Book chapters in “ Non-Biological Complex Drugs - The Science and the Regulatory Landscape ” Introduction : Defining the Position of Non-Biological Complex Drugs Iron Carbohydrate Complexes : Characteristics and Regulatory Challenges

Abstract

Albumin is a key plasmic carrier of hydrophobic molecules and is highly accumulated in tumors. Nanoparticle albumin bound (nab) technology is a nanoparticle drug delivery platform that utilizes the unique transport and binding properties of albumin to achieve enhanced tumor penetration and accumulation of albumin-bound hydrophobic drugs while eliminating the need for toxic solvents coadministered with poorly soluble drugs. The first product in the nab drug family and the first protein nanotechnology-based chemotherapeutic approved by the US Food and Drug Administration and the EMA is nab-paclitaxel (Abraxane®, ABI- 007; manufactured by Celgene Corporation, Summit, NJ). It is a Cremophor-free, albumin-bound nanoparticle formulation of paclitaxel with a mean particle size of approximately 130 nm. A proprietary process combines paclitaxel with albumin to create a colloidal suspension of nanoparticles. Paclitaxel and albumin are not covalently linked but rather associated through hydrophobic interactions. The particles of paclitaxel are in a noncrystalline, amorphous, readily bioavailable state, allowing for rapid drug release from the particles following intravenous administration. Nanoparticles of nab-paclitaxel are complex three dimensional constructs that require careful design and engineering, detailed orthogonal analysis methods, and a reproducible scale-up and manufacturing process to achieve a consistent product with the intended physicochemical characteristics, biological behavior, and pharmacological profiles. Due to its complexity, the safety and efficacy may be influenced by minor variations in the physicochemical properties or the manufacturing process and needs to be carefully examined in preclinical and clinical studies. Preclinical and clinical studies have demonstrated that nanoparticlebased nabpaclitaxel displays distinct pharmacokinetics (PK) and biodistribution profiles compared with conventional Cremophor-paclitaxel. nab-Paclitaxel exhibits a linear PK profile with faster clearance and increased volume of distribution, whereas Cremophor-paclitaxel forms micelles leading to prolonged exposure to the systemic circulation, slower tissue distribution, and increased drug toxicity. In preclinical and clinical studies, nab-paclitaxel demonstrated an increased antitumor efficacy and an improved safety profile compared with Cremophor-paclitaxel. Based on significant clinical benefit in pivotal trials, nab-paclitaxel has been approved for use in …