孙鹤FDA植物药有关问题2.ppt

科技部中医药国际化培训项目 MOST TCM Globalization Training “中国医药国际化－FDA注册法规与技术要求” The Critical Path in Botanical Drug Development for Global Market 2007年 3月8～10日 Considerations Marketing history Dosage form and formulation complexity Active constituent Available analytical methods Proposed indication Clinical benefit-risk ratio Ability to replicate study results Generic copies Regulatory issue Clinical Pharm. and Biopharm. Active constitute, marker or major components Bioavailability and bioequivalence Pharmacokinetics considerations Pharmacodynamic considerations Drug-drug interactions Dose adjustment in sub-population Other Biopharmaceutical Issues Example Multiple constituents in Ginkgo Leaf Single active constituent unidentified PK profile differs among known active constituents: Ginkgolide A, t1/2=4.5 hours Ginkgolide B, t1/2=10.6 hrs Bilobalide, t1/2=3.2 hr Special concerns These factors may modify: Product consistency Product stability Chemical structures Analytical methods Pharmacological effects Pharmacokinetic profiles other in vitro, in vivo variabilities PK considerations (1) When active constituent(s) of a botanical product is(are) clearly identified Pharmacological effects well identified Purified constituents for better CMC and clinical use Measurement of multiple constituents may be needed PPE may as it is for synthetic drug substances Example Factors modifying the PK of Quinine Age (t1/2 increase as age increase) Renal function (RF decrease, CL decrease) Hepatic function (nearly unchanged) disease (Camx increase in malaria patients) Smoking (CL increase) Dietary (vegetarian has decreased CL) Drug interaction (rifampicin increases CL) PK considerations (2) When active constituent(s) of a botanical drug is(are) not identified Concentration vs. time measurement for active constituent is not practical Measurement of multiple markers may be needed Acceptable analytical method may not be available Alternative PPE methods may be used Exa