Cancer Chemotherapy and Pharmacology

A phase I study investigating the safety and pharmacokinetics of highly bioavailable curcumin (Theracurmin®) in cancer patients

Authors: Masashi Kanai, Yoshihiko Otsuka, Kazunori Otsuka, Maremi Sato, Takafumi Nishimura, Yukiko Mori, Michiya Kawaguchi, Etsuro Hatano, Yuzo Kodama, Shigemi Matsumoto, Yoshiki Murakami, Atsushi, Imaizumi, Tsutomu Chiba, Jun Nishihira, Hiroyuki Shibata.

Abstract

Background

A growing number of preclinical studies have demonstrated that curcumin could be a promising anticancer drug; however, poor bioavailability has been the major obstacle for its clinical application. To overcome this problem, we developed a new form of curcumin (Theracurmin®) and reported high plasma curcumin levels could be safely achieved after a single administration of Theracurmin® in healthy volunteers. In this study, we aimed to evaluate the safety of repetitive administration of Theracurmin® in cancer patients.

Methods

Pancreatic or biliary tract cancer patients who failed standard chemotherapy were eligible for this study. Based on our previous pharmacokinetic study, we selected Theracurmin® containing 200 mg of curcumin (Level 1) as a starting dose, and the dose was safely escalated to Level 2, which contained 400 mg of curcumin. Theracurmin® was orally administered every day with standard gemcitabine-based chemotherapy. In addition to safety and pharmacokinetics data, NF-κB activity, cytokine levels, efficacy, and quality-of-life score were evaluated.

Results

Ten patients were assigned to level 1 and six were to level 2. Peak plasma curcumin levels (median) after Theracurmin® administration were 324 ng/mL (range, 47–1,029 ng/mL) at Level 1 and 440 ng/mL (range, 179–1,380 ng/mL) at Level 2. No unexpected adverse events were observed and 3 patients safely continued Theracurmin® administration for >9 months.

Conclusions

Repetitive systemic exposure to high concentrations of curcumin achieved by Theracurmin®did not increase the incidence of adverse events in cancer patients receiving gemcitabine-based chemotherapy.

Keywords

Curcumin Bioavailability Theracurmin® Gemcitabine Pancreatic cancer

Notes

Acknowledgments

We thank Kazuyuki Miura and Megumi Horikawa for their contributions to data management and Yasuko Nakagawa for her contribution to sample collection and preparation. This work was supported by a Grant-in-Aid from the Japan Society for the Promotion of Science (24590655) and the Japanese Research Foundation for Clinical Pharmacology.

Conflicts of interest

A. Imaizumi is a consultant to Theravalues Corporation, and Y. Otsuka is an employee of Theravalues Corporation.

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Ung thư hóa trị và dược lý

Một giai đoạn nghiên cứu điều tra về tính an toàn và dược động học của curcumin có tính sinh học cao (Theracurmin®) ở bệnh nhân ung thư

Tác giả: Masashi Kanai, Yoshihiko Otsuka, Kazunori Otsuka, Maremi Sato, Takafumi Nishimura, Yukiko Mori, Michiya Kawaguchi, Etsuro Hatano, Yuzo Kodama, Shigemi Matsumoto, Yoshiki Murakami, Atsushi, Imaizumi, Tsutomu Chiba, Jun Nishihira, Hiroyuki Shibata.

Tổng quan

Ngày càng nhiều nghiên cứu tiền lâm sàng đã chứng minh rằng chất curcumin có thể là một loại thuốc chống ung thư đầy triển vọng; tuy nhiên, sinh khả dụng kém là trở ngại lớn cho ứng dụng lâm sàng của nó. Để khắc phục vấn đề này, chúng tôi đã phát triển một dạng curcumin mới (Theracurmin®) và báo cáo mức độ curcumin huyết tương cao có thể đạt được một cách an toàn sau một lần sử dụng Theracurmin® ở những tình nguyện viên khỏe mạnh. Trong nghiên cứu này, chúng tôi nhằm mục đích đánh giá sự an toàn của việc sử dụng Theracurmin® lặp đi lặp lại ở bệnh nhân ung thư.

Phương pháp

Bệnh nhân ung thư tuyến tụy hoặc đường mật thất bại trong hóa trị liệu tiêu chuẩn đã đủ điều kiện cho nghiên cứu này. Dựa trên nghiên cứu dược động học trước đây của chúng tôi, chúng tôi đã chọn Theracurmin® chứa 200 mg curcumin (Cấp độ 1) làm liều khởi đầu và liều được nâng lên một cách an toàn đến Cấp độ 2, chứa 400 mg curcumin. Theracurmin® được dùng bằng đường uống mỗi ngày với hóa trị liệu dựa trên gemcitabine tiêu chuẩn. Ngoài dữ liệu về an toàn và dược động học, hoạt động của NF-κB, nồng độ cytokine, hiệu quả và điểm chất lượng cuộc sống đã được đánh giá.

Các kết quả

Mười bệnh nhân được chỉ định ở cấp 1 và sáu là cấp độ 2. Mức curcumin huyết tương tối đa (trung vị) sau khi dùng Theracurmin® là 324 ng / mL (phạm vi, 47 Nott1,029 ng / mL) ở Cấp 1 và 440 ng / mL (phạm vi , 179 Vang1.380 ng / mL) ở Cấp độ 2. Không có tác dụng phụ bất ngờ nào được quan sát và 3 bệnh nhân tiếp tục sử dụng Theracurmin® một cách an toàn trong 9 tháng.

Kết luận

Phơi nhiễm hệ thống lặp đi lặp lại với nồng độ curcumin cao đạt được bởi Theracurmin®did ​​không làm tăng tỷ lệ các tác dụng phụ ở bệnh nhân ung thư được hóa trị liệu dựa trên gemcitabine.

Từ khóa

Curcumin Sinh khả dụng Theracurmin® Gemcitabine Ung thư tuyến tụy

Ghi chú

Lời cảm ơn

Chúng tôi cảm ơn Kazuyuki Miura và Megumi Horikawa vì những đóng góp của họ cho việc quản lý dữ liệu và Yasuko Nakagawa vì những đóng góp của cô cho việc thu thập và chuẩn bị mẫu. Công trình này được hỗ trợ bởi một khoản tài trợ từ Hiệp hội khuyến khích khoa học Nhật Bản (24590655) và Quỹ nghiên cứu dược lý lâm sàng Nhật Bản.

Xung đột lợi ích

A. Imaizumi là một nhà tư vấn cho Theravalues ​​Corporation và Y. Otsuka là một nhân viên của Theravalues ​​Corporation.

- Dược sĩ Sơn Điền Trung (Tổng hợp và dịch)-

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