复方药品创新研发策略

摘要/Abstract

摘要： 固定剂量复方药品研发是创新过程,目前已成为突破药物研究瓶颈的新出路之一。复方药品组方必须基于药物相互作用理论,充分利用与治疗目的相同的作用和效应,进行组方论证,进行多因素多水平分析和临床联合用药验证,确定目标组方,最后进入新药规范化研究和试验。复方药品的创新研发全过程(药学、药效学、药动学、毒理学和临床试验)与全创新药物同样规范和严格,并且必须进行拆方分析。本文从复方药品组方原则、研发策略、研发技术要求规范要点等方面进行了综述。

关键词: 复方药品研发, 药物相互作用理论, 多因素多水平分析技术, 组方原则, 技术要求规范

Abstract: Development of fixed-dose combination finished pharmaceutical products (FDC-FPPs, FDCs) is an innovative process and has become one of the breakthrough strategies for removing the bottlenecks in drug discovery. Formulating prescription of FDCs is based on drug interactions theory. The principle of formulating prescription is taking full advantage of the drugs' effects with a same remedy goal, then proceeding a demonstration of the prescription and multi-factor and multi-level analyses, verifying of clinical combinations, confirming of the goal prescription, finally accessing the normalize research and trials of new drug development. The whole process of FDCs research and development (pharmacy, pharmacodynamics, pharmacokinetics, toxicology and clinical trials) is as strict as such of the complete innovative drug, and need to optimize the formula and the ratio of prescription. This review summarizes the principles of formulating prescription, development strategy, and technical requirements specification of FDCs.

Key words: Development of FDCs, Drug interactions theory, Multi-factor and multi-level analysis technology, Principles of formulating prescription, Technical requirements specification

中图分类号:

R965.1

袁秉祥, 陈莉娜, 王冰. 复方药品创新研发策略[J]. 中国临床药理学与治疗学, 2013, 18(10): 1175-1181.

YUAN Bing-xiang, CHEN Li-na, WANG Bing. Strategy of fixed-dose combination innovative development[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2013, 18(10): 1175-1181.

参考文献

[1] 罗国安, 梁琼麟, 刘清飞, 等. 复方药物研发创新体系展望[J]. 世界科学技术-中医药现代化, 2009, 11(1):3-10.
[2] Khanna I. Drug discovery in pharmaceutical industry: productivity challenges and trends [J]. Drug Discov Today, 2012, 17(19/20):1088-1102.
[3] Wahlqvist ML, Lee MS, Chuang SY, et al. Increased risk of affective disorders in type 2 diabetes is minimized by sulfonylurea and metformin combination: a population-based cohort study [J]. BMC Med, 2012, 10(1):150.
[4] Xu TJ, Yuan BX, Zou YM, et al. The effect of insulin in combination with selenium on blood glucose and GLUT4 expression in the cardiac muscle of streptozotocin-induced diabetic rats [J]. Fundam Clin Pharmacol, 2010, 24(2):199-204.
[5] Trottier B, Machouf N, Thomas R, et al. Abacavir/lamivudine fixed-dose combination with ritonavir-boosted darunavir: a safe and efficacious regimen for HIV therapy [J]. HIV Clin Trials, 2012, 13(6):335-342.
[6] Ward D, Grant R. Rilpivirine/tenofovir/emtricitabine fixed-dose combination is an efficacious and well-tolerated “switch” regimen for patients on therapy [J]. J Int AIDS Soc, 2012, 15(6):18351.
[7] Inoue M. Tighter control of postprandial hyperglycemia with mitiglinide/voglibose fixed-dose combination in Japanese patients with type 2 diabetes mellitus [J]. Expert Opin Pharmacother, 2012, 13(16):2257-2268.
[8] Williams SA, Buysman EK, Hulbert EM, et al. Hemoglobin A1c outcomes and health care resource use in type 2 diabetes mellitus patients treated with combination oral antidiabetic drugs through step therapy and loose-dose and fixed-dose combinations [J]. Manag Care, 2012, 21(7):40-48.
[9] Kjeldsen SE, Messerli FH, Chiang CE, et al. Are fixed-dose combination antihypertensives suitable as first-line therapy [J]? Curr Med Res Opin, 2012, 28(10):1685-1697.
[10] Punzi H, Shojaee A, Maa JF, et al. Efficacy and tolerability of fixed-dose amlodipine/olmesartan medoxomil with or without hydrochlorothiazide in Hispanic and non-Hispanic patients whose blood pressure is uncontrolled on antihypertensive monotherapy [J]. Ther Adv Cardiovasc Dis, 2012, 6(4):149-161.
[11] Taylor AA, Ragbir S. Three in one: safety, efficacy, and patient acceptability of triple fixed-dose combination medicine in the management of hypertension [J]. Patient Prefer Adherence, 2012, 6:555-563.
[12] Hatala R, Pella D, Hatalová K, et al. Optimization of blood pressure treatment with fixed-combination perindopril/amlodipine in patients with arterial hypertension [J]. Clin Drug Investig, 2012, 32(9):603-612.
[13] Angiolillo DJ, Hwang C, Datto C, et al. Impact of a fixed-dose combination of naproxen and esomeprazole magnesium on serum thromboxane B2 inhibition by low-dose aspirin over 5 days in healthy adults: a phase I, randomized, double-blind, placebo-controlled, noninferiority trial [J]. Clin Ther, 2011, 33(12):1883-1893.
[14] 刘宇, 张明升. 影响血液及造血系统药[M] //袁秉祥, 臧伟进,主编.图表药理学. 北京: 人民卫生出版社, 2010:104-109.
[15] Teo KK, Liang Y. Polypill: lights and shadows [J]. Curr Hypertens Rep, 2010, 12(4):276-281.
[16] Reichmann H, Emre M. Optimizing levodopa therapy to treat wearing-off symptoms in Parkinson's disease: focus on levodopa/carbidopa/entacapone [J]. Expert Rev Neurother, 2012, 12(2):119-131.
[17] Gupta SK, Sosler S, Lahariya C. Introduction of Haemophilus influenzae type b (Hib) as pentavalent (DPT-HepB-Hib) vaccine in two states of India [J]. Indian Pediatr, 2012, 49(9):707-709.
[18] 黄晓晖, 谢海棠, 史军, 等. 现代定量药理学的研究进展及展望[J]. 中国临床药理学与治疗学, 2009, 14(6):601-612.
[19] 蔡周权, 代勇, 李明芬. 正交设计法在药物制剂研究中的应用进展[J]. 现代医药卫生, 2005, 21(24):3395-3396.
[20] 方开泰. 均匀设计——数论方法在试验设计的应用[J]. 应用数学学报, 1980, 3(4):363-372.
[21] Zheng QS, Sun RY. Quantitative design of drug compatibility by weighted modification method [J]. Acta Pharmacologica Sinica, 1999, 20(11):1043-1051.
[22] 徐为人, 汤立达. 加强成药性综合评价提高我国新药创制效率[J]. 中国医药技术经济与管理, 2007, 1(7):6-12.
[23] ICH. International Conference on Harmonization (ICH) - Draft Guidance: E12A Principles for Clinical Evaluation of New Antihypertensive Drugs [S]. ICH Steering Committee, 2 march, 2000.
[24] EMA. Guideline on clinical investigation of medicinal products in the treatment of hypertension [S]. London, 18 November, 2010. EMA/238/1995/Rev. 3.
[25] NIH. JNC 7 Express: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and treatment of High Blood Pressure [S]. U. S. National Institute of Health-National Heart, Lung, and Blood Institute, NIH Publication No. 03-5233, May 2003.
[26] 中国高血压防治指南修订委员会. 中国高血压防治指南2010 [J]. 中华高血压杂志, 2011, 19(8):701-743.
[27] EMEA. Guidance on the non-clinical development of fixed combinations of medicinal products (draft) [S]. London, 13 October, 2005. CHMP /EMEA/CHMP /SWP /258498 /2005.
[28] EMEA. Guidance on the non-clinical development of fixed combinations of medicinal products [S]. London, 24 January, 2008. EMEA/CHMP /SWP /258498 /2005.
[29] 郑青山, 何迎春, 杨娟, 等. 药物相互作用分析与复方药效模拟: 一个方法学研究[J]. 中国药理学通报, 2007, 23(8):1106-1112.