14 Biologics, Nanomedicine

Dendrimers

highly branched spherical polymers built from a central core molecule

Biosimilar/ biosimilarity

highly similar to, and has no clinically meaningful differences in safety, purity, and potency from, an existing FDA-approved reference product

Interchangeable biological product

biosimilar product that meets additional requirements; produces the same clinical result as the referee product in any given patient

Biopharmaceutical

medicines derived from a biological source (derived from living organisms)

Amphiphatic

molecules that contain hydrophilic and hydrophobic sections; form micelle systems

The list for approved biosimilars for biologics is known as?

purple book

Mononuclear phagocyte system

rapid engulfment by macrophages; will absorb opsonins resulting in rapid removal from circulation due to engulfment by liver and spleen machrophages

Which of the following is an example of an appropriate biosimilar meaning? A. etanercept-BIO1 B. etanercept-122 C. etanercept-BIO D. etanercept-szzs

D. etanercept-szzs

Describe the totality-of-evidence approach for determining biosimilarity

Evaluates: - Analytical studies of structure, function, and bioactivity - Animal studies to assess toxicity - Human clinical studies to assess immunogenicity, PK, and PD

Describe the naming of biosimilars

FDA recommends that reference biologics and biologics have nonproprietary names that share a core drug substance name and a suffix that is unique to each product Suffix should be: 1. Four lowercase letters 2. Unique 3. Be devoid of meaning Example: - Core name: infliximab - Suffix: infliximab-dyyb

A biosimilar has the same glycosylation patterns as the reference listed product. True or False

False

Biosimilars are interchangeable with the reference biological product. True or False

False

Biologics

Medicines derived from a biological source - Often lg. (>1000 g/mol), complex molecules - Sometimes are complex combinations of sugars, proteins, or nucleic acids - Mainly administered by the parenteral route but some administered through other routes

Describe the design of Protein nanoparticles

- Abraxane is a protein nanoparticle formulation where paclitaxel is bound to albumin - Albumin helps to solubilize the drug - Binding to albumin helps to target the drug to the tumor through the EPR effect

Describe the design of dendrimers

- Are highly branched spherical polymers built from a central core molecule - Can be attached to peripheral groups covalently or by electrostatic interactions - Can be encapsulated within the dendrimer - Can increase drug solubility - Alter PK profile - Protects against degradation

Discuss micelles and liposomes including how these systems protect against toxicity and drug metabolism, evade phagocytic cells, and target site of action

- Can carry both water soluble drugs and lipophilic drugs - Can modify the PK profile - Protects against drug toxicity and DMEs - Hydrophilic coating prevents detection by macrophages in the liver and spleen - Lengthens circulation time extensively relative to uncoated liposomes

Describe the design of liposomes

- Closed spherical vesicles consisting of an aqueous core surrounded by one or more bilayer membranes - Can carry both water-soluble drugs and lipophilic drugs - Modify the PK profile of the drug - Can protect against drug toxicity and DMEs - Most common type of nanomedicine - Can consist of a single bilayer membrane or multiple bilayers - Must have energy inputted into the system to form

Describe the design of Antibody-drug conjugates

- Conjugation of a drug molecule to an antibody - Allows active targeting to a particular receptor or protein - Construction: antibody, linker group, and drug - Some antibody-drug conjugates target radioisotopes for imaging

Describe the design of Solid polymeric nanoparticles

- Drug is incorporated into a polymer matrix or attached to the surface of the polymer - Polymers are diodegradable - Drug release is dictated by degradation rate of the matrix - Polymer matrix can help protect the drug from degradation - Can passively target drugs to tumors through EPR effect - Can be coated with PEG to provide "stealth" properties

Describe the design of nanoparticles

- Drug particle reduced to nanometer size range - Helps increase surface area and improves dissolution - Contain just the drug, not a matrix of polymer and drug - To reduce aggregation and poor wettability - Often formulated with surfactants that absorb to the surface of the particles

Discuss Polymer-drug conjugates including PEGylated proteins - PEGylated proteins

- Drugs are conjugated to polymers - Water soluble polymer backbone - A linker group: helps to minimize the polymer from blocking therapeutic activity, can be cleaved by hydrolysis, enzyme degradation, pH, amides, amines, carbamates, and esters - Used for chemotherapies and proteins - Improve solubility - Enhance bioavailability - Extend half life - Protect against degradation

Describe the design of PEGylated liposomes and micelles

- Liposomes and micelles cleared by phagocytic cells - Attachment of polyethylene glycol or other hydrophilic polymer to the surface of the system can help it to evade the MPS - Hydrophilic coating prevents detection by macrophages in the liver and spleen - Lengthens circulation time extensively relative to uncoated liposomes - Called 'Stealth liposomes/ micelles'

Describe the types of drugs considered biologics

- Peptide and protein drugs: monoclonal antibodies, hormones, insulin, growth factor - Nucleic acids - Carbohydrates - Blood-derived products - Vaccines - In vivo diagnostic allergenic products - Immunoglobulin products - Gene therapy products - Products containing cells or microorganisms

Describe the process of creating biologics through recombinant methods and the difficulty in producing identical therapeutic proteins

- Protein drugs are made of hundreds of amino acids - Most protein drugs created in cells through recombinant methods - Each manufacturer uses a unique process or cell system to create a biologic product - Impossible to produce the same therapeutic protein with identical glycosylation patterns - Not possible to create an exact copy of a brand name biologic

Describe the design of microspheres

- Similar to solid polymeric nanoparticles but are >1 micrometer in size - Drug is incorporated into a biodegradable matrix - Drug release is dictated by degradation rate of the matrix and size of the microspheres

Describe the design of Micelles

- Use of surfactants to self-assemble into micelles - Polymeric micelles are specially designed micelles made from block copolymers - Amphiphatic molecules self-assemble and have an aqueous core - Can increase drug solubility - Alter PK profile - Protect against degradation

Describe the construction of polymer-drug conjugates and antibody-drug conjugates

Antibody - Specific for a tumor-associated antigen that has restricted expression on normal cells Linker group - Attaches the cytotoxic agent to the antibody Drug

Biologics that are highly similar to the brand name reference are called what? A. biological generics B. biosimilars C. protein drugs D. generics

B. biosimilars

Which of the following are issues with delivery of protein drugs? A. good membrane permeability B. rapid enzyme degradation C. clearance of the mononuclear phagocytic system D. denaturation of protein drug

B. rapid enzyme degradation C. clearance of the mononuclear phagocytic system D. denaturation of protein drug

Given Purple Book data, determine whether a product is a biosimilar or an interchangeable biological product

Biosimilar will have suffix in drug name

Differentiate between a biosimilar and an interchangeable biological product

Biosimilar: highly similar to, and has no clinically meaningful difference in safety, purity, and potency from, and existing FDA approved reference product - Same safety and effectiveness - Reference product is the biological product already approved by the FDA against which a proposed biosimilar product is compared - Cannot be substituted Interchangeable biological product: biosimilar product that meets additional requirements - Produce same clinical result as reference - Must evaluate the safety and decreased efficacy of switching between products - May be substituted for the reference product by a pharmacist w/o the intervention of a HCP

Discuss what is meant by "highly similar" and "no clinically meaningful differences

Highly similar: a biosimilar manufacturer mist demonstrate the product is highly similar to the reference product by analyzing the structure and function of the reference product - May have minor differences in clinically active compounds (ie. Buffer ingredients) No clinically meaningful differences - No differences from the reference product in terms of safety, purity, and potency - Demonstrated through PK and PD studies, an assessment of clinical immunogenicity, and add. clinical studies

Describe how the size of microspheres can alter the release rate of the drug

Initial release rate decreases as sphere diameter increases

Discuss how the addition of PEG creates a 'stealth' nanomedicine

Liposomes and micelles are primarily cleared by phagocytic cells - Taken up by mononuclear phagocytic system and leads to accumulation in the liver and spleen Attachment of polyethylene glycol or other hydrophilic polymer to the surface of the system can help it to evade the MPS - Hydrophilic coating prevents detection by macrophages in the liver and spleen - Lengthens circulation time extensively relative to uncoated liposomes - Called "stealth liposomes/ micelles"

Define nanotechnology and discuss its impact on drug delivery

Nanotechnology: the design, characterization, and production of drug delivery devices that have dimensions between 1nm and 1000 nm Impact on drug delivery: - Enhanced solubility and dissolution - Enhanced drug delivery - Altered PK - Decreased drug degradation - Decreased toxicity

Differentiate between passive and active targeting. Describe the EPR effect and compare it with active targeting approaches

Passive targeting through EPR - Solid tumors have poorly differentiated and disorganized capillary systems that are leaky and allow accumulation within the tumor - Tumors have poor lymphatic drainage leading to further accumulation - Termed passive as it relies on size/ circulation time of nanomedicine and tumor biology - Nanomedicine releases contents by allowing drug to diffuse out of carrier or by degradation of the polymer Active targeting - Increases the quantity of drug delivered to a targeted region through specific processes - Antibody targeting - Cell surface receptor targeting - Use of carbs, vitamins, or other components cells needs - Acidic/ hypoxic environment of a tumor - Prodrugs cleaved at intended site of action

Micelles and liposomes are both made up of amphiphatic molecules. True or False

True

Most protein drugs are synthesized using recombinant methods in mammalian or bacterial cells. True or False

True

Describe the construction of polymer-drug conjugates

Water soluble polymer backbone - PEG most widely used A linker group - Helps to minimize the polymer from blocking therapeutics activity - Can be cleaved by hydrolysis, enzyme degradation, pH - Amides, amines, carbamates, esters Drugs - Most often used for chemotherapies and proteins

Liposomes

closed spherical vesicles consisting of an aq. core surrounded by one or more bilayer membranes

Antibody drug conjugate

conjugation of a drug molecule to an antibody; allows active targeting to a particular receptor or protein

A polymer built from a central core molecule is a?

dendrimer

Polymer-drug conjugate

drug molecules are conjugates to polymers to improve solubility, enhance bioavailability, extend half-life, and protect against degradation

Nanocrystals

drug particle size is reduced to the nanometer size range; increases total surface area and improves dissolution

A spherical vesicle made of an aqueous core and one or more bilayer membranes is a?

liposome

EPR effect

passive targeting to tumors, nanomedicine releases contents by allowing drug to diffuse out of carrier or by degradation of polymer

Microspheres

similar to solid polymeric nanoparticles but are >1 micrometer in size; drug is incorporated into a biodegradable matrix, drug release is dictated by degradation rate of the matrix and the size of the microspheres

Nanotechnology

the design, characterization, and production of drug delivery devices that have dimensions between 1nm and 1000nm

Micelles

use of surfactants to self-assemble into micelles; increase drug solubility, alter PK profile, and protect against degradation