PK Versus PD Consider the following situations Appropriate transportation v Metabolism-activated pro-drugs Pharmacogenetics OSOCH3 OLOCH3 N >P4502c19 HOOC Lack of efficacy Cl HS Cl White 2% clopidogre Black 4% Sales of $9B active metabolites Chinese 14% worldwide in 2010 SANOFI Platelet ADP receptor A Bristol-Myers squibb P2Y12 antagonist Together we can prevail
PK versus PD Pharmacogenetics P450 2C19 clopidogrel Platelet ADP receptor P2Y12 antagonist active metabolites Lack of efficacy White 2% Black 4% Sales of $9B Chinese 14% worldwide in 2010 Consider the following situations： Appropriate transportation Metabolism-activated pro-drugs
食物药物相互作用 (Food-drug interactions Grapefruit-drug interactions 抑制CYP3A4,P-糖蛋白及 OATPs 至少与85种药物发生相互作用 benzodiazepines, ritonavir, sertraline.) 需考虑食物-药物相互作用潜力的药物 CYP3A4底物 生物利用度低 Other food-drug interactions: alcohol, nicotine, caffeine
食物药物相互作用 （Food–drug interactions） Grapefruit–drug interactions • 抑制CYP3A4，P-糖蛋白及OATPs • 至少与85种药物发生相互作用 （benzodiazepines, ritonavir, sertraline…） 需考虑食物-药物相互作用潜力的药物： • CYP3A4底物 • 生物利用度低 Other food-drug interactions: alcohol, nicotine, caffeine, …
PK versus Safety Consider the following situations v Fast elimination v Rapid distribution to other non target tissues (Distribution) (Metabolism Accumulation) Morphine administration is In the United states and the associated with both analgesia and United Kingdom, paracetamol constipation toxicity is the most common The blood's ability to clot must be cause of acute liver failure carefully monitored while a person The grey syndrome has occurred takes warfarin in premature and other newborn infants receiving large doses of chloramphenicol
PK versus Safety Consider the following situations： Fast elimination Rapid distribution to other nontarget tissues (Distribution) • Morphine administration is associated with both analgesia and constipation • The blood's ability to clot must be carefully monitored while a person takes warfarin. （Metabolism & Accumulation） • In the United States and the United Kingdom, paracetamol toxicity is the most common cause of acute liver failure. • The grey syndrome has occurred in premature and other newborn infants receiving large doses of chloramphenicol
Pier The Long Path from Idea to Drug Registrations Clinical Data Analysis 1 New Medicine S800MM Full Development DA△MAA 121yr Studies in 100-300 Source: Burial Patients(Phase ll) Candidate Medicine Tested in Company 3-10, 000 Patients(Phase ll) Candidate Medicine Studies in Healthy Exploratory Develpment In vivo Efficacy Project Team safety nd Plans Synthesis Screening Project Discovery Concept Complex Targets, Instability, PK, Safety, Efficacy, Selectivity, Synthesis 100 Approaches Manufacture, Commercial Failure is 75% cost of drug
类药性的意义 理化性质 分子量、氢键数(极性 表面积)、亲脂性、熔 点、水溶解性、可旋 转键数(分子柔性) 药代动力学性质 生物利用度(F),血药 浓度峰值(c),达 峰时间(Tmx),半衰 期(T12),清除率 表观分布容积 (Va)
类药性的意义 理化性质 分子量、氢键数（极性 表面积）、亲脂性、熔 点、 水溶解性、可旋 转键数（分子柔性） 药代动力学性质 生物利用度(F)，血药 浓度峰值（Cmax），达 峰时间（Tmax），半衰 期（T1/2），清除率 （CL），表观分布容积 （Vd）