生物技术药物的药代动力学特点及检测.pptxVIP

生物技术药物的药代动力学特点及检测第1页/共41页 Selected Blockbuster Protein Pharmaceuticals第2页/共41页 生物技术药物重组蛋白多肽类单克隆抗体及其片断寡核苷酸疫苗制剂基因治疗药物（核酸制剂）干细胞药物？第3页/共41页 蛋白肽类药物药代动力学吸收分布代谢与排泄第4页/共41页 蛋白肽类药物吸收小分子多肽：被动吸收大分子多肽：水溶性：细胞间隙脂溶性：膜脂扩散胞饮淋巴系统吸收：po干扰素；高度脂溶性？影响蛋白肽类药物吸收因素药物稳定性；细胞渗透性：MW1000，鼻粘膜》肠粘膜第5页/共41页 Correlation between MW and the cumulative recovery of sc rINF alpha-2a, cytochrome c, inulin and 5-fluoro-2 -deoxyuridine (FUDR) in the efferent lymph in sheep第6页/共41页 蛋白肽类药物吸收非肠道给药( Parenteral Route)：IVM＝SC＝IP鼻腔肺直肠回肠阴道颊口服鼻腔给药(Intranasal administration);Inhale administration;口服给药(Oral administration )Peroral administration经皮给药(Transdermal administration);其他给药途径: 结肠、回肠、子宫、阴道、颊、眼睛等。第7页/共41页 IM 和SC给药生物利用度IM AdministrationDrugBioavailability (%)Alefacept63Interferon alpha-2a80Triptorelin83SC AdministrationDrugBioavailability (%)Anakinra95Cetrorelix85Darbepoetin37Follitropin66Ganirelix91Interferon beta-1b50Teriparatide95第8页/共41页 Pharmacokinetics of IM ADI-SS PEG 20,000 mw in humans with hepatocellular carcinoma第9页/共41页 Intranasal administration易给药；鼻粘膜上皮细胞有大量的微绒毛和广泛分布的血管淋巴管；无肝首过效应；伪首过效应(Pseudo－first－pass effect)；多肽、蛋白酶（主要是氨肽酶）；calcitonin, oxytoxin, LH-RH, growth hormone, interferone, vaccines；分子量up to 2 KDa: pharmacologically acitive；血脑屏障：IGF-1。第10页/共41页 Inhalation administrationEase of administrationlarge surface area (75 m2)High vascularityBypass of first-pass metabolism Insulin for Type II diabetesDornase-alpha for cyctic fibrosisProteases in the lungLocal effectsEffect of molecular weight?第11页/共41页 Plasma bioavailability of therapeutic peptides versus MW after pulmonary administration第12页/共41页 Oral administrationGenerally not therapeutically active;Factors for lack of systemic bioavailability:high gastrointestinal enzyme activitygastrointestinal mucosa as an absorption barrier;cytochrome P450 3A and p-glycoprotein activityAvailable oral forms: cyclosporine (30%) and desmopressin (0.16%);Absorption enhancers; encapsulation in microparticles or nanoparticles.第13页/共41页 蛋白肽类药物的分布分布容积小：0.04-0.2 L/kg vs. 1