Philippart M, Schmidt J, Bittner B
Department of Pharmaceutical Sciences, University of Utrecht, Utrecht, Netherlands.
F. Hoffmann-La Roche Ltd., Global Product Strategy, Product Optimization, Basel, Switzerland.
Drug Res (Stuttg). 2016 Mar;66(3):113-20. doi: 10.1055/s-0035-1559654. Epub 2015 Nov 4.
Since the early 1980s, therapeutic proteins and peptides have become established as an important class of pharmaceuticals. Due to their low oral bioavailability, which results from pre-systemic degradation and poor gastrointestinal absorption, most therapeutic proteins and peptides are administered intravenously. While subcutaneous formulations of some therapeutic proteins and peptides have been shown to improve patient convenience and reduce medical resource utilization, oral administration is generally the preferred administration route. Some therapeutic proteins and peptides employing novel oral delivery technologies have reached late-stage clinical development. To develop a new oral formulation of a therapeutic protein or peptide currently marketed as an injectable product, technical, nonclinical, and clinical studies are required to demonstrate similar safety and efficacy compared with the existing administration route. Since there is little experience with oral therapeutic proteins and peptides, this review provides recommendations for bridging from an approved intravenous or subcutaneous regimen to novel oral administration of the same therapeutic protein or peptide, based on precedents from intravenous-to-subcutaneous bridging approaches for trastuzumab, rituximab, tocilizumab, and bortezomib. If the pharmacokinetic/pharmacodynamic relationship is well characterized, demonstration of comparability in prespecified pharmacokinetic parameters might form a basis for establishing similar efficacy and safety of the oral formulation vs. the reference product. Although oral administration of therapeutic proteins and peptides remains challenging, given recent progress with novel delivery technologies, intravenous/subcutaneous-to-oral nonclinical and clinical bridging programs may soon be utilized to support approval of new oral formulations.
自20世纪80年代初以来，治疗性蛋白质和肽已成为一类重要的药物。由于其口服生物利用度低，这是由全身前降解和胃肠道吸收不良导致的，大多数治疗性蛋白质和肽通过静脉注射给药。虽然一些治疗性蛋白质和肽的皮下制剂已被证明可提高患者便利性并减少医疗资源利用，但口服给药通常是首选的给药途径。一些采用新型口服给药技术的治疗性蛋白质和肽已进入临床后期开发阶段。要开发一种目前作为注射剂销售的治疗性蛋白质或肽的新型口服制剂，需要进行技术、非临床和临床研究，以证明与现有给药途径相比具有相似的安全性和有效性。由于口服治疗性蛋白质和肽的经验很少，本综述基于曲妥珠单抗、利妥昔单抗、托珠单抗和硼替佐米从静脉注射到皮下给药的桥接方法的先例，为从批准的静脉注射或皮下给药方案过渡到相同治疗性蛋白质或肽的新型口服给药提供建议。如果药代动力学/药效学关系得到充分表征，在预先指定的药代动力学参数中证明可比性可能构成确立口服制剂与参比产品具有相似疗效和安全性的基础。尽管治疗性蛋白质和肽的口服给药仍然具有挑战性，但鉴于新型给药技术的最新进展，静脉注射/皮下给药到口服的非临床和临床桥接方案可能很快会被用于支持新型口服制剂的批准。
