AbbVie, North Chicago, Illinois.
Clin Ther. 2013 Nov;35(11):1770-7. doi: 10.1016/j.clinthera.2013.09.002. Epub 2013 Oct 2.
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths and the fifth most common cancer globally. Hepatocellular carcinoma produces highly vascular tumors that overexpress vascular endothelial growth factor (VEGF), thus making VEGF a promising therapeutic target. The competitive inhibitor linifanib (ABT-869) has selectivity for VEGF and platelet-derived growth factor (PDGF) receptors and minimal activity against unrelated tyrosine and serine and threonine kinases. However, the optimal dosing regimen for linifanib in HCC patients is not yet known.
This study attempts to identify a linifanib dose or dosing regimen with an acceptable safety profile for a Phase III study in HCC patients.
The pharmacokinetic (PK) properties of linifanib were characterized from 2 Phase I and 3 Phase II clinical trials. Of the 266 patients evaluated, the median weight was 68 kg (range, 35-177 kg), 64% were male, and 87.6% of patients received an oral solution of linifanib, whereas 12.4% received a tablet formulation. Approximately 95% of patients received drug based on weight, with the remaining on a fixed-dosing regimen. A population PK analysis was conducted to characterize the linifanib exposure for each patient. Linifanib Cmax and AUC derived from the population PK properties were correlated with the rates of adverse events (AEs).
Linifanib PK properties are dose proportional for the 0.10-mg/kg to 0.25-mg/kg once daily dose range and are time independent after repeated oral dosing. The Tmax of linifanib is approximately 3 hours, and the t½ is approximately 1 day. The most common AEs related to linifanib PK were hypertension (P = 0.02 for Cmax and P = 0.01 for AUC), diarrhea (P = 0.001 for Cmax and P = 0.0012 for AUC), proteinuria (P = 0.001 for Cmax and P = 0.002 for AUC), and asthenia (P = 0.03 for AUC). Weight and sex were identified as covariates for Cmax, and sex was identified as a covariate for AUC. The predicted AE range for females was slightly higher compared with males; however, the AE range is tighter for the weight range for fixed dosing compared with weight-based dosing, regardless of sex.
The PK properties of linifanib support a one-compartment model with first-order absorption and elimination. Comparison of weight-based and fixed dosing revealed predicted AE rates to be similar, with a tighter AE range for fixed dosing. The safety profile of linifanib, therefore, supports a 17.5 mg fixed starting dose for Phase III clinical studies.
肝细胞癌（HCC）是癌症相关死亡的第三大常见原因，也是全球第五大常见癌症。肝细胞癌产生高度血管化的肿瘤，过度表达血管内皮生长因子（VEGF），因此 VEGF 成为有前途的治疗靶点。竞争性抑制剂乐伐替尼（ABT-869）对 VEGF 和血小板衍生生长因子（PDGF）受体具有选择性，对无关的酪氨酸和丝氨酸/苏氨酸激酶的活性最小。然而，乐伐替尼在 HCC 患者中的最佳剂量方案尚不清楚。
本研究旨在确定乐伐替尼在 HCC 患者的 III 期研究中的一个具有可接受安全性特征的剂量或剂量方案。
乐伐替尼的药代动力学（PK）特性来自 2 项 I 期和 3 项 II 期临床试验进行了表征。在评估的 266 名患者中，中位体重为 68kg（范围为 35-177kg），64%为男性，87.6%的患者接受乐伐替尼口服溶液，而 12.4%的患者接受片剂制剂。大约 95%的患者根据体重给药，其余患者则采用固定剂量方案。进行群体 PK 分析以描述每位患者的乐伐替尼暴露情况。从群体 PK 特性得出的乐伐替尼 Cmax 和 AUC 与不良事件（AE）的发生率相关。
乐伐替尼 PK 特性在 0.10mg/kg 至 0.25mg/kg 每日一次剂量范围内呈剂量比例关系，并且在重复口服给药后与时间无关。乐伐替尼的 Tmax 约为 3 小时，t1/2 约为 1 天。与乐伐替尼 PK 相关的最常见 AE 为高血压（Cmax 为 P=0.02，AUC 为 P=0.01）、腹泻（Cmax 为 P=0.001，AUC 为 P=0.0012）、蛋白尿（Cmax 为 P=0.001，AUC 为 P=0.002）和乏力（AUC 为 P=0.03）。体重和性别被确定为 Cmax 的协变量，性别被确定为 AUC 的协变量。与男性相比，女性的预测 AE 范围略高；然而，与体重为基础的剂量相比，固定剂量的 AE 范围更窄，无论性别如何。
乐伐替尼的 PK 特性支持具有一级吸收和消除的单室模型。体重为基础的剂量与固定剂量的比较表明，AE 发生率相似，固定剂量的 AE 范围更窄。因此，乐伐替尼的安全性特征支持 III 期临床研究中使用 17.5mg 的固定起始剂量。
