15新藥安全藥理學(xué)研究及進(jìn)展-文庫吧資料
2025-01-05 14:37本頁面
【正文】 H M C H L 4 x 4拉丁方實(shí)驗(yàn)設(shè)計(jì) ICH要求 Animal ID Compound/Dose Period Dose Period 1 Day 1 Dose Period 2 Day 4 Dose Period 3 Day 8 Dose Period 4 Day 11 L H C M H M L C C L M H M C H L L H C M H M L C C L M H M C H L 4 x 8拉丁方實(shí)驗(yàn)設(shè)計(jì) ICH要求 ? Drug to increase gastrointestinal (GI) motility ? Over million prescriptions in 1996 (US) ? 34 patients TdP, 23 long QT (19931996) ? Cardiotoxicity reported when used with Ketoconazole and/or Erythromycin ? Case report of 8year old girl–intensive care ICH要求 Cisapride Story ICH要求 Drug Interactions Leading to QT? ? Drug to increase gastrointestinal (GI) motility ? Over million prescriptions in 1996 (US) ? 34 patients TdP, 23 long QT 19931996 ? Cardiotoxicity reported when used with Ketoconazole and/or Erythromycin ? Case report of 8year old girl–intensive care ? 4 deaths and 16 resuscitated from 1993 to 1996 ? Drug withdrawn from US market –July, 2023 ICH要求 Cisapride Story ? FDA remended removal of Terfenadine containing products from the market in 01/1997 ? FDA issued warning letter to Doctors about cardiac safety of Cisapride ? Postmarketing surveillance became more important – Medwatch reporting system ? Safety pharmacology guidances were approved to look at cardiovascular, respiratory and CNS sideeffects of drug candidates –ICH S7A and S7B ? Screening for QT prolongation is now an integral part of drug development (lead optimization to clinical) ICH要求 Regulatory Response “ The study results can be used to elucidate the mechanism of action and, when considered with other information, estimate risk for delayed ventricular repolarization and QT interval prolongation in humans.” ICH S7B: Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals (October 2023) ? Mechanism of action can be a goal of studies ? Use data with other data to estimate risk for QT prolongation in humans ICH要求 ICH Guideline S7B, 2023 QTc (msec) Male Female Normal 430 450 Borderline 431450 451470 Prolonged 450 470 Bazett: QTc = QT / RR Fridericia: QTc = QT / RR ICH要求 QTc Interval ICH要求 QTc Interval ?心率 ?年齡 ?性別 ?種屬 252。新藥安全藥理學(xué)研究與進(jìn)展 第二軍醫(yī)大學(xué)藥物安全性評(píng)價(jià)中心 陸國才 袁伯俊 內(nèi) 容 CFDA安全藥理研究要求 1 ICH安全藥理研究要求 2 安全藥理研究趨勢(shì)展望 3 ? 安全藥理學(xué) ：研究藥物治療范圍內(nèi)或治療范圍以上的劑量時(shí)，潛在不期望出現(xiàn)的對(duì)生理功能的不良影響 ? 次要藥效學(xué) ：主要研究藥物非期望的、與治療目的不相關(guān)的效應(yīng)和作用機(jī)制 概 念 CFDA要求 ? 核心組合試驗(yàn) (Core Battery) 中樞神經(jīng)系統(tǒng)、心血管系統(tǒng)和呼吸系統(tǒng)研究 ? 追加的安全藥理學(xué)研究（ Followup） 對(duì)中樞神經(jīng)系統(tǒng)、心血管系統(tǒng)和呼吸系統(tǒng)進(jìn)行深入的研究 ? 補(bǔ)充的安全藥
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