Pharmacokinetics and pharmacodynamics of biotechnology drugs

Slide 1: 

Pharmacokinetics and pharmacodynamics of biotechnology drugs K.JAYA RAJ KUMAR AMIST UNIVERSITY MALAYSIA

Slide 2: 

Objectives Describe the pharmacokinetics and pharmacodynamics of biotechnology drugs, including proteins and peptides, monoclonal antibodies, oligonucleotides , cancer vaccines and other immunotherapeutic agents, and gene therapy agents.

Slide 3: 

These new products include proteins, peptides, monoclonal antibodies, oligonucleotides , vaccines against microbiological and non-microbiological diseases, and gene therapy treatments. Pharmacists need to understand the pharmacokinetics and pharmacodynamics of these therapeutic products of biotechnology, which will constitute an ever increasing proportion of the medications that they will be called on to provide to patient introduction

Slide 4: 

Protein and peptide drugs in current use

Slide 5: 

Conti…

Slide 6: 

Conti…

Slide 7: 

Conti…

Slide 8: 

Only the smallest peptides in this table are administered orally. This is because large peptides and proteins are subject to degradation and inactivation in the gastrointestinal tract. Systemic bioavailability would be negligible. One drug ( becaplermin ) is applied topically (since its site of action is the surface of the skin), the table has no examples of transdermally delivered drugs. This is because the relatively large molecular weights of these compounds interfere with systemic absorption across the skin. The majority of these drugs are administered parenterally , either subcutaneously, intramuscularly, or systemically by intravenous injection or infusion. Many of the drugs in this table have very high systemic absorption from subcutaneous and intramuscular dosage forms.

Slide 9: 

An example of an inhaled protein is Dnase ( Pulmozyme ). It is an enzyme used to break down thick mucus secretions in the respiratory tracts of patients with cystic fibrosis. An inhaled protein that requires systemic absorption in order to exert its therapeutic effect is the inhalable form of human insulin, Exubera , which was on the market briefly in 2007. After administration to the lungs by dry powder inhaler, its disposition and efficacy were found to be comparable to those of subcutaneously administered insulin, while its absorption was somewhat faster. Other inhaled insulin products are in development. One small peptide, desmopressin , has sufficiently bioavailability after intranasal administration to elicit a systemic therapeutic response.

Slide 10: 

Sizes of compounds in the table range from 1 to 320 kDa . The smallest substance, oxytocin , is a peptide of nine amino acid residues that is produced by chemical synthesis. The largest compound in the table, antihemophilic factor, is a large glycoprotein produced by recombinant DNA technology. Many of the large peptides and proteins in the table were at one time extracted from blood or urine; however, in order to prevent possible infection, these are now produced recombinantly . There is even an example in the table of a recombinantly produced hepatitis B vaccine, which can claim the advantage of being ‘‘free of association with human blood or blood products. Apparent volumes of distribution of these proteins and peptides are relatively small (rarely exceeding the volume of extracellular fluid) and roughly inversely correlated with their molecular weights. However, irrespective of the value of the distribution volume, each protein is distributed to the tissue containing receptors for its therapeutic activity in an amount adequate to elicit effect. This specific distribution, though most important for effect, is often of too small in magnitude to affect the value of the overall volume of distribution.

Slide 11: 

For proteins, the total volume of distribution at steady state (representative of both central and tissue compartments) is usually not more than twice the initial volume of distribution (representative of the vasculature and the well perfused organs and tissues). Pegylation often decreases the volume of distribution of a protein drug. Several of these protein and peptide drugs have short elimination half lives, as recorded in intravenous studies. However, when these drugs are administered by subcutaneous or intramuscular injection, delayed absorption causes plasma drug concentrations to remain high for an appreciable period of time. Other drugs with short elimination half lives have been glycosylated or pegylated to increase their molecular weight and extend their half life.

Slide 12: 

Some proteins are degraded in the liver by intracellular catabolism within hepatocytes . Small polypeptides (<1 kDa ) can be transported to these cells by passive diffusion (if sufficiently lipophilic ) or by carrier-mediated 3 5 0 Basic Pharmacokinetics uptake (for more polar molecules). Receptor mediated endocytosis in the liver is important for moderate-sized proteins (50–200 kDa ), depending on surface charge or the presence of sugar molecules. Even though it has a molecular weight of 5.8 kDa , which is below that range, insulin is eliminated to a considerable extent by receptor-mediated endocytosis in the liver. The largest proteins (200–400 kDa ) are opsonized by association with immunoglobulins and then subject to phagocytosis . Protein complexes or aggregates (>400 kDa ) are also eliminated by phagocytosis .

Slide 13: 

Elimination of these drugs may be complex processes with dose-dependent, saturable pharmacokinetics. Plasma concentrations of these protein drugs may, in fact, correlate poorly with therapeutic effect. The drug may be cleared from blood not because of an elimination process but instead because it is taken up by a receptor, where it may reside for some time, exerting its therapeutic effect. The concentration of drug at this receptor will not be reflected by its blood concentration. The curve of therapeutic effect as a function of time may be temporally displaced with respect to the curve of plasma drug concentration over time, requiring the use of indirect pharmacokinetic/ pharmacodynamic modeling. Other complicating factors may be at play. For example, over time the formation of antibodies to a protein may neutralize the protein or change its pharmacokinetic profile .

Slide 14: 

Monoclonal antibodies

Slide 17: 

With the exception of two modified products, abciximab and ranibizumab , the molecular weights of these antibodies are around 150 kDa (fairly large proteins). Many of these monoclonal antibodies are humanized to prevent the incidence of hypersensitivity reactions that can occur from antibodies from foreign species. Volumes of distribution generally do not exceed two times the volume of plasma water. Many of the elimination half lives of these compounds are measured in days, ensuring long physiological exposure after a dose.

Slide 18: 

Administration is intravenous, subcutaneous or intramuscular. Ranibizumab is an exception in that it is injected intra vitreally into the eye. Two monoclonal products, Bexxar and Zevalin , belong to the new class of radio immunotherapy drugs. These drugs, which act by delivering radioactive isotopes directly to cancer cells to kill them, are exhibiting good results in a high percentage of patients who are treated with them.

Slide 19: 

Gene Therapies Gene therapy products under development