Effect of renal failure on docetaxel exposure and adverse reactions in breast cancer patients

ZHOU Juxiang; WANG Shuangying; SHE Jiantao; ZENG Xianliang; ZHANG Jihong

doi:10.12206/j.issn.2097-2024.202203068

Volume 40 Issue 6

Nov. 2022

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Article Navigation > Journal of Pharmaceutical Practice and Service > 2022 > 40(6): 571-575

ZHOU Juxiang, WANG Shuangying, SHE Jiantao, ZENG Xianliang, ZHANG Jihong. Effect of renal failure on docetaxel exposure and adverse reactions in breast cancer patients[J]. Journal of Pharmaceutical Practice and Service, 2022, 40(6): 571-575. doi: 10.12206/j.issn.2097-2024.202203068

Citation:

ZHOU Juxiang, WANG Shuangying, SHE Jiantao, ZENG Xianliang, ZHANG Jihong. Effect of renal failure on docetaxel exposure and adverse reactions in breast cancer patients[J]. Journal of Pharmaceutical Practice and Service, 2022, 40(6): 571-575. doi: 10.12206/j.issn.2097-2024.202203068

Effect of renal failure on docetaxel exposure and adverse reactions in breast cancer patients

doi: 10.12206/j.issn.2097-2024.202203068

1.
a. Department of Pharmacy, b. Department of breast and Thyroid Surgery, Central hospital of Shaoyang, Shaoyang 422000, China
2.
a. Department of Pharmacy, b. Department of Breast and Thyroid Surgery, Central Hospital of Shaoyang, Shaoyang 422000, China

Received Date: 2022-03-16
Rev Recd Date: 2022-09-06

Available Online: 2022-11-28

Publish Date: 2022-11-25

Abstract

Objective To investigate the influence of renal failure on the area under curve (AUC) and adverse reactions of docetaxel in breast cancer patients, and provide evidence for the dosage of docetaxel in renal failure patients. Methods A retrospective study was conducted on 24 patients with breast cancer who had undergone radical mastectomy and received AC-T adjuvant chemotherapy in our hospital from January 2019 to November 2021. According to renal function cases, the patients were divided into two groups: renal failure group (n=5) and normal renal function group (n=19). The clinical characteristics such as gender, age, body weight and body surface area of patients in two groups, docetaxel dose, blood concentration, area under the curve, liver and kidney function, white blood cell count and absolute value of neutrophil before chemotherapy were collected. Single factor linear regression was used to analyze the influencing factors of the AUC of docetaxel. Adverse reactions after chemotherapy with docetaxel including nausea and vomiting, bone marrow suppression, constipation and liver function injury were collected. CTCAE 4.0 evaluation standard was used to evaluate adverse reactions. Results The clinical characteristics of creatinine [908.0 (819.0, 1018.0) μmol/L vs 54.8 (52.0, 65.0) μmol/L] and creatinine clearance rate [4.9 (4.3, 5.4) ml /min vs 86.3 (59.3, 92.5) ml/min] of the renal failure group and the normal renal function group have significant difference (P<0.001), while no significant difference (P>0.05) were found in the body surface area [1.4 (1.4, 1.5) m² vs 1. 6 (1.5, 1.6) m²], docetaxel dose [70.4 (69.4, 73.0) mg/m² vs 74.4 (72.3, 91.2) mg/m²], body weight [(51.4±3.8) kg vs (51.5±5.5) kg]. Liver function, white blood cells and neutrophils were within the normal range before chemotherapy with docetaxel. There was no significant difference in AUC value [(1.6±0.6) mg·h/L vs (1.8±0.8) mg·h/L] between the two groups after chemotherapy with docetaxel (P>0.05). Linear univariate regression analysis indicated that the blood concentration at the end of docetaxel infusion was significantly associated with AUC of docetaxel (P<0.001), while the body surface area, dose of docetaxel, body weight, liver and kidney function were not correlated with AUC of docetaxel (P>0.05). After chemotherapy with docetaxel, adverse reactions of patients in the two groups: nausea and vomiting (grade I incidence: 40% vs. 57.9%, grade II incidence: 60% vs. 42.1%), myelosuppression (grade I incidence: 60% vs. 84.2%, grade II incidence: 20% vs 15.8%) and constipation (all mild constipation) had no significant difference (P>0.05). Conclusion Renal failure did not affect the exposure of docetaxel and the adverse reactions after chemotherapy with docetaxel in breast cancer patients.
- renal failure,
- breast cancer,
- docetaxel,
- AUC,
- adverse reaction

References

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通讯作者: 陈斌, bchen63@163.com

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沈阳化工大学材料科学与工程学院沈阳 110142

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近年来由于糖尿病肾病、高血压肾病和癌症发病率的增加，肿瘤科医生会面对同时患有癌症和肾衰竭的患者^[1]。乳腺癌是女性常见的恶性肿瘤，而化疗是目前乳腺癌治疗的主要方法之一。紫杉类药物多西他赛是乳腺癌化疗中的主要细胞毒性药物，它通过干扰细胞有丝分裂和有丝分裂间期所必需的微管网络发挥抗肿瘤作用^[2]。而多西他赛的骨髓抑制、神经毒性等不良反应会影响其用量，甚至药物的选择。目前指南均推荐多西他赛按照体表面积进行给药^[3]，然而由于不同人群的基因多态性、生理状态、遗传特性，给予相同剂量的多西他赛仍会导致显著的药动学差异^[4]。现临床上已广泛应用治疗药物血药浓度监测（TDM）来降低药物的个体差异^[5]。已有大量研究表明^[5–12]，药时曲线下面积（AUC）为评价多西他赛体内暴露的药动学参数，并作为多西他赛剂量调整的依据。而在肾衰竭合并乳腺癌的患者中，多西他赛在剂量调整和透析对其的影响信息非常少^[1,13]，仍需开展进一步的研究。本研究旨在分析慢性肾衰竭对乳腺癌患者多西他赛的AUC及不良反应是否有影响，以便对此类患者的多西他赛给药剂量提供依据。

2. 结果

2.1. 两组患者一般临床特征

对2019年1月至2021年11月在我院进行了多西他赛血药浓度监测的乳腺癌患者进行筛选，24例患者纳入本研究，其中肾功能衰竭组5例，肾功能正常组19例，均为女性。患者年龄（54.7±9.3）岁，体表面积[1.6（1.5, 1.6）] m²，体重（51.5±5.1）kg，给药剂量[73.6（72.3,80.0）] mg/m²。患者体表面积、给药剂量、体重无统计学差异。两组患者在使用多西他赛化疗前肝功能相关指标及血象白细胞、中性粒细胞均在正常范围内（见表1）。

临床特点	总人数（n=24）	肾功能衰竭组（n=5）	肾功能正常组（n=19）	P	检验值
年龄（岁）	54.7±9.3	59.2±6.1	53.5±9.8	0.23	1.53
体表面积（m²）	1.6 （1.5, 1.6）	1.4 （1.4, 1.5）^▲	1.6 （1.5, 1.6）	0.05	3.86
给药剂量（mg/m²）	73.6（72.3,80.0）	70.4 （69.4, 73.0）	74.4（72.3, 91.2）	0.08	3.06
体重（kg）	51.5±5.1	51.4±3.8	51.5±5.5	0.97	0.001
白蛋白（g/L）	42.4±3.8	39.0±4.9^▲	43.2±3.0	0.02	6.12
谷草转氨酶（U/L）	24.6 （19.9, 31.7）	19.3 （19.1, 20.6）^▲	29.0（24.1, 34.9）	0.01	6.02
谷丙转氨酶（U/L）	21.4（15.0, 34.1）	13.7（11.2, 14.8）^▲▲	24.0（20.4, 39.4）	0.002	10.01
总胆红素（μmol/L）	11.0±3.7	9.0±2.9	11.5±3.7	0.17	1.95
直接胆红素（μmol/L）	2.4±1.1	1.9±0.8	2.5±1.1	0.27	1.28
肌酐（μmol/L）	60.5 （52.0, 285.8）	908.0 （819.0, 1 018.0）^▲▲	54.8 （52.0, 65.0）	< 0.001	11.42
肌酐清除率（ml/min）	69.3（17.9, 91.8）	4.9（4.3, 5.4）^▲▲	86.3（59.3, 92.5）	< 0.001	11.4
化疗前白细胞（×10⁹/L）	6.5±1.7	7.5±1.7	6.2±1.6	0.12	2.56
化疗前中性粒绝对值（×10⁹/L）	4.0（3.0, 4.9）	4.1（4.0, 8.7）	3.9 （2.5, 4.8）	0.21	1.55
^▲P<0.05,^▲▲P<0.01，与肾功能正常组比较。

2.2. 两组患者多西他赛血药浓度

表2中患者使用多西他赛的给药剂量73.6（72.3，80.0）mg/m²，两组间给药剂量无统计学意义。患者21天使用1次多西他赛，每次使用多西他赛剂量相同，因此每个患者4个多西他赛周期只需监测1次多西他赛血药浓度即可。其中两组多西他赛在2个时间点的血药浓度和多西他赛的AUC差异并无统计学意义。

指标	总人数（n=24）	肾功能衰竭组（n=5）	肾功能正常组（n=19）	P	检验值
多西他赛给药剂量（mg/m²）	73.6（72.3, 80.0）	70.4（69.4, 73.0）	74.4（72.3, 91.2）	0.08	3.06
多西他赛滴注结束时血药浓度（ng/ml）	682.4（460.2, 1 208.0）	650.0 （625.3, 750.0）	690.0（416.5, 1 239.0）	0.64	0.21
多西他赛滴注结束30min后血药浓度（ng/ml）	136.5±77.1	172.0±81.7	127.2±75.4	0.26	1.36
多西他赛AUC值（mg·h/L）	1.8±0.7	1.6±0.6	1.8±0.8	0.60	0.29

2.3. 多西他赛AUC的影响因素分析

线性单因素回归分析显示，多西他赛滴注结束时血药浓度与多西他赛的AUC有显著相关性（P<0.001）。而患者年龄、给药剂量、肝功能、肾功能、化疗前白细胞及中性粒细胞绝对值均与多西他赛AUC的水平没有相关性（P>0.05）（表3）。此分析结果说明患者肾功能衰竭并不影响多西他赛AUC水平。

因素	β	95%CI	P（t检验）
年龄（岁）	−0.01	−0.04～0.03	0.59
体表面积（m²）	1.09	−2.59～4.76	0.55
给药剂量（mg/m²）	0.01	−0.02～0.05	0.45
多西他赛滴注结束时血药浓度（ng/ml）	0.07^▲▲	0.04～0.09	< 0.001
多西他赛滴注结束30min后血药浓度（ng/ml）	0.34	−0.06～0.75	0.09
白蛋白（g/L）	0.05	−0.04～0.13	0.27
谷草转氨酶（U/L）	−0.27	−2.72～2.17	0.82
谷丙转氨酶（U/L）	−0.01	−0.02～0.01	0.46
总胆红素（μmol/L）	−0.07	−0.15～0.02	0.12
直接胆红素（μmol/L）	−0.23	−0.52～0.06	0.12
肌酐（μmol/L）	−0.02	−0.12～0.07	0.61
体重（kg）	0.02	−0.05～0.08	0.63
肌酐清除率（ml/min）	0.14	−0.76～1.05	0.74
化疗前白细胞（×10⁹/L）	0.02	−0.17～0.22	0.82
化疗前中性粒细胞（×10⁹/L）	0.41	−8.34～19.15	0.97
^▲▲P<0.01,与肾功能正常组比较。

2.4. 两组患者多西他赛不良反应

观察两组患者使用多西他赛后不良反应：恶心呕吐、骨髓抑制、便秘及肝功能损伤的发生率，两组间各类不良反应发生率差异无统计学意义（P>0.05），且两组患者均未出现肝功能损伤（见表4）。

不良反应	总人群	肾功能衰竭组（n=5）	肾功能正常组（n=19）	P	检验值
恶心呕吐,n （%）				0.63	Fisher
I	13 （54.2）	2 （40）	11 （57.9）
II	11 （45.8）	3 （60）	8 （42.1）
骨髓抑制, n （%）				0.22	Fisher
I	19 （79.2）	3 （60）	16 （84.2）
II	4 （16.7）	1 （20）	3 （15.8）
III	1 （ 4.2）	1 （20）	0 （0）
便秘, n （%）				1	Fisher
I	24 （100.0）	5 （100）	19 （100）

3. 讨论

多西他赛的药动学符合三房室模型^[22]，α半衰期为4.5 min，β半衰期为38.3 min，γ半衰期为12.2 h。它具有线性药动学特征，其峰值水平随着给药剂量和给药程序的不同而不同^[23-24]，AUC与给药剂量成比例增加。多西他赛主要经肝脏P450 CYP3A4系统代谢，经胆汁排泄到粪便，肾脏排泄量较小^[25]。虽然多西他赛在肾脏排泄量小，但肾功能不全仍可能影响药物在体内的累积，增加药物暴露，从而导致不良反应增加。目前在进行透析的肾衰竭患者中，多西他赛说明书和指南并没有相关的剂量推荐。

本研究为单中心、回顾性病例对照研究，根据患者肾功能的状态，将患者分为肾功能衰竭组和肾功能正常组进行对比研究。可观察到：（1）两组患者化疗前临床基线特征：肝功能、血常规、体表面积及给药剂量无明显差异。（2）两组患者使用多西他赛后体内暴露量AUC并无明显差异，对多西他赛AUC影响因素进行单因素线性回归分析发现患者肾功能状态肌酐清除率并不影响其多西他赛的AUC水平。（3）对两组患者的不良反应进行随访，其血液学毒性、消化道毒性、肝毒性也无明显差异。因此本研究证实了在慢性肾功能衰竭的患者中多西他赛的暴露量及不良反应与肾功能正常的患者并无明显差异。对于慢性肾衰竭患者给予多西他赛进行化疗时，剂量可按照肾功能正常的患者进行给药。本研究对于慢性肾功能衰竭而同时患有癌症需使用化疗药物多西他赛的患者的剂量指导具有重要的临床意义。

Reference (25)

[1]	JANUS N, THARIAT J, BOULANGER H, et al. Proposal for dosage adjustment and timing of chemotherapy in hemodialyzed patients[J]. Ann Oncol,2010,21(7):1395-1403.
[2]	HERBST R S, KHURI F R. Mode of action of docetaxel - a basis for combination with novel anticancer agents[J]. Cancer Treat Rev,2003,29(5):407-415.
[3]	江泽飞, 李健斌. 乳腺癌诊疗指南和临床实践历程[J]. 中华外科杂志, 2020, 58(2):85-90.
[4]	CHEW S C, SINGH O, CHEN X G, et al. The effects of CYP3A4, CYP3A5, ABCB1, ABCC2, ABCG2 and SLCO1B3 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of docetaxel in nasopharyngeal carcinoma patients[J]. Cancer Chemother Pharmacol,2011,67(6):1471-1478.
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