Abstract
Introduction
In this study, we assessed the pharmacokinetics (PK), bioequivalence, and safety of 150 mg capecitabine compared to the branded reference formulation in colorectal or breast cancer patients receiving a high-fat diet.
Methods
This was a multicenter, open, random, balanced, three-period, three-sequence and semi-repetitive cross study with 48 subjects. In each study period, the eligible subject received the test or reference formulation, followed by a 1-day washout period. Serial blood samples for pharmacokinetic assessment were collected at predose up to 8 h postdose. The plasma concentrations of capecitabine were analyzed by LC/MS–MS. Pharmacokinetic parameters (non-compartmental model) were assessed with WinNonlin software. The pharmacokinetic parameters assessed were the area under the plasma concentration-time curve from time 0 to the time of last measurable concentration (AUC0–t), the AUC from time zero to infinity (AUC0–∞), the peak plasma concentration of the drug (Cmax), the time needed to reach maximum concentration (Tmax), the elimination half-life (t1/2), and the terminal elimination rate (λz). All were analyzed using an analysis of variance (ANOVA) model after logarithmic transformation of the data. To establish the bioequivalence (BE) for capecitabine, reference-scaled average bioequivalence (RSABE) acceptance criteria and average bioequivalence (ABE) acceptance criteria were used. Safety and tolerability were assessed during the entire study period.
Results
Reference scaled maximum plasma concentration (Cmax) was higher than 0.294, permitting use of RSABE. The within-subject SDs of the reference intervention (SWR) for AUC0–t and AUC0–∞ were < 0.294, meeting ABE criteria. The point estimate for the geometric least squares mean (GLSM) ratio for the point estimate of Cmax was 0.962, within the range of 0.80–1.25. The 90% upper confidence boundary for the test/reference of GLSM ratios was 97.84–105.40% for AUC0–t and 97.33–103.51% for AUC0–∞, all of which were within the prespecified limits. The 90% confidence intervals for AUC0–t and AUC0–∞ and 95% upper confidence limit for Cmax indicated bioequivalence. No serious adverse events were found among the subjects.
Conclusions
According to the criteria for bioequivalence, the test formulation was bioequivalent to the reference formulation in terms of the rate and extent of absorption under fed conditions by measurement of total capecitabine and was safe and well tolerated.
Trial Registration
NCT04420871.
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Acknowledgements
The authors acknowledge the staff at Qilu Pharmaceutical Co., Ltd. (Jinan, China), for the administration of the study protocol and data collection. We thank the staff at Value Pharmaceutical Services Co., Ltd. (Nanjing, China), for sample assay and pharmacokinetic analysis. We also acknowledge the staff at Shanghai Mosim Co., Ltd (Shanghai, China), for their support of the statistical analysis. We are grateful to the volunteers who participated in this study.
Funding
This work was supported by Qilu Pharmaceutical Co., Ltd., and grants from the National Major Scientific and Technological Special Project for “Significant New Drugs Development” (2020ZX09201-018, 2020ZX09201-025, 2017ZX09304-024). The Rapid Service Fee was supported by a research grant from the Affiliated Hospital of Qingdao University. The authors retained full control of the content of the manuscript. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of data analysis.
Authorship
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.
Authorship Contributions
The study was designed by Yu Cao. Chen-Jing Wang wrote the paper and participated in performance. Ting Li was responsible for data statistics. Ping-ping Lin, Ye Tao, Xin Jiang, Xin Li and Qing Wen performed research.
Disclosures
Chen-Jing Wang, Ting Li, Ping-ping Lin, Ye Tao, Xin Jiang, Xin Li, Qing Wen and Yu Cao have nothing to disclose.
Compliance with Ethics Guidelines
This clinical study protocol was approved by the Medical Ethics Committees at Jinan central Hospital Affiliated to Shandong University (master ethics committee, no. 2018-090-01), the Affiliated Hospital of Qingdao University (no. QYFYEC 2018-092-01), the First Affiliated Hospital of Bengbu Medical College (no. 2018-094), the Fourth Hospital of Hebei Medical University (no. 2018137), the Affiliated Hospital of Jiangnan University (no. 2018-030-001), the Affiliated Cancer Hospital of Guizhou Medical University (no. 2018-11-28), the First Affiliated Hospital of Liaoning University of Traditional Chinese Medicine (no. 2018061CS(YW)-032-01), Chongqing Cancer Hospital (no. 2018(140)), the Affiliated Hospital of Hebei University (no. HDFY-LL-2018-33), and the First Affiliated Hospital of Nanchang University (no. 2018-094). All procedures were performed in compliance with the Declaration of Helsinki [19] as well as the International Conference on Harmonization Guideline for Good Clinical Practice [20]. Informed consent was obtained from all volunteers prior to enrollment in the study.
Data Availability
The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.
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Wang, Cj., Li, T., Lin, Pp. et al. Pharmacokinetic and Safety Comparison of Two Capecitabine Tablets in Patients with Colorectal or Breast Cancer Under Fed Conditions: A Multicenter, Randomized, Open-Label, Three-Period, and Reference-Replicated Crossover Study. Adv Ther 38, 4798–4814 (2021). https://doi.org/10.1007/s12325-021-01817-4
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DOI: https://doi.org/10.1007/s12325-021-01817-4