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 (AUC_0–t), the AUC from time zero to infinity (AUC_0–∞), the peak plasma concentration of the drug (C_max), the time needed to reach maximum concentration (T_max), the elimination half-life (t_1/2), and the terminal elimination rate (λ_z). 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 (C_max) was higher than 0.294, permitting use of RSABE. The within-subject SDs of the reference intervention (S_WR) for AUC_0–t and AUC_0–∞ were < 0.294, meeting ABE criteria. The point estimate for the geometric least squares mean (GLSM) ratio for the point estimate of C_max 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 AUC_0–t and 97.33–103.51% for AUC_0–∞, all of which were within the prespecified limits. The 90% confidence intervals for AUC_0–t and AUC_0–∞ and 95% upper confidence limit for C_max 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.

中文翻译：

---

两种卡培他滨片在进食条件下治疗结直肠癌或乳腺癌患者的药代动力学和安全性比较：一项多中心、随机、开放标签、三期和参考重复交叉研究

介绍

在这项研究中，我们在接受高脂肪饮食的结直肠癌或乳腺癌患者中评估了 150 mg 卡培他滨与品牌参考制剂相比的药代动力学 (PK)、生物等效性和安全性。

方法

这是一项多中心、开放、随机、平衡、三周期、三序列和半重复的交叉研究，涉及 48 名受试者。在每个研究期间，合格受试者接受测试或参考制剂，然后是 1 天的清除期。在给药前至给药后 8 小时收集用于药代动力学评估的系列血样。通过 LC/MS-MS 分析卡培他滨的血浆浓度。用 WinNonlin 软件评估药代动力学参数（非房室模型）。评估的药代动力学参数是从时间 0 到最后可测量浓度的时间 (AUC _{0– t} )的血浆浓度-时间曲线下面积、从时间 0 到无穷大的 AUC (AUC _0–∞ )、峰值血浆浓度药物（C_max )、达到最大浓度所需的时间 ( T _max )、消除半衰期 ( t _1/2 ) 和终末消除率 ( λ _z )。在对数据进行对数变换后，使用方差分析 (ANOVA) 模型对所有数据进行分析。为了确定卡培他滨的生物等效性 (BE)，使用了参考标度平均生物等效性 (RSABE) 接受标准和平均生物等效性 (ABE) 接受标准。在整个研究期间评估安全性和耐受性。

结果

参考比例最大血浆浓度 ( C _max ) 高于 0.294，允许使用 RSABE。AUC _{0– t}和 AUC _0–∞的参考干预的受试者内 SD ( S _WR ) < 0.294，符合 ABE 标准。C _max的点估计的几何最小二乘均值 (GLSM) 比率的点估计为 0.962，在 0.80–1.25 的范围内。GLSM 比率的测试/参考的 90% 置信上限为 AUC _{0– t 的}97.84–105.40% 和 AUC _{0–∞ 的}97.33–103.51% ，所有这些都在预先指定的范围内。AUC _0–的 90% 置信区间_t和 AUC _0–∞以及C _{max 的}95% 置信上限表明生物等效性。受试者中未发现严重不良事件。

结论

根据生物等效性标准，通过测量总卡培他滨，测试制剂在进食条件下的吸收速率和程度方面与参考制剂生物等效，并且是安全且耐受良好的。

试用注册

NCT04420871。