Carolina Urologic Research Center, 823 82nd Parkway, Suite B, Myrtle Beach, SC, 29572, USA.
Bayer AG, Berlin, Germany.
Target Oncol. 2019 Oct;14(5):527-539. doi: 10.1007/s11523-019-00674-0.
Darolutamide, an androgen receptor antagonist with a distinct molecular structure, significantly prolonged metastasis-free survival versus placebo in the phase III ARAMIS study in men with nonmetastatic castration-resistant prostate cancer (nmCRPC). In this population, polypharmacy for age-related comorbidities is common and may increase drug-drug interaction (DDI) risks. Preclinical/phase I study data suggest darolutamide has a low DDI potential-other than breast cancer resistance protein/organic anion transporter protein substrates (e.g., statins), no clinically relevant effect on comedications is expected.
Our objective was to evaluate the effect of commonly administered drugs on the pharmacokinetics of darolutamide and the effect of comedications potentially affected by darolutamide on safety in patients with nmCRPC.
Comorbidities and comedication use in the 1509 ARAMIS participants treated with darolutamide 600 mg twice daily or placebo were assessed. A population pharmacokinetic analysis evaluated whether comedications affected the pharmacokinetics of darolutamide in a subset of 388 patients. A subgroup analysis of adverse events (AEs) in statin users versus nonusers was conducted.
Most participants (median age 74 years) had at least one comorbidity (98.4% in both arms) and used at least one comedication (98.7% with darolutamide vs. 98.0% with placebo); these were similar across study arms. Despite frequent use of comedications with DDI potential, no significant effects on darolutamide pharmacokinetics were identified. Comedications included lipid-modifying agents (34.5%), β-blockers (29.7%), antithrombotics (42.8%), and systemic antibiotics (26.9%). AE incidence was similar across study arms in statin users and nonusers. Study limitations include the small sample size for sub-analyses.
These analyses suggest the pharmacokinetic profile of darolutamide is not affected by a number of commonly administered drugs in patients with nmCRPC. Although pharmacokinetic data have indicated that darolutamide has the potential to interact with rosuvastatin, used to assess DDI in these studies, this finding did not seem to translate into increased AEs due to statin use in the ARAMIS trial. Clinicaltrials.gov identifier: NCT02200614.
雄激素受体拮抗剂达罗他胺具有独特的分子结构，在非转移性去势抵抗性前列腺癌（nmCRPC）患者的 III 期 ARAMIS 研究中，与安慰剂相比，显著延长了无转移生存期。在这一人群中，由于年龄相关的合并症，联合用药治疗很常见，这可能会增加药物相互作用（DDI）的风险。临床前/ I 期研究数据表明，达罗他胺的 DDI 潜力较低-除了乳腺癌耐药蛋白/有机阴离子转运蛋白底物（如他汀类药物）外，预计不会对合并用药产生临床相关影响。
我们的目的是评估常用药物对达罗他胺药代动力学的影响，以及可能受达罗他胺影响的合并用药对 nmCRPC 患者安全性的影响。
评估了 1509 名接受达罗他胺 600mg 每日两次或安慰剂治疗的 ARAMIS 参与者的合并症和合并用药情况。对 388 名患者的亚组进行了群体药代动力学分析，以评估合并用药是否影响达罗他胺的药代动力学。对他汀类药物使用者与非使用者的不良事件（AE）进行了亚组分析。
大多数参与者（中位年龄 74 岁）至少有一种合并症（两组均为 98.4%），至少使用一种合并药物（达罗他胺组为 98.7%，安慰剂组为 98.0%）；两组间相似。尽管经常使用有 DDI 潜力的合并用药，但未发现达罗他胺药代动力学有显著影响。合并用药包括调脂药物（34.5%）、β受体阻滞剂（29.7%）、抗血栓药物（42.8%）和全身抗生素（26.9%）。他汀类药物使用者和非使用者的 AE 发生率在研究组间相似。研究的局限性包括亚分析样本量小。
这些分析表明，在 nmCRPC 患者中，许多常用药物不会影响达罗他胺的药代动力学特征。尽管药代动力学数据表明，达罗他胺可能与用于评估这些研究中 DDI 的瑞舒伐他汀相互作用，但这一发现似乎并未转化为 ARAMIS 试验中因他汀类药物使用而导致 AE 增加。临床试验.gov 标识符：NCT02200614。
