奥拉帕利的药代动力学增强：一项多中心、开放标签、随机、非劣效性试验（PROACTIVE-B）的研究方案。
Pharmacokinetic boosting of olaparib: Study protocol of a multicentre, open-label, randomised, non-inferiority trial (PROACTIVE-B).
作者信息
Overbeek Joanneke K, Guchelaar Niels A D, Mohmaed Ali Ma Ida, Sark Muriëlle, Hovenier Carolien, Kievit Wietske, Ligtenberg Marjolijn J L, Ottevanger Petronella B, Bloemendal Haiko J, Koolen Stijn L W, Mathijssen Ron H J, Boere Ingrid A, Huitema Alwin D R, Sonke Gabe S, Opdam Frans L, Ter Heine Rob, van Erp Nielka P
机构信息
Department of Pharmacy, Radboud University Medical Center, Nijmegen, the Netherlands.
Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands.
出版信息
Contemp Clin Trials Commun. 2025 Mar 29;45:101477. doi: 10.1016/j.conctc.2025.101477. eCollection 2025 Jun.
BACKGROUND
Pharmacokinetic (PK) boosting is the intentional use of a drug-drug interaction to enhance systemic drug exposure. PK boosting of the anticancer drug olaparib, a CYP3A-substrate, has the potential to reduce PK variability, side effects and financial burden associated with this drug. After establishing adequate pharmacokinetic exposure with boosting in the PROACTIVE-A study, the PROACTIVE-B study is designed to evaluate non-inferiority for both efficacy and toxicity of the boosted therapy compared to the standard monotherapy of olaparib.
METHODS
The PROACTIVE-B study is a nationwide, multicentre, prospective, randomized, non-inferiority trial. A total of 142 patients (128 patients with BRCA+, high-grade, FIGO III/IV ovarian cancer who receive olaparib as maintenance therapy; 14 patients with other approved indications for olaparib) who start olaparib treatment in line with the drug label will be randomized between the standard monotherapy of olaparib 300 mg twice daily (BID) and the boosted therapy of olaparib 100 mg BID with cobicistat 150 mg BID. The co-primary objectives are tolerability (dose reductions due to toxicity), and efficacy (progression-free survival at 12 months) in the ovarian cancer population. Secondary objectives include health status (EQ-5D-5L), patient satisfaction (Cancer Therapy Satisfaction Questionnaire (CTSQ)), and cost effectiveness using the institute for Medical Technology Assessment (iMTA) Productivity Cost Questionnaire (iPCQ) and iMTA Medical Consumption Questionnaire (iMCQ).
DISCUSSION
PK boosting of olaparib is a potentially valuable strategy to reduce the olaparib dose and the variability in olaparib exposure with fewer side effects. Moreover, the lower costs related to the boosted therapy contribute to a durable and accessible anticancer treatment for all patients.
TRIAL REGISTRATION
The PROACTIVE study has been published at ClinicalTrials.gov under NCT05078671 on October 14, 2021 and at EudraCT under 2021-004032-28 on August 24, 2021.
背景
药代动力学（PK）增强是指有意利用药物相互作用来提高全身药物暴露量。抗癌药物奥拉帕利是一种细胞色素P450 3A（CYP3A）底物，其PK增强有可能降低与该药物相关的PK变异性、副作用和经济负担。在PROACTIVE - A研究中确定了PK增强后的充分药代动力学暴露后，PROACTIVE - B研究旨在评估与奥拉帕利标准单药治疗相比，增强治疗在疗效和毒性方面的非劣效性。
方法
PROACTIVE - B研究是一项全国性、多中心、前瞻性、随机、非劣效性试验。共有142例开始按照药品标签进行奥拉帕利治疗的患者（128例携带BRCA+、高级别、国际妇产科联盟（FIGO）III/IV期卵巢癌且接受奥拉帕利维持治疗的患者；14例有奥拉帕利其他获批适应症的患者）将被随机分配至奥拉帕利标准单药治疗组（每日两次，每次300mg）和奥拉帕利增强治疗组（每日两次，每次100mg，联合考比司他每日两次，每次150mg）。共同主要目标是卵巢癌人群的耐受性（因毒性导致的剂量减少）和疗效（12个月时的无进展生存期）。次要目标包括健康状况（EQ - 5D - 5L）、患者满意度（癌症治疗满意度问卷（CTSQ）），以及使用医疗技术评估研究所（iMTA）生产力成本问卷（iPCQ）和iMTA医疗消费问卷（iMCQ）评估成本效益。
讨论
奥拉帕利的PK增强是一种潜在有价值的策略，可减少奥拉帕利剂量以及奥拉帕利暴露的变异性，且副作用更少。此外，增强治疗相关的较低成本有助于为所有患者提供持久且可及的抗癌治疗。
试验注册
PROACTIVE研究已于2021年10月14日在ClinicalTrials.gov上以NCT05078671的编号发布，并于2021年8月24日在欧盟临床试验数据库（EudraCT）上以2021 - 004032 - 28的编号发布。
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