非小细胞肺癌患者吉非替尼血药浓度在临床治疗中的影响因素

Influence Factors of Gefitinib Concentration in Patients with Non-Small Cell Lung Cancer in Clinical Treatment

摘要: 目的：明确伴有表皮生长因子受体阳性突变的非小细胞肺癌患者服药后血浆中吉非替尼的药物浓度的代谢规律，包括：达到稳态的时间、具体稳态浓度以及持续时间；探讨吉非替尼血药浓度的影响因素，以及其与患者情况和肿瘤之间的相关性，并为诊断治疗提供一定的指导。病例和方法：总共入组了41位患者，分别于服用吉非替尼后的第3天、第7天和之后每隔1~2月抽取患者的血液样本，由青岛大学附属医院药学部经液相色谱质谱联用法检测药物浓度。结果：吉非替尼血药浓度在服药后的第3天为0.16 μg/ml；第7天为0.22 μg/ml，第1月为0.25 μg/ml，第2月为0.2 μg/ml，第3月为0.28 μg/ml……稳态吉非替尼血药浓度中位值0.21 μg/ml，95%置信区间[0.19 μg/ml, 0.31 μg/ml]。稳态血药浓度男性为0.17 μg/ml ± 0.08 μg/ml；女性为0.27 μg/ml ± 0.13 μg/ml，P < 0.01；无吸烟史患者为0.24 μg/ml ± 0.13 μg/ml，有吸烟史患者为0.19 μg/ml ± 0.06 μg/ml，P > 0.05；术后患者为0.24 μg/ml ± 0.12 μg/ml，未接受手术患者为0.20 μg/ml ± 0.11 μg/ml，P > 0.05；青年(≥18, ≤40)患者为0.52 μg/ml ± 0.21 μg/ml；中年(>40, ≤65)患者为0.24 μg/ml ± 0.13 μg/ml，老年(>65)患者为0.25 μg/ml ± 0.13 μg/ml，中年组及老年组患者相比P > 0.05；体重正常(8.5 ≤ BMI < 24)的患者为0.21 μg/ml ± 0.10 μg/ml，过重(BMI ≥ 24)患者为0.25 μg/ml ± 0.12 μg/ml，P > 0.05。拥有EGFR19位点缺失的患者为0.29 μg/ml ± 0.12 μg/ml；而检测出EGFR21 L858R的患者为0.21 μg/ml ± 0.11 μg/ml，P < 0.05。结论：经过持续服药7天后，吉非替尼血药浓度达到稳态，稳态浓度为[0.19 μg/ml, 0.31 μg/ml]，且吉非替尼的稳态血药浓度受患者性别和EGFR基因突变类型的影响。

Abstract: Objective: To clarify the metabolic pattern of gefitinib concentration in plasma of NSCLC patients with EGFR positive mutation after taking medication, including: time to homeostasis, specific homeostasis concentration, and duration; to explore the influencing factors of gefitinib plasma concentration, as well as its correlation with patient conditions and tumors, and to provide certain guidelines for diagnosis and treatment. Patients and Methods: A total of 41 patients were enrolled. The plasma of the patients was collected on the 3rd day, 7th day and every 1~2 months after taking the drug, and the plasma concentration was detected by liquid chromatography mass spectrometry in the Department of Pharmacy, the Affiliated Hospital of Qingdao University. Results: The average plasma concentration of gefitinib was 0.16 μg/ml on the third day of treatment. The average concentration on day 7 was 0.22 μg/ml, the first month was 0.25 μg/ml, the second month was 0.2 μg/ml, and the third month was 0.28 μg/ml… The median steady-state plasma concentration of gefitinib was 0.21 μg/ml, 95% confidence interval [0.19 μg/ml, 0.31 μg/ml]. Steady-state plasma concentration was 0.17 μg/ml ± 0.08 μg/ml in males, 0.27 μg/ml ± 0.13 μg/ml in female, P < 0.01; the values were 0.24 μg/ml ± 0.13 μg/ml in patients without smoking history and 0.19 μg/ml ± 0.06 μg/ml in patients with smoking history, P > 0.05. The postoperative patients were 0.24 μg/ml ± 0.12 μg/ml, and the patients without operation were 0.20 μg/ml ± 0.11 μg/ml, P > 0.05. It was 0.52 μg/ml ± 0.21 μg/ml in young patients (≥18, ≤40); the values were 0.24 μg/ml ± 0.13 μg/ml in the middle aged (> 40, ≤65) patients, and 0.25 μg/ml ± 0.13 μg/ml in the elderly (>65) patients, P > 0.05. The values were 0.21 μg/ml ± 0.10 μg/ml in patients with normal body weight (8.5 ≤ BMI < 24) and 0.25 μg/ml ± 0.12 μg/ml in overweight patients (BMI ≥ 24), P > 0.05. The patients with EGFR19 deletion were 0.29 μg/ml ± 0.12 μg/ml. EGFR21 L858R was 0.21 μg/ml ± 0.11 μg/ml, P < 0.05. Conclusions: After 7 days of continuous administration, the plasma concentration of gefitinib reached steady state, the steady-state concentration was [0.19 μg/ml, 0.31 μg/ml], and it was affected by gender and EGFR gene mutation type.