Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Pharm Res. 2023 May;40(5):1239-1247. doi: 10.1007/s11095-023-03497-x. Epub 2023 Mar 22.
Olaparib is given in a fixed dose of twice-daily 300 mg in patients who are diagnosed with ovarian cancer, breast cancer, prostate cancer or pancreas cancer and has a high interpatient variability in pharmacokinetic exposure. The objective of this study was to investigate whether pharmacokinetic exposure of olaparib is related to efficacy and safety in a real-life patient' cohort.
A longitudinal observational study was conducted in patients who received olaparib for metastatic ovarian cancer of whom pharmacokinetic samples were collected. A Kaplan-Meier analyses was used to explore the relationship between olaparib exposure, measured as (calculated) minimum plasma concentrations (C), and efficacy, Univariate and multivariate cox-regression analyses were performed. Also, the C of patients who experienced toxicity was compared with patients who did not experience any toxicity.
Thirty-five patients were included in the exposure-efficacy analyses, with a median olaparib C of 1514 ng/mL. There was no statistical significant difference in PFS of patients below and above the median C concentration of olaparib, with a hazard ratio of 1.06 (95% confidence interval: 0.46-2.45, p = 0.9)). For seven patients pharmacokinetic samples were available before toxicity occurred, these patients had a higher C of olaparib in comparison with patients who had not experienced any toxicity (n = 33), but it was not statistically significant (p = 0.069).
Our study shows that exposure of olaparib is not related to PFS. This suggests that the approved dose of olaparib yields sufficient target inhibition in the majority of patients.
奥拉帕利以每日两次 300mg 的固定剂量用于诊断为卵巢癌、乳腺癌、前列腺癌或胰腺癌的患者，其药代动力学暴露的个体间差异很大。本研究的目的是调查奥拉帕利的药代动力学暴露与真实患者队列中的疗效和安全性是否相关。
对接受奥拉帕利治疗转移性卵巢癌的患者进行了一项纵向观察性研究，采集了药代动力学样本。采用 Kaplan-Meier 分析来探讨奥拉帕利暴露（以（计算）最小血浆浓度 [C] 表示）与疗效之间的关系。进行了单变量和多变量 Cox 回归分析。此外，还比较了经历毒性的患者与未经历任何毒性的患者的 C 值。
在暴露-疗效分析中纳入了 35 名患者，奥拉帕利的中位 C 值为 1514ng/mL。C 值低于和高于奥拉帕利中位数的患者的无进展生存期（PFS）无统计学显著差异，风险比为 1.06（95%置信区间：0.46-2.45，p=0.9）。对于 7 名患者，在发生毒性之前有药代动力学样本可用，这些患者的奥拉帕利 C 值高于未经历任何毒性的患者（n=33），但无统计学显著差异（p=0.069）。
我们的研究表明，奥拉帕利的暴露与 PFS 无关。这表明批准的奥拉帕利剂量在大多数患者中产生了足够的靶抑制。
