以酪胺酸激酶抑制劑治療癌症之台灣族群藥物動力學研究
以酪胺酸激酶抑制劑治療癌症之台灣族群藥物動力學研究
癌症已經長達三十餘年蟬聯國人十大死因之首，造成家庭與國家重大損失，也是目前醫學上仍未解的難題。針對無法開刀切除的腫瘤，傳統上只能使用全身性化學治療或者是放射治療。而隨著癌症治療的進步，抗癌的選擇更為多元化也逐漸趨於「精準醫療」。直至今日，許多癌症已被證實與異常的基因表現或是分子傳遞路徑的有關，因此標靶治療的發展就應運而生，陸續也開發了許多口服小分子標靶藥物。這些口服標靶藥物的發展，不僅僅服用方便，讓病人不用住院就可持續接受腫瘤的治療，其副作用也較傳統化學治療還低一些。
酪胺酸激酶抑制劑（Tyrosine kinase inhibitor，TKI）是能阻斷酪胺酸激酶的藥物，是標靶治療之原型。在人體中，酪胺酸激酶家族僅佔蛋白質激酶中的少數，卻佔致癌基因中較高的比例。酪胺酸激酶抑制劑機轉便是堵住酪胺酸激酶的活性部位，進而阻斷活化訊息之傳遞，阻止癌細胞生長來治療癌症。目前已經開發了許多酪胺酸激酶抑制劑，例如Imatinib、Dasatinib、Nilotinib、Gefitinib、Erlotinib、Afatinib、Osimertinib、Regorafenib、Sunitinib、Lenvatinib和Sorafenib，陸續都經實驗證實可用於治療不同的癌症種類。直至今日，口服標靶藥物的使用劑量皆是根據大型樞紐臨床試驗而訂，無論人種、性別或體型等差異都採用同樣的劑量，不同於傳統化學治療或單株抗體藥物是按體表面積或體重來計算。此外，這些樞紐臨床試驗的受試者大多數都是白種人，體形平均較小的東方人所占比例極低。依照實證醫學來說，這些藥物幾乎可說是依照白種人的試驗結果來訂定劑量，但種族與體型的差異與藥物代謝息息相關，採用固定劑量（fixed-dose）的方式的確忽略了許多人種之間的差異，同樣劑量亞洲人很可能會比白種人暴露更高濃度的藥物，進而可能影響到療效與副作用。
有鑑於此，我們與藥學院團隊合作，預計針對有使用下列九種常見酪胺酸激酶抑制劑（Afatinib、Dasatinib、Imatinib、Lenvatinib、Nilotinib、Osimertinib、Regorafenib、Sunitinib、Sorafenib）的相關癌症病患來進行台灣族群藥物動力學分析研究，希望可以使用真實病人服藥前/後的血清藥物動力學數據來分析後藥物及代謝物濃度，利用非線性混合效應模式軟體（Nonlinear mixed-effect model, NONMEM），計算族群藥物動力學（Population pharmacokinetics）與臨床成效之關聯性分析，幫助探討台灣人影響藥物動力學、藥效學、毒性反應之因素，提供未來更適用於病人使用酪胺酸激酶抑制劑之劑量處方，藉此找出最適合台灣人的治療方針。
【應用與亮點】：
1.探討台灣族群使用常見酪胺酸激酶抑制劑之藥物代謝動力學研究。
2.探討台灣族群最適宜之藥物劑量，降低用藥後副作用。
【研究團隊】
團隊成員：葉宗讓、陳立宗、王照元、吳宜珍、黃耀斌
代表單位：高雄醫學大學 癌症研究中心
團隊簡介：本團隊隸屬於於癌症研究中心，從臨床照護病人上常見的問題為開端，經由藥學院團隊專業之分析，最終目標為提供未來更適用於病人使用酪胺酸激酶抑制劑之劑量處方，找出最適合台灣人的治療方針。
研究聯繫Email：1030307@kmuh.org.tw
A pharmacokinetic analysis in Taiwanese population under tyrosine kinase inhibitors in the treatment of cancer
A pharmacokinetic analysis in Taiwanese population under tyrosine kinase inhibitors in the treatment of cancer
Cancer has been the leading cause of death for over thirty years in Taiwan and remains a major challenge in medicine. Traditionally, surgical resection, systemic chemotherapy and radiation therapy are three main treatment options. With advances in oncological field, more and more novel anti-cancer therapies are developed, and treatments are moving towards "precision medicine". Today, many cancers have been found to be associated with abnormal gene expression or molecular signaling pathways, leading to the development of targeted therapy. Many oral small molecule targeted drugs have been developed as a result and the development of these oral targeted drugs not only offers greater convenience for patients who can receive tumor treatment without hospitalization, but their side effects are also lower than those of traditional chemotherapy.
Tyrosine kinase inhibitors (TKIs) are drugs that can block tyrosine kinases, and are the prototype of targeted therapy. In the human body, the tyrosine kinase family accounts for only a small proportion of protein kinases, but a higher proportion in oncogenes. Till now, a variety of tyrosine kinase inhibitors have already been developed and launched in market, such as imatinib, dasatinib, nilotinib, gefitinib, erlotinib, afatinib, osimertinib, regorafenib, sunitinib, lenvatinib and sorafenib. Each of them has different mechanism of action and each of them is used for different types of cancer. Just like other drugs, the doses of TKIs are determined based on pivotal clinical trials, with the same doses used regardless of differences in ethnicity, gender, or body size. This is different from traditional chemotherapy or monoclonal antibody drugs, which are dosed based on body surface area or weight. Additionally, the majority of participants in these pivotal clinical trials are Caucasian, with a very low representation of East Asians who typically have smaller body sizes. However, the differences in race and body size are closely related to drug metabolism. The use of fixed-dose regimens does indeed overlook many differences between ethnic groups. For example, Asians may be exposed to higher concentrations of drugs than Caucasians at the same dose, which could affect efficacy and side effects.
In light of this, we are conducting a pharmacokinetic analysis studies on the Taiwanese population for nine commonly used tyrosine kinase inhibitors (afatinib, dasatinib, imatinib, lenvatinib, nilotinib, osimertinib, regorafenib, sunitinb and sorafenib) in relation to their corresponding cancer types (non-small cell lung cancer, head and neck cancer, gastrointestinal stromal tumor, renal cell carcinoma, chronic myeloid leukemia, hepatocellular carcinoma, colorectal cancer). We collected serum pharmacokinetic data from real patients before/after medication to analyze pre- and post-dosing drug and metabolite concentrations using nonlinear mixed-effect model software (NONMEM), and to calculate the correlation between population pharmacokinetics, clinical efficacy and toxicity. Using these data, we could survey the more appropriate dosage and finding the most suitable treatment strategies for Taiwanese population.
Application and Highlights:
1.Investigation of pharmacokinetics of common tyrosine kinase inhibitors in Taiwanese population.
2.Determination of optimal drug dosages for Taiwanese population to reduce medication-related side effects.
Research Team Members: Tsung-Jang Yeh, Li-Tzong Chen, Jaw-Yuan Wang, I-Chen Wu, Yaw-Bin Huang
Representative Department: Center for Cancer Research
Introduction of Research Team: Our team belongs to the Cancer Research Center. We started by addressing common issues in clinical care for cancer patients and combined with the professional analysis of our pharmacy team. Our ultimate goal is to provide more suitable dosage prescriptions for cancer patients using tyrosine kinase inhibitors and to find the most appropriate treatment plan for Taiwanese populations.
Contact Email: 1030307@kmuh.org.tw
