Early Development of Therapeutic Biologics - Pharmacokinetics

Abstract

Modern biologics are biotechnology-derived pharmaceuticals. They are mostly used for diagnosis, prevention and treatment of serious and chronic diseases. Today, therapeutic biologics range from traditional biologics like blood and blood components, fractionated blood products, and antitoxins to modern biologics such as monoclonal antibodies, cytokines (e.g. interferon, interleukine), tissue growth factors, vaccines directed against non-infectious disease targets, and gene transfer products. Chemical as well as pre-clinical development are major challenges for biologics due to their different physicochemical properties (mostly protein structure) compared to small molecules. They demonstrate much more complex pharmacokinetic behaviour, which strongly influences their pre-clinical testing strategy. Biologics are often highly species-specific in action and immunogenic in test animal species and humans. Immunogenicity of therapeutic biologics may influence their pharmacokinetic behaviour as well as pharmacodynamics and toxicity. Biologics are frequently regulated by different procedures compared to small molecules. New guidances are evolving which reflect the rapid development of new technologies in this field. Bioanalytical method development and validation is a prerequisite not exclusively for pharmacokinetic studies but for the whole pre-clinical and clinical development. Due to their unique properties, different kinds of bioanalytical assays (mass assays, activity assays, immunogenicity assays) are necessary in early development of biologics.

Site-specific enzymatic polysialylation of therapeutic proteins using bacterial enzymes

“…In rodents, the halflife of glycosylated A1AT is much shorter, with values in the literature ranging from 3-20 h (33-35). Biologics often demonstrate complex and species-specific pharmacokinetic profiles compared to small molecules due to their unique physiochemical properties (36). In this study, the half-life of injected A1AT in mice was in the order of hours, but through polysialylation of existing glycan structures, the half-life was extended to days without any loss of in vitro protease inhibitor activity.…”

Migraine, Neurogenic Inflammation, Drug Development - Pharmacochemical Aspects

“…The development of such monoclonal antibodies represents a great challenge compared to that of small molecules as their immunogenicity influences the pharmacokinetic properties and their toxicity. Therefore, different types of bioanalytical assays are needed for their early development [72]. Another disadvantage might be the result of systemic immunological presenting as an immune response against the therapeutic protein.…”

Review article: The pharmacokinetics and pharmacodynamics of drugs used in inflammatory bowel disease treatment

“…Pharmacokinetics and pharmacodynamics The bioavailability of anti-TNF and anti-IL-12/23 monoclonal antibodies after subcutaneous and intramuscular administration [infliximab (IFX) is administered intravenously] is often low to intermediate, being explained by the proteolytic degradation of the mAb in the interstitial fluid or the lymphatic system: adalimumab (ADL) 64 %, certolizumab pegol (CZP) 80 %, golimumab (GLM) 53 % and ustekinumab (UTK) 57 % [211]. mAbs have only a very limited ability to distribute from the blood compartment to the peripheral tissue by diffusion.…”