Lessons learned: 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.
Background: 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.
Methods: 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.
Results: 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 (AUCTAU) of sorafenib was not significantly affected by ritonavir; however, a trend for decreased AUCTAU of the CYP3A4 metabolite sorafenib-N-oxide (3.8-fold decrease; p = .08) suggests other metabolites may be increased.
Conclusion: 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. The Oncologist 2017;22:505-e49.
经验总结
• 口服靶向药物是卡波西肉瘤（KS）的理想治疗药物, 但用于HIV患者时, 必须考虑到药物相互作用。在本项有关KS治疗的研究中, 索拉非尼在低于美国食品药品监督管理局批准用于治疗肝细胞癌和其他癌症的剂量下耐受性较差, 并且仅表现出较低的活性。
• 索拉非尼通过CYP3A4途径代谢, 而本研究中大部分患者经常使用的抗逆转录病毒药物利托那韦可抑制该途径。研究中观察到的索拉非尼毒性可能是由于利托那韦对CYP3A4的强效抑制作用所致。
• 合并感染HIV且适合接受索拉非尼治疗的癌症患者应首选合并使用预期无相互作用的抗逆转录病毒药物, 用以替代利托那韦。
摘要
背景.索拉非尼是一种以血管内皮生长因子受体（VEGFR）、c‐kit受体和血小板源性生长因子受体（PDGFR）为靶点治疗卡波西肉瘤（KS）的药物。我们使用索拉非尼进行了一项Ib期研究, 评价其与利托那韦（具有强效CYP3A4抑制活性的HIV药物）之间的药物相互作用。
方法.本研究入组了两个队列：接受利托那韦治疗的HIV相关KS患者（队列R）和未接受利托那韦治疗的HIV相关KS或经典型KS患者（队列NR）。队列R的索拉非尼剂量水平1（R1）为200 mg每日一次, 队列NR的索拉非尼剂量水平1（NR1）为200 mg每12小时一次。在第1周期第8天评价了稳态药代动力学。评估了KS缓解情况和相关因素。
结果.入组了10例患者（9例为HIV+）：R1中8例, NR1中2例。中位CD4+计数（HIV+）为500 细胞数/μL。剂量限制性毒性（DLT）为3级脂肪酶升高（R1）、4级血小板减少症（R1）和3级手足综合征（NR1）。7例可评价患者中有2例达到了部分缓解（PR；29%；95% CI：4%‐71%）。利托那韦未显著影响索拉非尼的稳态给药间隔曲线下面积（AUCTAU）, 但是, CYP3A4代谢物索拉非尼‐N‐氧化物的AUCTAU 有降低趋势（降低3.8倍； p = 0.08）, 表明其他代谢物的生成可能有所增加。
结论.索拉非尼耐受性较差, 抗KS活性不高。CYP3A4强抑制剂可能引起索拉非尼毒性, 而既往研究表明利托那韦属于CYP3A4抑制剂。如果可能涉及与索拉非尼合用, 应选择预期无相互作用的抗逆转录病毒药物, 用以替代利托那韦。The Oncologist 2017;22:505‐e49
Trial registration: ClinicalTrials.gov NCT00287495.
© AlphaMed Press; the data published online to support this summary is the property of the authors.