Recent advances in pharmaceutical biotechnolgy have successfully proven to be a life-changing and quality-driven on treatment regimens for many who suffer from chronic illnesses, such as diabetes, autoimmune disseases and cancer. Monoclonal antibodies are an important group of therapeutic proteins with a specific mechanism of action. In comparison with intravenous delivery subcutaneous administration offers many key advantages. Delivery and absorption of monoclonal antibodies, distinctly after subcutaneous administration, represent notable challenge due to the higher molecular weight of molecules in comparison with other therapeutics and their susceptibility to degradation.
Drug absorption model is a tool that can be developed to predict bioavailability of the active pharmaceutical ingredient. There are many existing absorption models for small molecules (solid dosage forms for per os use), as well as pharmacopoeial tests and extensive data from years-long practice. Unfortunately, treatments with biologics are quite new and still in development and under constant monitoring, therefore not enough data and studies have been conducted. High binding affinity of monoclonal antibodies to their pharmacological targets often leads to non-linear distribution and elimination patterns (dose-dependant and target dynamics). Poor correlation between preclinical outcomes with human is common due to interspecies physiological and anatomical variability, as due to the higher injection volumes used in preclinical species (respective to their total body surface area). Despite the fact that allometric scaling has been successfully used to predict clearance of monoclonal antibodies its use in absorption and bioavailabilty prediction was often disputed.
A systematic literature review of already existing studies and meta-analysis was conducted using a well-defined search profile. Actual absorption models could not be established withing this Master's thesis, hence we tried to point out some of the key knowns and unknowns of this field. A comprehensive evaluation of several factors influencing absorption has been carried out with influence of physiology and interspecies scaling as well as formulation properties with excepients brought to the front.
Local metabolism, degradation, drug/formulation precitpation and early elimination of the drug during its transit through the lymphatics before reaching systemic circulation are some of the reasons for incomplete subcutaneous bioavailability (< 100%). Morphology differences, such as presence of panniculus carnosus (a striated muscle present in subcutis of lower animal species), and tissue mobility (furred animals) contribute to poor correlation of bioavailability with humans.
Neonatal Fc receptor (FcRn) has an important role in mediating the long circulating half-life of endogenous IgG and albumin by salvaging the IgG and albumin mediated by pH-dependant mechanisms.
|
