Stanisławiak-Rudowicz Joanna, Szałek Edyta, Adamiak Aneta, Urjasz Hanna, Więckowska Barbara, Grześkowiak Edmund, Mądry Radosław
Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, Poznań, Poland.
Department of Gynaecological Oncology, Poznań University Clinical Hospital, Poznań, Poland.
Rep Pract Oncol Radiother. 2024 Mar 18;29(1):113-121. doi: 10.5603/rpor.99026. eCollection 2024.
Olaparib is the first poly(ADP-ribose) polymerase inhibitor approved in Europe for the treatment of platinum-sensitive patients with newly diagnosed or recurrent platinum-sensitive ovarian cancer with a confirmed BRCA mutation or homologous recombination deficiency (HRD). Epidemiological studies have shown an incompatible association between ovarian cancer and obesity, but there have also been scientific reports indicating that obesity, especially severe obesity, increases the risk of ovarian cancer. Olaparib has a wide range of side effects, especially anaemia and neutropenia, which may lead to dose reduction or therapy discontinuation. Therefore, therapeutic drug monitoring (TDM) is recommended. The aim of the study was a retrospective analysis of threshold value of the trough concentration of olaparib (C) and haematological adverse reactions after olaparib treatment (300 mg/12 h) in excess-weight and normal body mass index (BMI) patients with ovarian cancer.
The pilot study was conducted on 38 ovarian cancer patients who were divided into two groups: I - normal BMI patients (BMI = 18.5-24.9 kg/m; n = 14), II - excess-weight patients, i.e. overweight and obese patients (BMI ≥ 25 kg/m; n = 24). The severity of neutropenia and anaemia was graded according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). The values of the mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), and red blood cell distribution width (RDW) parameters were also taken into account. HPLC-UV method (λ = 254 nm) was applied to measure olaparib plasma concentrations.
There were no statistically significant differences in olaparib C between the groups - 1602.86 . 1567.40 ng/mL (p = 0.9156). However, the overweight and obese patients had slightly higher dose/kg-adjusted olaparib C - 204.17 . 159.32 ng/mL/mg/kg. The incidence of grade 1 anaemia in the groups was as follows: I - 42.86%, II - 41.67%. Grade 2 and 3 anaemia was observed only in group II - 4.17% and 8.33%, respectively. The incidence of neutropenia in the groups of patients was as follows: grade 1: group I - 21.43%, group II - 20.83%; grade 2: group I - 7.14%, group II - 4.17%.
The incidence of haematological adverse reactions to olaparib, such as neutropenia and grade 1 anaemia in the group of overweight and obese patients was the same as in the normal BMI group. The overweight and obese patients were characterised by higher severity of haematological adverse reactions to olaparib and slightly higher dose/kg-adjusted olaparib C. After one month of treatment with olaparib the overweight and obese patients had significantly lower red blood cells (RBC) and haemoglobin (Hgb) levels than the patients with normal BMI, which may indicate that anaemia develops faster in this group of patients.
奥拉帕利是欧洲首个获批用于治疗铂敏感的新诊断或复发的铂敏感型卵巢癌且伴有确诊的BRCA突变或同源重组缺陷（HRD）患者的聚（ADP - 核糖）聚合酶抑制剂。流行病学研究表明卵巢癌与肥胖之间存在不一致的关联，但也有科学报告指出肥胖，尤其是重度肥胖，会增加卵巢癌风险。奥拉帕利有广泛的副作用，尤其是贫血和中性粒细胞减少，这可能导致剂量减少或治疗中断。因此，建议进行治疗药物监测（TDM）。本研究的目的是对超重和正常体重指数（BMI）的卵巢癌患者在接受奥拉帕利治疗（300mg/12小时）后，奥拉帕利谷浓度（C）阈值及血液学不良反应进行回顾性分析。
对38例卵巢癌患者进行了初步研究，这些患者被分为两组：I组 - 正常BMI患者（BMI = 18.5 - 24.9kg/m²；n = 14），II组 - 超重患者，即超重和肥胖患者（BMI≥25kg/m²；n = 24）。根据不良事件通用术语标准（CTCAE v5.0）对中性粒细胞减少和贫血的严重程度进行分级。还考虑了平均红细胞体积（MCV）、平均红细胞血红蛋白（MCH）、平均红细胞血红蛋白浓度（MCHC）和红细胞分布宽度（RDW）参数的值。采用HPLC - UV法（λ = 254nm）测定奥拉帕利血浆浓度。
两组之间奥拉帕利C无统计学显著差异 - 1602.86. 1567.40ng/mL（p = 0.9156）。然而，超重和肥胖患者的剂量/千克调整后的奥拉帕利C略高 - 204.17. 159.32ng/mL/mg/kg。两组中1级贫血的发生率如下：I组 - 42.86%，II组 - 41.67%。仅在II组中观察到2级和3级贫血 - 分别为4.17%和8.33%。患者组中性粒细胞减少的发生率如下：1级：I组 - 21.43%，II组 - 20.83%；2级：I组 - 7.14%，II组 - 4.17%。
超重和肥胖患者组中奥拉帕利血液学不良反应的发生率，如中性粒细胞减少和1级贫血，与正常BMI组相同。超重和肥胖患者的特点是对奥拉帕利血液学不良反应的严重程度更高，且剂量/千克调整后的奥拉帕利C略高。在接受奥拉帕利治疗一个月后，超重和肥胖患者的红细胞（RBC）和血红蛋白（Hgb）水平明显低于正常BMI患者，这可能表明该组患者贫血发展更快。
