Centre for Applied Pharmacokinetic Research, University of Manchester, UK.
Division of Pharmacy and Optometry, University of Manchester, UK.
Br J Clin Pharmacol. 2021 Apr;87(4):2053-2063. doi: 10.1111/bcp.14614. Epub 2020 Dec 19.
Chemotherapy-induced neutropenia has been associated with an increase in overall survival in non-small cell lung cancer patients. Therefore, neutrophil counts could be an interesting biomarker for drug efficacy as well as linked directly to toxicity. For drugs where neutropenia is dose limiting, neutrophil counts might be used for monitoring drug effect and for dosing optimisation.
The relationship between drug effect on the first cycle neutrophil counts and patient survival was explored in a Phase III clinical trial where patients with non-small cell lung cancer were treated with docetaxel. Once the association has been established, dosing optimisation was performed for patients with severe toxicities (neutropenia) without compromising drug efficacy (overall survival).
After taking into account baseline prognostic factors, such as Eastern Cooperative Oncology Group performance status, smoking status, liver metastasis, tumour burden, neutrophil counts and albumin levels, a model-predicted drug effect on the first cycle neutrophil counts was strongly associated with patient survival (P = .005). Utilising this relationship in a dose optimisation algorithm, 194 out of 366 patients would have benefited from a dose reduction after the first cycle of docetaxel. The simulated 1-year survival probabilities associated with the original dose and the individualised dose were not different.
The strong relationship between drug effect on the first cycle neutrophil counts and patient survival suggests that this variable could be used to individualise dosing, possibly without needing pharmacokinetic samples. The algorithm highlights that doses could be reduced in case of severe haematological toxicities without compromising drug efficacy.
化疗引起的中性粒细胞减少与非小细胞肺癌患者的总生存期延长有关。因此，中性粒细胞计数可能是一种有趣的药物疗效生物标志物，并且与毒性直接相关。对于中性粒细胞减少为剂量限制毒性的药物，中性粒细胞计数可用于监测药物作用和剂量优化。
在一项 III 期临床试验中，对接受多西他赛治疗的非小细胞肺癌患者的中性粒细胞计数与患者生存之间的药物作用关系进行了探索。一旦确定了这种关联，就对中性粒细胞减少毒性严重（无中性粒细胞减少）但不影响药物疗效（总生存期）的患者进行了剂量优化。
在考虑了基线预后因素（如东部合作肿瘤学组体能状态、吸烟状况、肝转移、肿瘤负荷、中性粒细胞计数和白蛋白水平）后，模型预测的第一周期中性粒细胞计数的药物作用与患者生存密切相关（P=0.005）。在剂量优化算法中利用这种关系，在多西他赛的第一个周期后，366 名患者中有 194 名将从剂量减少中受益。与原始剂量和个体化剂量相关的模拟 1 年生存率没有差异。
第一周期中性粒细胞计数的药物作用与患者生存之间的密切关系表明，该变量可用于个体化给药，可能不需要药代动力学样本。该算法强调，如果出现严重的血液学毒性，可降低剂量而不影响药物疗效。
