A Pharmacodynamic Study of the P‐glycoprotein Antagonist CBT‐1® in Combination With Paclitaxel in Solid Tumors

• Published in: The oncologist (Dayton, Ohio) Ohio), 2012-04, Vol.17 (4), p.512-e523
• Main Authors: Kelly, Ronan J., Robey, Robert W., Chen, Clara C., Draper, Deborah, Luchenko, Victoria, Barnett, Daryl, Oldham, Robert K., Caluag, Zinnah, Frye, A. Robin, Steinberg, Seth M., Fojo, Tito, Bates, Susan E.
• Format: Article
• Language: English
• Subjects: Abdominal Neoplasms - drug therapy; Abdominal Neoplasms - metabolism; Adult; Aged; Alkaloids - pharmacology; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Clinical Trial Reports; Drug Interactions; Female; Humans; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Liver - drug effects; Liver - metabolism; Male; Middle Aged; Paclitaxel - pharmacokinetics; Paclitaxel - pharmacology; Radiopharmaceuticals - pharmacokinetics; Rhodamine 123 - pharmacokinetics; Technetium Tc 99m Sestamibi - pharmacokinetics
• ISSN: 1083-7159; 1549-490X
• DOI: 10.1634/theoncologist.2012-0080

Background. This pharmacodynamic trial evaluated the effect of CBT‐1® on efflux by the ATP binding cassette (ABC) multidrug transporter P‐glycoprotein (Pgp/MDR1/ABCB1) in normal human cells and tissues. CBT‐1® is an orally administered bisbenzylisoquinoline Pgp inhibitor being evaluated clinically. Laboratory studies showed potent and durable inhibition of Pgp, and in phase I studies CBT‐1® did not alter the pharmacokinetics of paclitaxel or doxorubicin. Methods. CBT‐1® was dosed at 500 mg/m2 for 7 days; a 3‐hour infusion of paclitaxel at 135 mg/m2 was administered on day 6. Peripheral blood mononuclear cells (PBMCs) were obtained prior to CBT‐1® administration and on day 6 prior to the paclitaxel infusion. 99mTc‐sestamibi imaging was performed on the same schedule. The area under the concentration–time curve from 0–3 hours (AUC0‐3) was determined for 99mTc‐sestamibi. Results. Twelve patients were planned and enrolled. Toxicities were minimal and related to paclitaxel (grade 3 or 4 neutropenia in 18% of cycles). Rhodamine efflux from CD56+ PBMCs was a statistically significant 51%–100% lower (p < .0001) with CBT‐1®. Among 10 patients who completed imaging, the 99mTc‐sestamibi AUC0‐3 for liver (normalized to the AUC0‐3 of the heart) increased from 34.7% to 100.8% (median, 71.9%; p < .0001) after CBT‐1® administration. Lung uptake was not changed. Conclusion. CBT‐1® is able to inhibit Pgp‐mediated efflux from PBMCs and normal liver to a degree observed with Pgp inhibitors studied in earlier clinical trials. Combined with its ease of administration and lack of toxicity, the data showing inhibition of normal tissue Pgp support further studies with CBT‐1® to evaluate its ability to modulate drug uptake in tumor tissue. 摘要 背景. 本次药效动力学试验评估了 CBT‐1® 在正常人类细胞和组织中通过 ATP 结合盒 （ABC） 多药转运蛋白 P 糖蛋白 （Pgp/MDR1/ABCB1） 外排的影响。 CBT‐1® 为一种口服给药的双苄基异喹啉类 Pgp 抑制剂， 目前正在进行临床评估。 实验室研究显示了该制剂对 Pgp 强大而持久的抑制作用， CBT‐1® I 期研究并未改变紫杉醇或多柔比星的药代动力学。 方法. CBT‐1® 给药剂量为 500 mg/m2， 连用 7 天； 紫杉醇剂量为 135 mg/m2， 连续输注 3 小时， 第 6 天给药。 分别在给予 CBT‐1® 前、 第 6 天输注紫杉醇前收集外周血单核细胞 （PBMC）。 99mTc 甲氧基异丁基异腈成像按照同样的时间表进行。 0 ∼ 3 小时浓度‐时间曲线下面积 （ AUC0‐3） 确定为 99mTc 甲氧基异丁基异腈 AUC0‐3。 结果. 12 例患者按计划入组。 毒性反应非常轻微， 与紫杉醇的使用有关（18% 的疗程中出现 3/4 级中性粒细胞减少）。 CBT‐1® 使用后， CD56+ PBMC 的罗丹明荧光染料外排显著下降 51% ∼ 100% （p < 0.0001）。 完成成像的 10 例患者中， CBT‐1® 使用后， 肝脏 99mTc 甲氧基异丁基异腈 AUC0‐3（按照心脏 AUC0‐3标准化）从 34.7% 升至 100.8% （中位值， 71.9%； p < 0.0001）。 肺部摄取量无改变。 结论. 早期关于 Pgp 抑制剂的临床试验观察到， CBT‐1® 能够将 Pgp 介导的 PBMC 和正常肝脏外排抑制到一定程度。 同时考虑到 CBT‐1® 方便给药且无毒性反应， 上述显示正常组织 Pgp 抑制效应的