Center for Translational Medicine, University of Maryland, Baltimore, MD, USA.
The Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
Cancer Chemother Pharmacol. 2019 Feb;83(2):319-328. doi: 10.1007/s00280-018-3731-4. Epub 2018 Nov 20.
Veliparib is an oral inhibitor of poly(ADP-ribose) polymerase enzyme. Combination of veliparib and temozolomide was well-tolerated and demonstrated clinical activity in older patients with relapsed or refractory acute myeloid leukemia (AML) or AML arising from pre-existing myeloid malignancies. We aimed to perform quantitative assessments of pharmacokinetics, efficacy, and safety of veliparib in this patient population to inform future trial design.
Population pharmacokinetic analysis was performed using Phoenix NLME with pharmacokinetic data obtained from 37 subjects after oral administration of veliparib in a Phase I study with and without temozolomide. Effect of covariates (age, sex, BMI, creatinine clearance (CL), and co-administration of temozolomide) on the pharmacokinetics of veliparib were evaluated, as well as impact of veliparib exposure on mucositis (dose-limiting toxicity), objective response rate (ORR), and overall survival.
A two-compartment model with first-order elimination and a first-order absorption with lag-time adequately described veliparib pharmacokinetics. CL and body weight were clinically significant covariates for veliparib disposition. The proportion of subjects with all grade mucositis increased with veliparib exposure (AUC). However, no trend in ORR and overall survival was observed with increasing exposure.
Veliparib with temozolomide presents a promising combination for older patients with myeloid leukemias. An exposure-safety relationship was established for this combination. Further clinical investigations aimed at elucidating the veliparib exposure-efficacy/safety relationship and optimizing dosing recommendations for maximizing benefit-risk in patients with advanced myeloid malignancies should study veliparib doses ranging up to 120 mg in combination with temozolomide.
维利帕尼是一种聚（ADP-核糖）聚合酶酶的口服抑制剂。维利帕尼与替莫唑胺联合使用在复发或难治性急性髓细胞白血病（AML）或源自先前存在的髓样恶性肿瘤的 AML 老年患者中耐受良好，并显示出临床活性。我们旨在对该患者人群中维利帕尼的药代动力学、疗效和安全性进行定量评估，为未来的试验设计提供信息。
采用 Phoenix NLME 进行群体药代动力学分析，使用从接受维利帕尼口服治疗的 37 名受试者中获得的药代动力学数据，该研究包括与替莫唑胺联合用药和不联合用药的研究。评估了协变量（年龄、性别、BMI、肌酐清除率（CL）和替莫唑胺联合用药）对维利帕尼药代动力学的影响，以及维利帕尼暴露对黏膜炎（剂量限制毒性）、客观缓解率（ORR）和总生存的影响。
一个具有一级消除的两室模型和一个具有滞后时间的一级吸收能够充分描述维利帕尼的药代动力学。CL 和体重是维利帕尼处置的临床重要协变量。随着维利帕尼暴露量（AUC）的增加，所有等级黏膜炎的受试者比例增加。然而，随着暴露量的增加，未观察到 ORR 和总生存率的趋势。
维利帕尼与替莫唑胺联合使用为老年髓样白血病患者提供了一种有前途的联合用药方案。建立了该联合用药的暴露-安全性关系。进一步的临床研究旨在阐明维利帕尼暴露-疗效/安全性关系，并优化剂量建议，以最大限度地提高患有晚期髓样恶性肿瘤患者的获益风险，应该研究维利帕尼联合替莫唑胺的剂量范围高达 120mg。
