Batch number, 17081501; expiration date: July 31, 2020) was manufactured by Reyoung Pharmaceutical Co., Ltd., China. The reference (R) product (batch number, 601519; expiration date: September 30, 2019) was procured from Les Laboratories Servier, France.

Study procedure

This trial consisted of two distinct phases, namely a fasting study and a fed study, each comprising 28 participants. A washout period of 7 days was implemented between these phases to ensure independence. In each study, the eligible participants were randomly assigned to two groups with different sequences: sequence 1 (TR) and sequence 2 (RT). Fourteen participants were included in each sequence group. All participants were admitted to the Phase I ward at 21:00 a day before the administration of the drugs in each period with unified life management. The participants were not allowed to consume any food or drink outside the diet center and refrained from eating for a minimum of 10 hours. In the arm where fasting was implemented, the participants were administered the drugs (T or R) after fasting for at least 10 hours on the first and eighth days of the trial. In the fed arm, a high-fat meal was provided to the participants 30 minutes prior to drug administration in the morning of both the first and eighth days of the trial. The medications were taken with 240 mL of warm water, and the subjects remained seated for 4 hours following ingestion. Food and water consumption was allowed within a time frame of 4 hours and 1 hour following the administration of the medications, respectively. The subjects consumed their midday and evening meals at intervals of 4 hours and 10 hours, respectively, following the administration of the medications.

Collection and preservation of samples

Blood samples (3 mL) were obtained during each study phase. The specimens were collected using vacutainers containing an anticoagulant (dipotassium ethylene diamine tetraacetic acid) at various time intervals: prior to administration (-1 hour) and subsequent to administration (10, 20, 30, and 45 minutes post-dosing, as well as 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 12.0, 24.0, and 36.0 hours after administering the dose) in both the fasting and fed groups. The blood samples were promptly immersed in an ice-cold water bath following collection and underwent centrifugation within 45 minutes at a force of 2000 ×g for 10 minutes using a refrigerated centrifuge operating at temperatures between 2 and 8°C. The plasma supernatants were stored at − 90 to − 60°C before analysis.

Methods of analysis

The plasma samples were pretreated using protein precipitation methods. The plasma concentrations of TMZ were determined using high-performance liquid chromatography-mass spectrometry. The quantitative linear extent of TMZ was 0.500–200.000 ng/mL, and the quantification threshold was set at a minimum of 0.500 ng/mL.

Safety assessments

Safety assessments were conducted for all participants and included measurement of vital signs, physical examinations, measurement of clinical laboratory parameters, 12-lead electrocardiography, and assessment of adverse events (AEs), during the trial and the follow-up periods. The study medications were thoroughly examined by the clinical investigators to assess any potential correlation between their administration and reported AEs.

Pharmacokinetic and statistical analyses

The PK parameters of TMZ, including AUC_0 − t (area under the concentration-time curve from time 0 to the last blood sample collection), AUC_0−∞ (area under the concentration-time curve from time 0 to infinity), C_max (maximum concentration), T_max, and t_1/2 (half-life), were calculated using noncompartmental PK analysis with Phoenix WinNonlin8.0. All TMZ plasma concentrations below the quantification threshold's lower limit before T_max were considered 0, whereas those below the lower limit after T_max were treated as missing.

The data were analyzed using SAS Version 9.4 (SAS Institute Inc., Cary, North Carolina) and presented using descriptive statistics. C_max, AUC_0 − t, and AUC_0−∞ were logarithmically transformed, and a linear mixed-effects model was employed for the analysis of variance. The geometric mean ratios of C_max, AUC_0 − t, and AUC_0−∞ between the formulations were calculated at a 90% confidence level. These ratios were then converted to the ratio scale using the antilog transformation. The threshold for statistical significance was established at P < 0.05.

Participants

Fifty-six healthy Chinese volunteers participated in the trial, with 28 participants in the fasting and fed groups. All participants in the fasting arm successfully completed the study. However, one participant (C025 from the RT sequence) in the experimental group decided to discontinue involvement in the study before commencing the second phase for personal reasons. The baseline demographic data of the participants are presented in Table 1.

Pharmacokinetic properties

All participants in both the fasting and fed arms were included in the PK analysis. The profiles showing the average plasma concentration levels over time and PK parameters of TMZ in both arms are depicted in Figure 1, Figure 2, and Table 2. No significant differences were observed in C_max, AUC_0-t, and AUC_0-_∞ among sequences, treatments, and study periods.

Assessment of bioequivalence

The bioequivalence analysis included 28 participants in the fasting group and 27 participants in the fed group. The bioequivalence of both products in fasting and fed conditions was analyzed using SAS Version 9.4, and the results are presented in Table 3. The 90% confidence intervals (CIs) of ratios calculated using the geometric mean method of C_max, AUC_0-t, and AUC_0-_∞ comparing the two products were within acceptable limits. This suggests that the products were bioequivalent when administered in both fasted and postprandial states.

Safety evaluations

The safety analysis included data collected from all participants in both the fasting and non-fasting groups. For the participant who withdrew during the second period, only the data collected in the initial period were incorporated (the reference formulation was administered to the participant during the initial period). No significant AEs or fatalities were documented during the entire duration of the study. Thirteen participants in the fasting arm experienced 16 AEs, whereas 10 in the fed arm experienced 11 AEs. The most common AE was elevated blood triglyceride levels. The intensity of all the AEs was low. The investigators reviewed the relationship between AEs and the formulations and judged them to be possibly unrelated. A summary of the AEs is presented in Table 4.

This study aimed to evaluate the similarity in drug absorption and safety between brands of TMZ dihydrochloride tablets (20 mg) in Chinese individuals in both fasted and postprandial conditions. The PK profiles of the test and reference formulations showed that both products demonstrated bioequivalence when administered to healthy Chinese individuals during fasting and fed conditions. The severity of all AEs recorded in this study was mild, demonstrating that both formulations are safe and well-tolerated.

Formulations with > 30% intra-subject variability for a PK parameter (C_max, AUC_0 − t, and AUC_0−∞) are highly unpredictable (Haidar et al., 2008; Li et al., 2021; Su et al., 2023). In the present study, the coefficients of variation of the PK parameters for both formulations were < 30%, suggesting that the intra-subject variability between the formulations was small and that TMZ is not highly variable. The PK characteristics (C_max, T_max, and t_1/2) observed in this study align with findings from previous studies involving cohorts of Chinese individuals without any health issues (Zhang et al., 2013; Zhu et al., 2020), which emphasizes the validity of the presented results.

The common AEs associated with TMZ therapy include nausea, headache, dizziness, epigastric pain, and itching (Bouccara, 1999; McClellan and Plosker, 1999; Prescrire International, 2002). Some rare AEs include nausea, dizziness, epigastric pain, itching, headache, Parkinsonism, and gait disorders (Massó et al., 2005). One of the participants in the present study experienced dizziness; however, its severity was mild. None of the other abovementioned rare AEs were detected during the study.

This research has some limitations. First, all the participants were Chinese, mostly Han, with no other ethnic groups being enrolled. Individuals from the same racial background might negatively influence the outcome. Second, no sex-based comparisons were performed. Gender disparities could potentially exert a certain influence on the research outcomes. In addition, as this study was carried out on a population without any health issues, it has certain constraints and may not be fully representative of the connection between medication outcomes and adverse drug events in patients with diseases. Hence, to obtain a more holistic understanding while examining AEs in patient populations using this medication, it is necessary to extend the duration of medication usage.

The PK profiles of TMZ dihydrochloride tablets (20 mg) were assessed in this study, revealing that both the test and reference products were bioequivalent when administered to healthy Chinese individuals under fasting and fed conditions. Furthermore, both formulations are well-tolerated and do not pose any safety concerns.

Acknowledgments: This work was supported by the Guangzhou Science and Technology Project [grant number 202103000002]; Guangdong Province Hospital Pharmacy Research Fund [grant number 2024A31]; and Guangzhou Panyu Central Hospital [grant numbers 2021Y001, PY-2023-010, PY-2023-007, PY-2023-026].

Funding: This work was supported by the Guangzhou Science and Technology Project [grant number 202103000002]; Guangdong Province Hospital Pharmacy Research Fund [grant number 2024A31]; and the Affiliated Panyu Centra Hospital of Guangzhou Medical University [grant numbers 2021Y001, PY-2023-010, PY-2023-007, PY-2023-026].

Competing Interests: The authors have no relevant financial or non-financial interests to disclose.

Author Contributions: All authors contributed to the study's conception and design. Material preparation, data collection, and analysis were performed by Dongmei Tan, Fucai Zhang, Xihua Fu, Jianfen Su, Zuoheng Xu, Hui Yang, and Yanping Mu. The first draft of the manuscript was written by Dongmei Tan and Fucai Zhang, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Ethics approval: This study was performed in line with the principles of the Declaration of Helsinki. Ethics approval was granted by the Independent Ethics Committee of the Affiliated Panyu Centra Hospital of Guangzhou Medical University (May 8, 2018; PYZXYYEC [2018] P32).

Consent to participate: Informed consent was obtained from all participants included in the study.

Consent to publish: The authors affirm that human research participants provided informed consent for the publication of the charts in Figure 1–2 and Table 1–4.

Data Availability: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Clinical trial registration: This research was registered in the China Drug Trials registry (http://www.chinadrugtrials.org.cn; CTR20181186, registration date: July 30, 2018).

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Tables 1 to 4 are available in the Supplementary Files section.

No competing interests reported.

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Version 1

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Evaluation of the pharmacokinetics, bioequivalence, and safety of two preparations of 20 mg trimetazidine

Status:

Version 1

Abstract

Figures

Introduction

Methods

Study design and setting

Participants

Drugs

Study procedure

Collection and preservation of samples

Methods of analysis

Safety assessments

Pharmacokinetic and statistical analyses

Results

Participants

Pharmacokinetic properties

Assessment of bioequivalence

Safety evaluations

Discussion

Conclusions

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1