Phase 1 Program, Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 455, Houston, TX 77030, USA.
Cancer Chemother Pharmacol. 2011 Dec;68(6):1507-16. doi: 10.1007/s00280-011-1635-7. Epub 2011 Apr 17.
Patupilone is a novel microtubule-targeting cytotoxic agent with potential interaction with CYP3A4/CYP2C19 enzymes. Midazolam and omeprazole are primarily metabolized by CYP3A4 and CYP2C19, respectively. We evaluated the inhibitory effects of patupilone on the CYP3A4/CYP2C19 pathways.
This study had 2 parts: in an initial core phase, patients were randomly assigned to receive midazolam 4 mg or omeprazole 40 mg PO (days 1 and 29) and patupilone 10 mg/m(2) IV (days 8 and 29). Patients without progression continued patupilone every 3 weeks until disease progression or unacceptable toxicity (extension phase).
Forty-six patients were treated. The areas under the concentration-time curves (AUC)s of midazolam with or without patupilone co-administration were similar. The C (max) of midazolam when co-administered with patupilone was highly variable and was lower compared with midazolam alone; however, the oral clearance and terminal half-lives were similar. Both the C (max) and AUC of omeprazole when co-administered with patupilone were highly variable and lower than with omeprazole alone. However, the oral clearance and terminal half-lives were similar. The latter data suggest that patupilone decreased the absorption of omeprazole (by ~20%). The overall safety profile was consistent with that of previous single-agent patupilone studies; 2 partial responses (ovarian and pancreatic cancer) and 1 complete response (serous ovarian adenocarcinoma) were observed.
Patupilone was not a potent CYP3A4 or CYP2C19 inhibitor. No dose adjustment is required when omeprazole or midazolam is used in patients treated with patupilone. Patupilone exhibited promising antitumor activity in heavily pretreated patients with ovarian and pancreatic cancer.
帕他膦酮是一种新型微管靶向细胞毒性药物，可能与 CYP3A4/CYP2C19 酶相互作用。咪达唑仑和奥美拉唑主要分别通过 CYP3A4 和 CYP2C19 代谢。我们评估了帕他膦酮对 CYP3A4/CYP2C19 途径的抑制作用。
本研究分为 2 部分：在初始核心阶段，患者被随机分为接受咪达唑仑 4mg 或奥美拉唑 40mg PO（第 1 天和第 29 天）和帕他膦酮 10mg/m²IV（第 8 天和第 29 天）。无进展的患者继续每 3 周接受帕他膦酮治疗，直到疾病进展或不可接受的毒性（扩展阶段）。
46 名患者接受了治疗。咪达唑仑与帕他膦酮联合用药或单独用药的浓度-时间曲线下面积（AUC）相似。咪达唑仑与帕他膦酮联合用药时的 C（max）变化很大，且低于单独使用咪达唑仑时的 C（max）；然而，口服清除率和半衰期相似。奥美拉唑与帕他膦酮联合用药时的 C（max）和 AUC 变化很大，且低于单独使用奥美拉唑时的 C（max）和 AUC；然而，口服清除率和半衰期相似。后一组数据表明，帕他膦酮降低了奥美拉唑的吸收（约 20%）。总体安全性与先前的帕他膦酮单药研究一致；观察到 2 例部分缓解（卵巢癌和胰腺癌）和 1 例完全缓解（浆液性卵巢腺癌）。
帕他膦酮不是一种有效的 CYP3A4 或 CYP2C19 抑制剂。当帕他膦酮治疗的患者使用奥美拉唑或咪达唑仑时，无需调整剂量。帕他膦酮在卵巢癌和胰腺癌等经大量预处理的患者中显示出有前景的抗肿瘤活性。
