Uldrick Thomas S, Gonçalves Priscila H, Wyvill Kathleen M, Peer Cody J, Bernstein Wendy, Aleman Karen, Polizzotto Mark N, Venzon David, Steinberg Seth M, Marshall Vickie, Whitby Denise, Little Richard F, Wright John J, Rudek Michelle A, Figg William D, Yarchoan Robert
HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland, USA
HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland, USA.
Oncologist. 2017 May;22(5):505-e49. doi: 10.1634/theoncologist.2016-0486. Epub 2017 Mar 24.
Oral targeted agents are desirable for treatment of Kaposi sarcoma (KS); however, in patients with HIV, drug-drug interactions must be considered. In this study to treat KS, sorafenib was poorly tolerated at doses less than those approved by the U.S. Food and Drug Administration for hepatocellular carcinoma and other cancers, and showed only modest activity.Sorafenib's metabolism occurs via the CYP3A4 pathway, which is inhibited by ritonavir, a commonly used antiretroviral agent used by most patients in this study. Strong CYP3A4 inhibition by ritonavir may contribute to the observed sorafenib toxicity.Alternate antiretroviral agents without predicted interactions are preferred for co-administration in patients with HIV and cancers for which sorafenib is indicated.
We conducted a phase Ib study of sorafenib, a vascular epithelial growth factor receptor (VEGFR), c-kit, and platelet derived growth factor receptor (PDGFR)-targeted treatment in Kaposi sarcoma (KS). We evaluated drug-drug interactions between sorafenib and ritonavir, an HIV medication with strong CYP3A4 inhibitory activity.
Two cohorts were enrolled: HIV-related KS on ritonavir (Cohort R) and HIV-related or classical KS not receiving ritonavir (Cohort NR). Sorafenib dose level 1 in cohort R (R1) was 200 mg daily and 200 mg every 12 hours in cohort NR (NR1). Steady-state pharmacokinetics were evaluated at cycle 1, day 8. KS responses and correlative factors were assessed.
Ten patients (nine HIV) were enrolled: R1 (eight), NR1 (two). Median CD4 count (HIV) was 500 cells/µL. Dose-limiting toxicities (DLTs) were grade 3 elevated lipase (R1), grade 4 thrombocytopenia (R1), and grade 3 hand-foot syndrome (NR1). Two of seven evaluable patients had a partial response (PR; 29%; 95% CI 4%-71%). Steady-state area under the curve of the dosing interval (AUC) of sorafenib was not significantly affected by ritonavir; however, a trend for decreased AUC of the CYP3A4 metabolite sorafenib-N-oxide (3.8-fold decrease; = .08) suggests other metabolites may be increased.
Sorafenib was poorly tolerated, and anti-KS activity was modest. Strong CYP3A4 inhibitors may contribute to sorafenib toxicity, and ritonavir has previously been shown to be a CYP3A4 inhibitor. Alternate antiretroviral agents without predicted interactions should be used when possible for concurrent administration with sorafenib. 2017;22:505-e49.
口服靶向药物适用于治疗卡波西肉瘤（KS）；然而，对于感染HIV的患者，必须考虑药物相互作用。在这项治疗KS的研究中，索拉非尼在低于美国食品药品监督管理局批准用于肝细胞癌和其他癌症的剂量时耐受性较差，且仅显示出适度的活性。索拉非尼通过CYP3A4途径代谢，而ritonavir（本研究中大多数患者使用的一种常用抗逆转录病毒药物）可抑制该途径。ritonavir对CYP3A4的强烈抑制作用可能导致观察到的索拉非尼毒性。对于感染HIV且有索拉非尼适应证的癌症患者，优选无预测相互作用的替代抗逆转录病毒药物进行联合给药。
我们开展了一项索拉非尼的Ib期研究，索拉非尼是一种靶向血管内皮生长因子受体（VEGFR）、c-kit和血小板衍生生长因子受体（PDGFR）的药物，用于治疗卡波西肉瘤（KS）。我们评估了索拉非尼与ritonavir（一种具有强烈CYP3A4抑制活性的HIV药物）之间的药物相互作用。
招募了两个队列：接受ritonavir治疗的HIV相关KS（队列R）和未接受ritonavir治疗的HIV相关或经典KS（队列NR）。队列R中索拉非尼剂量水平1（R1）为每日200 mg，队列NR中（NR1）为每12小时200 mg。在第1周期第8天评估稳态药代动力学。评估KS反应和相关因素。
共招募了10名患者（9名HIV感染者）：R1组8名，NR1组2名。HIV感染者的CD⁴细胞计数中位数为500个/µL。剂量限制性毒性（DLT）为3级脂肪酶升高（R1组）、4级血小板减少（R1组）和3级手足综合征（NR1组）。7名可评估患者中有2名出现部分缓解（PR；29%；95%CI 4%-71%）。索拉非尼给药间隔的稳态曲线下面积（AUC）不受ritonavir的显著影响；然而，CYP3A4代谢产物索拉非尼-N-氧化物的AUC有下降趋势（下降3.8倍；P = 0.08），提示其他代谢产物可能增加。
索拉非尼耐受性差，抗KS活性适度。强烈的CYP3A4抑制剂可能导致索拉非尼毒性，且ritonavir此前已被证明是一种CYP3A4抑制剂。可能的情况下，与索拉非尼同时给药时应使用无预测相互作用的替代抗逆转录病毒药物。2017；22：505-e49。
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