Pfizer Inc., La Jolla, California, USA.
The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
J Clin Pharmacol. 2020 Oct;60(10):1334-1343. doi: 10.1002/jcph.1626. Epub 2020 May 28.
Poly(ADP-ribose) polymerase inhibitors, such as talazoparib, may affect hematopoiesis. This analysis characterized the relationship between talazoparib exposure and the most common grade ≥ 3 hematopoietic adverse events (AEs) leading to dose modification in the phase 2 (ABRAZO) and phase 3 (EMBRACA) trials. The relationship between time-varying average talazoparib concentration (C ), along with other baseline variables, and grade ≥ 3 anemia, thrombocytopenia, and neutropenia were evaluated both by graphical examination and using univariate and multivariate Cox proportional hazard models. The results indicated that higher C was associated with a higher risk of anemia and thrombocytopenia. A trend toward an association between higher C and neutropenia was observed, although not statistically significant. Higher risk of all tested safety end points was associated with lower baseline hemoglobin. Higher risk of neutropenia was associated with lower baseline absolute neutrophil count and lower body weight. These findings support the proposed management of AEs through talazoparib dosing modification.
聚（ADP-核糖）聚合酶抑制剂，如他拉唑帕尼，可能会影响造血功能。本分析描述了他拉唑帕尼暴露与导致 2 期（ABRAZO）和 3 期（EMBRACA）试验剂量调整的最常见≥3 级血液学不良事件（AE）之间的关系。通过图形检查以及使用单变量和多变量 Cox 比例风险模型，评估了时变平均他拉唑帕尼浓度（C）与其他基线变量与≥3 级贫血、血小板减少症和中性粒细胞减少症之间的关系。结果表明，较高的 C 与贫血和血小板减少症的风险增加相关。观察到较高 C 与中性粒细胞减少症之间存在关联的趋势，但无统计学意义。所有测试的安全性终点的较高风险与较低的基线血红蛋白相关。中性粒细胞减少症的风险与较低的基线绝对中性粒细胞计数和较低的体重相关。这些发现支持通过他拉唑帕尼剂量调整来管理 AE 的建议。
