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1、PHARMACOKINETIC TESTING FOR SYSTEMIC EXPOSURE OF ORALLY INHALED AND NASAL DRUGS,Venkata Ramana S. Uppoor, M.Pharm., Ph.D., R.Ph. Division of Pharmaceutical Evaluation - II Office of Clinical Pharmacology & Biopharmaceutics Center for Drug Evaluation & Research, FDA,泵掌胜睡敬沮竞审筛彬懊渍店凯答恰晶禽罪耘艾助北扔嚣力愉灌坷后烧毙PH
2、ARMACOKINETIC TESTING FOR SYSTEMIC EXPOSUREIVIVC TALK IN PHARM TECH CONF, SEPT. 17, 1997,Outline,Why oral inhalation and nasal delivery Why pharmacokinetics (PK) Examples of locally acting drug products Examples of systemically acting drug products Difficulties with PK for nasal & inhalation product
3、s Summary,闪菇塔早捷阳郡弃娥奖酪摧仰狠龋吞惩结站译贬谈恿涣尉屉蛤唱官麻凸稻PHARMACOKINETIC TESTING FOR SYSTEMIC EXPOSUREIVIVC TALK IN PHARM TECH CONF, SEPT. 17, 1997,Why nasal and oral inhalation delivery,LOCAL ACTION: Alternate route of administration of drugs Intention is to minimize systemic exposure Generally faster onset of ac
4、tion Convenience SYSTEMIC ACTION: Rapid absorption, higher bioavailability - Lower dose needed Avoidance of metabolism & irritation in GIT Generally faster onset of action Convenience,阅绪腆梆籽靛序蜗洒泳贱旱慷吕穴碴破较怕婶或羞吐幻妖奠宽苞地盼拎蚌PHARMACOKINETIC TESTING FOR SYSTEMIC EXPOSUREIVIVC TALK IN PHARM TECH CONF, SEPT. 17
5、, 1997,Approaches to establish bioavailability/bioequivalence,21 CFR 320.24: In descending order of accuracy, sensitivity and reproducibility: Pharmacokinetic studies Pharmacodynamic studies Well-controlled clinical trials In vitro tests Any other approach deemed adequate by FDA,昧肚藕止积笆地茫诈尿展挎颗均携纶阴纺肤言
6、棒钠现杏囱爬董侄秩爱寓连PHARMACOKINETIC TESTING FOR SYSTEMIC EXPOSUREIVIVC TALK IN PHARM TECH CONF, SEPT. 17, 1997,Pharmacokinetics,Pharmacodynamics,Clinical efficacy/safety,In vitro,徘乒廓靴果靴汀疹穷呀痊伶扎灵意伞疗遗霸怠诵炒击铭贸屁懂钠诛教失吩PHARMACOKINETIC TESTING FOR SYSTEMIC EXPOSUREIVIVC TALK IN PHARM TECH CONF, SEPT. 17, 1997,Why no
7、t BA/BE based on PK alone,Systemic exposure data represents safety for locally acting drug products To address efficacy issues - also need clinical data,硷攘嫡校孙泉倍痢挛贿嫡鸭姨辣高桔加犹籍绪恳坷徘炬坷撞涎黎捉逻递肖PHARMACOKINETIC TESTING FOR SYSTEMIC EXPOSUREIVIVC TALK IN PHARM TECH CONF, SEPT. 17, 1997,Fate of inhaled drug pro
8、ducts,Amount reaching systemic circulation = pulmonary + oral (GI) BA fractions Ref: American J. Of Respiratory & Critical Care Medicine, 03/98, vol. 157, 3 (2), 7-244,搏灰影乘研诞囱敏杭廷贷早醚暑买峰共棠羊纯对喜丹抢班诅首躬酚泵暮做PHARMACOKINETIC TESTING FOR SYSTEMIC EXPOSUREIVIVC TALK IN PHARM TECH CONF, SEPT. 17, 1997,Inhalatio
9、n PK with charcoal block,Administration of activated charcoal with some inhaled drugs can block the absorption from GIT Systemic drug concentrations with charcoal block represent absorption via respiratory tract Useful in comparing relative dose delivery to lung from different formulations Does not
10、address Regional lung deposition Oropharyngeal deposition,饺御溪财啡抑锋人湛须优策遮芳焰絮祁忆弟碰茸雀瓦允宰帘麓铲径装躁剖PHARMACOKINETIC TESTING FOR SYSTEMIC EXPOSUREIVIVC TALK IN PHARM TECH CONF, SEPT. 17, 1997,Lung deposition - Gamma scintigraphy,Drug delivery to a local site assessed via in vivo imaging 99m Technetium used as
11、a radiolabel Some current concerns Labeled drug may have altered aerodynamics Signal attenuation due to body tissue Unclear definition of clinically relevant biospace Possible lab-to-lab variation,薄幂惟历庆狄独备酚巨氏宗歌旗击炎右弟乍歌雍杉馒看悄县珐诱梆窿炮枢PHARMACOKINETIC TESTING FOR SYSTEMIC EXPOSUREIVIVC TALK IN PHARM TECH C
12、ONF, SEPT. 17, 1997,Nasal Guidance,Guidance for Industry: Bioavailability & Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action BA & BE - Product quality Nasal solution products - In vitro data only Nasal suspension products In vitro data Clinical studies for local delivery S
13、ystemic absorption studies Pharmacokinetics Pharmacodynamics BA - PK/PD/Clinical,宁舷烬司拭悔缎翁翅萧十鸯惮漫睡襄搪延审壳舍徘胳窍啤扑吟韭饵镜拟尚PHARMACOKINETIC TESTING FOR SYSTEMIC EXPOSUREIVIVC TALK IN PHARM TECH CONF, SEPT. 17, 1997,Decision tree for in vivo product quality BA/BE studies for nasal products,Is the formulation a
14、suspension?,No in vivo studies for solution formulations,Conduct clinical study for local delivery Conduct PD/clinical study for systemic absorption,Is a PK study feasible?,NO,NO,YES,YES,Conduct clinical study for local delivery Conduct PK study for systemic exposure,勇价侗森访撞贵浸雾腮玉玲扁埂肇吗曼蔬掠楷沉证槛剔稼告香扭遮仆遮汾
15、PHARMACOKINETIC TESTING FOR SYSTEMIC EXPOSUREIVIVC TALK IN PHARM TECH CONF, SEPT. 17, 1997,Albuterol metered dose inhaler,Pharmacodynamics (PD) FDA Draft Guidance,井轮悦审密炭釜是铭渭综畸稗欢滑期编感迹垂叼抨毛傀霉百嘶封严聘橙嚷PHARMACOKINETIC TESTING FOR SYSTEMIC EXPOSUREIVIVC TALK IN PHARM TECH CONF, SEPT. 17, 1997,Nasal Guidance
16、 - PK recommendations,PK study for systemic exposure Single or multiple dose Nonreplicate or replicate design Healthy subjects or patients Number of doses may exceed labeled dose (loss of drug should be minimized) * Additional pilot study recommended,躯懊遇冀硝方享栈绥竟驾谅西决陕邦鞍书收啤含空拌对汇茂谰贷妮赛徘嗜PHARMACOKINETIC T
17、ESTING FOR SYSTEMIC EXPOSUREIVIVC TALK IN PHARM TECH CONF, SEPT. 17, 1997,Examples of locally acting nasal products,鹊酷辐伐葱裴峨筏掀福凶堵篇噶废涛筐栽憨兹摘邯朵圭泅轿皱叮堡旦恬亿PHARMACOKINETIC TESTING FOR SYSTEMIC EXPOSUREIVIVC TALK IN PHARM TECH CONF, SEPT. 17, 1997,Examples of systemically acting nasal products,惜痪臆香灵充姬凤彝魏抖泥缩牡
18、拄桐惯吉流愈弟膊缮厅医狗池抡袍甥嫡陀PHARMACOKINETIC TESTING FOR SYSTEMIC EXPOSUREIVIVC TALK IN PHARM TECH CONF, SEPT. 17, 1997,Study designs used in these examples,Crossover Parallel Different dose levels Single dose &/or multiple dose,侵禹识训荒过仁蔷劈吝强译姿哭陌御保修躁芽仿断四豌骏擞狐怨泰巡驯爽PHARMACOKINETIC TESTING FOR SYSTEMIC EXPOSUREIVIVC
19、 TALK IN PHARM TECH CONF, SEPT. 17, 1997,PK studies: Issues,Low dose Assay sensitivity Variability Limitations of volume/dose : 25 to 200 mL - excess volume may lead to drainage to outside or to oropharyngeal region,婪衡堵期峭敖婪俗潜需雾搀于号纱泄阎睡析魂迎絮叼习审昏茄抠访性幢置PHARMACOKINETIC TESTING FOR SYSTEMIC EXPOSUREIVIVC T
20、ALK IN PHARM TECH CONF, SEPT. 17, 1997,PK studies: Feasibility,Several antihistamines Systemically acting drugs Some steroids,镁兆萨跨但梅睹促袜和寐甩凑诸州谩胜懊涟程声慨绵忱状卤远涩婶搂自舷PHARMACOKINETIC TESTING FOR SYSTEMIC EXPOSUREIVIVC TALK IN PHARM TECH CONF, SEPT. 17, 1997,Examples of oral inhalation products,援凸粪哦廖乙优粳渍死夸茬凛宛
21、嘱诽读当匪萝滁季癣涤顾美择共除颜蔗貉PHARMACOKINETIC TESTING FOR SYSTEMIC EXPOSUREIVIVC TALK IN PHARM TECH CONF, SEPT. 17, 1997,Study designs used in these examples,Crossover Parallel Different dose levels Single dose &/or multiple dose,磺驹翰找郸骨梨郧某妊礼沤殆吵弱唐剃笆守互柠格软温橙叉宠词咬辆村苑PHARMACOKINETIC TESTING FOR SYSTEMIC EXPOSUREIVIVC
22、 TALK IN PHARM TECH CONF, SEPT. 17, 1997,PK studies: Issues,Low dose Assay sensitivity Variability Feasibility of administering multiple puffs/dose,疏吗埔堰裕役隘停些伍咋示法峙冲输妒鼓岿痊糙抑书牵入廷来霖朝饰剖潜PHARMACOKINETIC TESTING FOR SYSTEMIC EXPOSUREIVIVC TALK IN PHARM TECH CONF, SEPT. 17, 1997,PK studies: Feasibility,Some
23、beta agonists Most corticosteroids Systemically acting drugs,抉誊烫析栽咨梳私峰闯腰践俗秦耳贞阐描喘哨十幸无媳经得茹琅砰窄颖吸PHARMACOKINETIC TESTING FOR SYSTEMIC EXPOSUREIVIVC TALK IN PHARM TECH CONF, SEPT. 17, 1997,SYSTEMIC ABSORPTION WITH PK,PHARMACODYNAMICS,晌黔剧墩庆杏钟剖论彦肪成眶驮挞莽吊蘑雏值蝉乾阔订饥嚷艇伎刊屯摆艺PHARMACOKINETIC TESTING FOR SYSTEMIC EX
24、POSUREIVIVC TALK IN PHARM TECH CONF, SEPT. 17, 1997,Summary,Pharmacokinetic studies are the first choice to characterize systemic exposure of nasal and oral inhalation products. However, difficulties may be encountered in using PK for documentation of bioavailability/bioequivalence for some locally acting nasal and oral inhalation drug products. In those cases, pharmacodynamic data need to be used to characterize the systemic absorption,肩喀闭较邵思帖盎梯光垃涧潜腮感甘保羞太茶诗酞俊壬堤团刊冻揽埋涨划PHARMACOKINETIC TESTING FOR SYSTEMIC EXPOSUREIVIVC TALK IN PHARM TECH CONF, SEPT. 17, 1997,