Biologics are defined as therapeutic agents that are produced from living organisms by recombinant DNA technology, chemical synthesis by the use of nucleotides or amino acids and manufacturing by biotechnological processes. The development of the biologics is a major advancement in the medicine as they are a huge success.
When compared to the small drug molecules the pre-clinical toxicity and safety remains a challenge in the development of the biologics . Pharmacokinetics of Biologics: The biologics have unique Absorption, distribution, metabolism and elimination (ADME) characteristics when compared to the small molecules.
This in turn will lead to significant differences in the development of biologics . Absorption: Biologics have very negligible oral bioavailability. It is mainly because of their large molecular weight, polarity, limited chemical stability and enzymatic degradation of biologics in the gastrointestinal tract. Various drug delivery strategies of biologics are been under investigation like chemical modifications, formulation vehicles, absorption enhancers and encapsulation of biologics molecules into nanoparticles.
So non-invasive routes like oral, nasal, ophthalmic, transdermal and pulmonary routes are important for the delivery of biologics. The main mode of delivery of biologics is by parenteral administration, i. e they can be administered through intravenous (IV), subcutaneous (SC) and intramuscular (IM) injections.
The Tmax values are high for the biologics following the subcutaneous and intramuscular administrations when compared to the small molecules because of their large 1 | P a g e molecular size. The main reason for this longer Tmax values can be attributed to the slow lymphatic uptake . Distribution: The biologics have relatively limited distribution because of their large molecular size, charge, route of administration.
They have slow distribution from the blood to the peripheral tissue. Biologics like monoclonal antibodies distribute from blood into the peripheral tissue by a process called convective transport through capillary walls. Another process called transcellular trafficking is also responsible for the distribution of monoclonal antibodies. The transcellular movement is generally initiated by three processes namely fluid phase pinocytosis, receptor mediated endocytosis and phagocytosis. The fluid phase pinocytosis is a major pathway through which the monoclonal antibodies enter the endothelial cells.
When these monoclonal antibodies enter the endothelial cells then FcRn recycling pathway will help in bidirectional transport either into interstitial space or the vascular space. As a result of the tight binding between the monoclonal antibodies and its target their tissue distribution may not be homogenous .
Metabolism/ Elimination: Biologics like monoclonal antibodies are mainly eliminated through intracellular lysosomal proteolytic degradation and this occurs throughout the entire body whereas the small molecules are either cleared by renal excretion or hepatic metabolism. Some biologics like IgA antibodies are eliminated by biliary secretions. The biologics < 69 kDa molecular weight are mainly eliminated by renal excretion.
Generally biologics like monoclonal antibodies exhibit non-linear pharmacokinetics. The non-linear pharmacokinetic profile is mainly because of the target mediated drug disposition and linear portion of the antibody drug pharmacokinetic profile is result of Fc receptor mediated clearance . 2 | P a g e A non-specific linear clearance pathway of the biologics is mediated by the interactions between the Fc region of the antibody and the Fc receptors (FcRn and Fc? R). The FcRn is expressed throughout the body in various cells and tissues.
The Fc mediated clearance pathway is a common pathway which is shared by both endogenous IgG and exogenous monoclonal antibodies which have a functional Fc domain. These Fc receptors play a very important role in protecting the IgG from lysosomal degradation and thereby regulating the IgG levels (Fig 1) . Biologics can be metabolized in various body organs like liver, kidney, blood and extravascular sites of administration.
Hepatocytes play a vital role in the catabolism of the biologics in the liver. Biologics are not metabolized by the CYP enzymes as they metabolise the small molecules but instead are metabolized by the same pathways as that of many proteins. Biologics can be eliminated from the body by metabolism or catabolism and excretion. The reticuloendothelial system plays a very important role in the elimination of biologics such as IgG.
Factors Affecting Pharmacokinetics of Biologics: Charge: The role of charge on the pharmacokinetics and distribution of the biologics is well characterized. The non-specific clearance of the biologics is dependent on their isoelectric point (pI). When the pH is less than the pI then biologics exhibit net positive charge and at a pH higher than pI the biologics exhibit net negative charge. Any change in the charge can result in the differences in the distribution in the tissue and their kinetic profiles.
Increase in the positive charge causes increased blood clearance and tissue retention and a decrease in the 3 | P a g e positive charge results in the increased whole body clearance and decreased tissue retention . Fc Engineering: Fc engineering is the best approach to control the t1/2 of the biologics. Fc engineering is generally done by introduction of amino acid mutations and modification of Fc linked oligosaccharide structures.
The most common method to increase the t1/2 of the biologics is the attachment of the Fc domain in order to protect the biologics molecules from endosomal degradation . Glycoengineering: Glycosylation at asparagine and serine or threonine residues occurs more frequently in the biologics. It is plays a crucial role in influencing the serum t1/2 , immunogenicity and activity of the biologics.
Glycosylation plays a very important role in ADME of the biologics through several mechanisms like changing the total charge of the molecule, protecting the proteolytic sites, masking the immunogenic sites by decreasing the degradation of the molecule.
Glycoengineering plays a vital role in increasing the drug exposure by decreasing the clearance . PEGylation: The biologics molecules can be modified by covalent conjugation with the polyethylene glycol (PEG) which is a non-toxic and a non immunogenic polymer. PEGylation improves the prolonged residence of the native molecules in the body by decreasing the clearance and also from the degradation of the enzymes and thus improving the pharmacokinetic and pharmacodynamics properties.
This can help the biologics molecules to achieve maximal clinical potency . 4 | P a g e Clinical Pharmacology issues in the development of biologics: Drug- Drug interactions potential for the biologics: The drug -drug interactions between the biologics is very less common when compared to the small molecules because of the difference in the mechanisms of clearance.
The most well documented therapeutic Drug- Drug interaction mechanisms for biologics are the cytokine mediated changes in the drug metabolising enzymes. Clinical study is the most routine method to carry out studies on the drug-drug interactions of biologics. Mostly these studies include the investigation of impact of change in protein levels on the clearance of therapeutic proteins and displacement of therapeutic proteins from the binding proteins.
Factors like patient population, effect of biologics molecules on P450 enzyme, disease status are taken into consideration for determination of the Drug- Drug interactions . Issue of Immunogenicity: The use of biologics has a problem of immunogenicity. Owing to the size of the biologics and most of them being proteins or monoclonal antibodies when injected into the human body it recognizes them as foreign body particles and immune system fights against these foreign proteins.
The consequences may include loss of therapeutic efficacy of the biologics and also may sometimes lead to life threatening events . Generally a risk mitigation strategy for potential immunogenicity mediated adverse events is developed and implemented during the study and development of the biologics. It takes into account the protein structure, manufacturing process and target population . 5 |
P a g e Population specifics: i. Paediatrics: The major principle underlying the paediatric trials is to reduce the burden of trials in the paediatric population for the paediatric indications.
For example, to calculate the relative bioavailability of paediatric oral formulations it should be evaluated in the adult population instead of the paediatric population. If a paediatric pharmacokinetic study is to be conducted then it is recommended to use population pharmacokinetics and sparse sampling based on the optimal sampling theory .
If the disease progression and the exposure response is similar between the adults and the children then a different clinical development plan should be followed. If the disease progression is different in the children and adults then safety and efficacy trials should be carried out in the paediatric population. In such cases the blood that is withdrawn should be very much minimised in paediatric studies.
If a paediatric study is to be carried out then patient population instead of healthy volunteers is used. Dosing based on the body size and use of formulation and viable strength suitable for paediatric population should be used . Renal Impairment: For the biologics with molecular weight greater than 69 kDa, these molecules do not require evaluation of the effect of renal impairment for the use of licensing applications.
The effect of renal impairment on the biologics with molecular weight less than 69 kDa is not consistent . Hepatic Impairment: Hepatic impairment does not affect the exposure to biologics. It is very unlikely that the biologics will get catabolised in the liver and there are very few reports which conducted the 6 |
P a g e studies to investigate the effect of hepatic impairment on the pharmacokinetics of the biologics. One exception is a antitumour antibiotic Mylotarg. It has been found that the Mylotarg is been metabolised in the liver and a total of 11 metabolites have been found .
ii. Elderly: The clinical pharmacology reports in the elderly are very scarce. In some cases it was found that the age has an effect on the pharmacokinetic parameters of certain biologics. One example is Canakinumab which is an IgG1 based antibody. This drug has a reduced absorption rate in the elderly . Race/ Gender:
The effect of race or gender on the exposure of the biologics was found to be insignificant. The effects of race and gender are investigated as covariate on pharmacokinetic parameters using population pharmacokinetic modelling . 7 | P a g e.Figure 1: shows the protection of IgG antibody from degradation by Fc receptor . 8 | P a g e References: 1. Shi S. Biologics:
An update and challenge of their Pharmacokinetics. Current Drug Metabolism. 2014;15: 271-290. 2. Zhao L, Ren T, Wang DD. Clinical pharmacology considerations in biologics development. Acta Pharmacologica Sinica. 2012; 33:1339-1347.
3. Zhao L, Shang EY, Sahajwalla CG. Application of pharmacokinetics- pharmacodynamics/clinical response modelling and simulation for biologics drug development. Journal of Pharmaceutical Sciences. 2012;101(12):4367-4382.