Pharmaceutics 2 Exam 6
What does the first letter of a TE code represent?
A codes: Considered therapeutically equivalent to another pharmaceutically equivalent drug B codes: Considered not therapeutically equivalent
What does the second letter of a TE code for an A-rated drug mean?
- AA: Dosage forms not suspected to have bioequivalence problems • These are often solution dosage forms - AN, AO, AP, or AT: Gives information about specific routes - AB: Shown to have no bioequivalence problems through in vivo or in vitro evidence • These are the drugs that have had bioequivalence studies or in vitro biowaivers completed
What is absolute bioavailability and relative bioavailability?
- Absolute bioavailability: Compares oral (extravascular) dose with IV • Comparison of AUC of other routes with AUC by IV administration reveals whether any drug is lost during absorption. - Relative bioavailability: Compares two oral (extravascular) doses with each other • Comparison of AUCs of three different formulations of a drug via the same route of administration
What does the third letter of a TE code represent?
- Assigned when multiple sources of the drug are available but these sources are not considered therapeutically equivalent to each other - Two or more reference listed drugs that are not bioequivalent to each other - Example: Procardia XL and Adalat CC ◦ Both nifedipine but not therapeutic equivalent to each other ◦ Adalat CC is AB1 ◦ Procardia XL is AB2
Why are radiopharmaceuticals used?
- Diagnostic purposes - via external imaging, and noninvasive measuring - Therapeutic applications - by targeting radioactivity to a specific site in the body **Minimizing dose of radiation to the patient, and avoiding off-target damage to healthy tissue. • How do they work? - Consist of a radioisotope complexed with an organic molecule, such as a monoclonal antibody - Organic molecule determines biodistribution throughout body - Radioisotope provides source of radiation at target tissue
What is bioavailability (F)?
- FDA definition: • "The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action." • Cannot easily measure concentrations at the site of action - More common definition of bioavailability: • The fraction of the dose of intact drug that reaches systemic circulation • A measure of the extent of absorption of a drug
What are the pharmacokinetic parameters used to quantify rate and extent of absorption?
- Peak concentration (Cmax) • Both rate and extent of absorption - Time to peak (Tmax) • Rate of absorption - Area Under the Curve (AUC) • AUC0-t or AUC0-∞ • Extent of absorption
What does the second letter of a TE code represent?
- Provides additional information about the dosage form or actual/potential bioequivalence problem
What is statistical evaluation of bioequivalence?
- The 90% confidence intervals for both Cmax and AUC for the test product must be within 80-125% of the reference product • Often expressed as a percentage but not always • 80-125% = 0.8-1.25 • The bioavailability of most generic drugs differs from brand name by <4% • Variability between brand and generic is the same as variability between batches of the same brand-name drug • Inside = Bioequivalence • Outside = Bioinequivalent • In and Out = Inconclusive
What characteristics may be different between pharmaceutically equivalent drugs?
- shape - release mechanism - scoring - excipients (including colors, flavors, preservatives) - packaging - expiration time - labeling (to some extent)
What are the steps in determining therapeutic equivalency?
1) Determine if you have pharmaceutical equivalents - Same active ingredient(s) - Same strength or concentration - Same dosage form and route of administration 2) If the products are pharmaceutically equivalent, look at the TE code provided in the Orange Book to determine if the products are bioequivalent. 3) If the products are pharmaceutical equivalents and have the same TE code, they are therapeutically equivalent.
What TE codes are the most important?
AA = No issues with bioequivalence AB = Meet necessary bioequivalence standards AB1/AB2/AB3 = Meet necessary bioequivalence standards but are not bioequivalent to each other. (Cannot interchange AB1 for AB2 or AB3.) BD = documented bioequivalence problems BP = active ingredient(s) with potential bioequivalence concerns BX = insufficient data to determine bioequivalence
What does the second letter of a TE code for a B-rated drug mean?
B-rated drugs = Drug products for which actual or potential bioequivalence problems have not been resolved by adequate evidence of bioequivalence. - Second letter: gives more information about the bioequivalence problem or dosage form
What is bioequivalence?
Bioequivalence is defined by the FDA as: - the absence of a significant difference in the rate and extent to which the active ingredient becomes available at the site of action when administered at the same dose • A better definition of bioequivalence... - Two drug products (test vs. reference) do not differ significantly in their rate and extent of absorption ◦ Have comparable relative bioavailabilities - Will be "bioequivalent" to each other
What are the potential benefits and drawbacks for oral insulin in novel oral delivery systems?
Potential Benefits • Ease of dosing (Increased acceptance and adherence) • Decreased skin and injection- related infections • Decreased need for patient dose measurements • Extrapolation of method to use with other injection-only drugs (Monoclonal antibodies, protein drugs, etc) Potential Drawbacks • Expensive! (Disposable/non-reusable technology) • Slower onset of action (compared to SC insulin) • May be difficult to account for sliding-scale regimen • Many factors may alter absorption in stomach
What are pharmaceutical alternatives?
Same active drug but have.... - Different salt forms (i.e. phosphate vs HCL) - Different dosage strength (i.e. 10mg vs 20mg) - Different type of dosage form (i.e. IR vs ER or cap vs tab)
What does it mean when biosimilars are highly similar?
‒ A biosimilar manufacturer must demonstrate the product is highly similar to the reference product by analyzing the structure and function of the reference product and proposed biosimilar ‒ May have minor differences in clinically inactive components (i.e. buffer ingredients)
What does polymer conjugation do?
‒ Improve solubility ‒ Enhance bioavailability ‒ Extend half life ‒ Protect against degradation ‒ Promote targeting to specific tissues
What does it mean when biosimilars have no clinically meaningful differences?
‒ No clinically meaningful differences from the reference product in terms of safety, purity, and potency (safety and effectiveness). ‒ Demonstrated through human pharmacokinetic and pharmacodynamic studies, an assessment of clinical immunogenicity, and, if needed, additional clinical studies.
How can liposomes and micelles target tumors or other tissues?
‒ Passive processes ◦ EPR effect ‒ Active processes ◦ Attaching monoclonal antibodies specific for a tumor or any target cell ◦ Prodrugs cleaved at intended site of action ◦ Many others
What are products are considered biologics?
‒ Peptide and protein drugs: ◦ Monoclonal antibodies ◦ Hormones ◦ Insulin ◦ Growth factors ‒ Nucleic acids ‒ Carbohydrates (ie heparin) ‒ Blood-derived products ‒ Vaccines ‒ In vivo diagnostic allergenic products ‒ Immunoglobulin products ‒ Gene therapy products ‒ Products containing cells or microorganisms
What is the Enhanced Permeability and Retention Effect (EPR) effect?
‒ Solid tumors have poorly differentiated and disorganized capillary systems that are 'leaky' and allow the liposomes to accumulate within the tumor ‒ Release contents by allowing drug to diffuse out of carrier or by degradation of the polymer ‒ Carriers are too large to be absorbed by diffusion through capillary membranes
What are biosimilars?
• A biosimilar is highly similar to, and has no clinically meaningful differences in safety, purity, and potency from, an existing FDA-approved reference product. ‒ Will have the same safety and effectiveness ‒ The reference product is the biological product already approved by the FDA against which a proposed biosimilar product is compared • The goal is to demonstrate biosimilarity between the proposed biosimilar product and the reference product, not to independently establish the safety and effectiveness of the proposed product. ‒ Less data needs to be collected → less cost, faster approval
What is an interchangeable product?
• A biosimilar product that meets additional requirements • "An interchangeable product is expected to produce the same clinical result as the reference product in any given patient." • For products administered more than once, the manufacturer must evaluate the safety and decreased efficacy of switching between products
What are novel drug delivery systems?
• A range of drug delivery systems have been developed to deliver biologics and small molecular weight drugs • Designed to protect from degradation, facilitate uptake, provide sustained release, and direct molecules to their target • May utilize nanotechnology
What is an interchangeable biological product?
• An interchangeable biological product may be substituted for the reference product by a pharmacist without the intervention of the health care provider who prescribed the reference product ‒ In WA, the prescriber has indicated "Substitution Permitted" on the prescription. ‒ Only interchangeable biological products can be substituted for brand name biologic. A biosimilar cannot be substituted.
What class of drugs can waive bioequivalence testing?
• BCS Class I drugs are eligible for a waiver of in vivo bioequivalence testing • Bioequivalence testing can be waived and in vitro dissolution testing substituted for drugs contained in dosage forms with the following properties: - High solubility - High permeability - Rapid dissolution - Similar dissolution profile to brand product - Wide therapeutic window - Excipients used in dosage form used previously in FDA approved IR solid dosage forms • Large amount of evidence suggests a correlation between in vitro data and in vivo exposure
What are biologics?
• Biologics are medicines derived from a biological source (ie derived from living organisms) ‒ Also called biopharmaceuticals or biological products • Biologics are often large (MW >1000 g/mol), complex molecules • Sometimes biologics are complex combinations of sugars, proteins, or nucleic acids • Mainly administered by the parenteral route but some administered through other routes (nasal, respiratory, etc)
What are data required for biosimilars?
• Biosimilarity based on a totality-of-evidence approach that evaluates: ‒ Analytical studies of structure, function, and bioactivity ‒ Animal studies to assess toxicity ‒ Human clinical studies to assess immunogenicity, pharmacokinetics, and pharmacodynamics
Are biosimilars considered generic drugs?
• Biosimilars and generic drugs are versions of brand name drugs and may offer more affordable treatment options to patients. • Biosimilars are not generic drugs. ‒ Generic drug molecules are identical to the brand name drug. Generic drugs must demonstrate bioequivalency between the brand and generic. ‒ Biosimilars must be highly similar to the reference product and have no clinically meaningful differences.
What is therapeutic equivalence (TE)?
• Both pharmaceutically equivalent and bioequivalent - Pharmaceutical equivalent: Same active ingredient(s), strength/concentration, dosage form, and route - Bioequivalent products have comparable bioavailability • The rate and extent of absorption of the test drug is not significantly different from the reference drug • Therapeutically equivalent drug products can be substituted or interchanged - Will produce the same clinical effect and safety profile • Drug products that are therapeutic equivalents are denoted as such by the FDA by therapeutic equivalence codes (TE codes) - OTC Drugs are not assigned TE codes • TE codes are published in the Orange Book
What are antibody-drug conjugates?
• Conjugation of a drug molecule to an antibody • Construction: ‒ Antibody ➝ target a particular receptor or protein ‒ Linker group ‒ Drug
What are dendrimers?
• Dendrimers are highly branched spherical polymers built from a central core molecule ‒ Each additional layer of branching referred to as a generation • Drug molecules: ‒ Can be attached to peripheral groups covalently or by electrostatic interactions ‒ Can be encapsulated within the dendrimer • No current dendrimers on the market
What are polymer-drug conjugates?
• Drug molecules are conjugated to polymers • Construction: ‒ Water soluble polymer backbone ◦ Polyethylene glycol (PEG) most widely used ‒ A linker group ◦ Helps to minimize the polymer from blocking therapeutic activity ◦ Can be cleaved by hydrolysis, enzyme degradation, pH ◦ Amides (most common), amines, carbamates, esters ‒ Drug ◦ Most often used for chemotherapies and proteins ‒ Targeting group
What are peptide and protein drugs?
• Peptide drugs are made of a small number of amino acids (MW 1 - 5 kDa) • Protein drugs are made of hundreds of amino acids (MW 6 - 150 kDa) • Most protein drugs created in cells through recombinant methods ‒ This is in comparison to small molecule drugs that are produced through chemical synthesis
How are biologics regulated?
• Drugs are approved by the FDA under the Federal Food, Drug, and Cosmetics Act (FD&C Act) • Biologics are approved under the Public Health Service (PHS) Act ‒ The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) created an abbreviated licensure path for biosimilars and interchangeable biological products • Insulin, glucagon, heparin, human growth hormone, and others were previously regulated as drugs not biologics • Starting March 23, 2020, the FDA will transition to regulating these agents (insulin, growth hormone, etc) as biological products (i.e. transition from regulation under FD&C Act to PHS Act) • The transition of insulin and other products from approved drugs to biological products will open products to potential biosimilar and interchangeable competition.
Is it possible to make an exact copy of a biologic drug?
• Each manufacturer uses a unique process or cell system to create a biological product. Production processes are usually proprietary. • Impossible to produce exactly the same therapeutic protein with identical glycosylation patterns » Not possible to create an exact copy of a brand name biologic
What are features of MIT's new design on oral insulin for novel oral delivery systems?
• Encapsulated device for PO delivery • Insulin needle attached to compressed spring • When swallowed, spring is released, injecting insulin into stomach wall • Device self-orients to ensure contact with stomach wall • Patient does not see needle, or feel injection
What is a reference formulation?
• Every generic product is compared to a reference formulation. • Most often that reference formulation is the reference listed drug (RLD) - RLD = the brand name product that was the first approved for that particular drug/dosage form • Sometimes the RLD is no longer on the market. This makes it so the generic manufacturer cannot compare their formulation to the RLD. • In these cases, the FDA assigns a reference standard (RS) to which all generics are compared. - This reference standard is generally a generic that has been on the market for a long period of time.
What are pharmaceutical equivalents?
• FDA considers drug products to be pharmaceutical equivalents if they meet these three criteria: 1. Same active ingredient(s) (incl. salt form) 2. Same strength or concentration 3. Same dosage form and route of administration
What is the purple book?
• FDA-approved biological products, including biosimilar and interchangeable products. ‒ Database: https://purplebooksearch.fda.gov/ ‒ Lists: https://www.fda.gov/drugs/therapeutic-biologics-applications- bla/purple-book-lists-licensed-biological-products-reference-product- exclusivity-and-biosimilarity-or • CBER list and CDER list ‒ CBER list = vaccines, allergen tests ‒ CDER list = mABs, other protein drugs • "B" is used if biosimilar • "I" is used if interchangeable
What are authorized generics?
• Generics that are identical to the brand. • Made by the brand company or subsidiary but repackaged for sale under the generic name - Used to compete with generic companies • These generic products will look the same as the brand
Does equal amount result in equal response?
• Having an equal amount of drug in a dosage form does not guarantee you will have an equivalent response - For instance 10 mg drug in brand name does not mean an equal response if 10 mg of the same drug is given in a different formulation - Different excipients and different manufacturing processes can result in two dosage forms with the same amount of drug to behave very different clinically
What is the orange book?
• In 1980, the FDA published the Approved Drug Products with Therapeutic Equivalence Evaluations - Better known as the Orange Book - Lists of generic versions of medications are therapeutic equivalents to the reference listed drug
What is bioequivalence testing?
• In vivo pharmacokinetic studies most commonly used to determine bioequivalence • Assesses the relative bioavailability of the test formulation to that of the reference formulation • Conducted in randomized crossover design in healthy volunteers - Plasma levels of the drug are measured over time - Healthy volunteers are randomized to take one dose of a reference formulation and then one dose of test formulation with washout periods in between - Usually single dose, sometimes multiple dose studies • Plasma samples analyzed for drug concentrations • Calculation of AUC, Cmax • Data is log transformed • Ratios of each parameter are calculated: 𝑀𝑒𝑎𝑛 𝐴𝑈𝐶 𝑡𝑒𝑠𝑡/𝑀𝑒𝑎𝑛 𝐴𝑈𝐶 𝑟𝑒𝑓𝑒𝑟𝑒𝑛𝑐𝑒 𝑀𝑒𝑎𝑛 𝐶𝑚𝑎𝑥 𝑡𝑒𝑠𝑡/𝑀𝑒𝑎𝑛 𝐶𝑚𝑎𝑥 𝑟𝑒𝑓𝑒𝑟𝑒𝑛𝑐𝑒 • 90% confidence intervals calculated:
What are oral insulin for novel oral delivery systems?
• Insulin is most commonly delivered subQ in outpatient setting • Many patients are uncomfortable with using needles for self-injection - Low adherence - Poor outcomes • Why is it difficult to formulate PO insulin? - Rapidly degraded by enzymes in stomach and intestinal lumen - Macromolecule with poor bioavailability - Poor stability
What are microspheres and nanoparticles?
• Microspheres are spherical particles ranging from 100 nm to 1 micron (smaller ones are called nanoparticles) ‒ Can be solid or porous ‒ Can also be hollow (microcapsules) • Microspheres can be given IM, SQ ‒ Can act as a depot dosage form • Nanoparticles can be given IV • Drug incorporated within a biodegradable polymer matrix ‒ PLA and PLGA cage must be degraded before the drug is released from the microsphere. • Protects from drug metabolizing enzymes
What are PEGylayed proteins?
• Most polymer-drug conjugates are PEGylated proteins ‒ Covalent attachment of protein drugs to large polyethylene glycol polymers (40 kDa) • Conventional formulations or proteins require frequent dosing ‒ Peptidases in all tissues can break down protein drug
What are delivery issues with protein drugs?
• Peptide and protein drugs are prone to numerous stability problems ‒ Denature on exposure to heat, extremes in pH, organic solvents ‒ Aggregation ‒ Deamination • Optimization of in vivo efficacy ‒ Large MW and very water soluble which results in poor permeability ◦ Move through membranes by endocytosis ◦ Consequently, many administered parenterally (mainly IV, sometimes subQ or IM) ‒ Vulnerable to rapid enzymatic degradation by peptidases • Rapid engulfment by macrophages ‒ Will adsorb opsonins (complement) resulting in rapid removal from circulation due to engulfment by liver and spleen macrophages ‒ Known as mononuclear phagocytic system
What are PEGylated liposomes and micelles?
• Phagocytic cells that are a primary reason for removal of liposomes and micelles • Attachment of polyethylene glycol to the surface of the system ‒ Hydrophilic coating prevents detection by macrophages in the liver and spleen ‒ Lengthens circulation time extensively relative to uncoated liposomes ‒ Called stealth liposomes
What factors influence bioavailability?
• Physiochemical properties of the drug substance - Salt form - Crystalline or amorphous form - Particle size • Pharmaceutical excipients • Dosage form characteristics - Disintegration rate - Dissolution time • Physiologic factors and patient characteristics - Gastric emptying time - Intestinal transit time - Gastric contents (food, liquids, other drugs) - GI pH - Drug metabolism and transport
When is generic substitution not appropriate?
• Remember that pharmaceutically equivalent drug products may differ in characteristics such as: - shape - release mechanism* - labeling (to some extent) - scoring - excipients (including colors, flavors, preservatives) • Generic substitution is not appropriate if one of the above is an important consideration
What is targeted therapy of radiopharmaceuticals?
• Short-range radioisotope particles - Alpha or beta particles - Cause local damage (cell destruction) • Targeted uptake in specific tissues - Tumor/cancer cell destruction - Palliative pain treatment for bone cancer - Arthritis
What are liposomes?
• Spherical bilayers of phospholipids • Can carry both water-soluble drugs and lipophilic drugs ‒ Loaded with drug either in their aqueous core or in the bilayer itself • Protects against drug toxicity, drug metabolizing enzymes • Can consist of a single bilayer membrane or multiple bilayers • Classified based on size and number of lamellae (number of bilayers): • Unlike micelles that form spontaneously, liposomes must have energy inputted into the system to form
How are biosimilars named?
• The FDA has recommended that reference biologics and biosimilars have nonproprietary names that share a core drug substance name AND a suffix that is unique to each product. • The proposed suffix should be 1) four lowercase letter, 2) be unique, and 3) be devoid of meaning. ‒ Core name: infliximab ‒ Suffix: infliximab-dyyb
How is bioequivalence testing classified?
• The FDA requires in vivo pharmacokinetic bioequivalence studies in most cases • Other in vivo methods to determine bioequivalence: - Pharmacodynamic studies - Comparative clinical trials • Manufacturers can submit for a waiver of in vivo testing of an IR product by use of the Biopharmaceutics Classification System (BCS)
What is pharmaceutical nanotechnology?
• The design, characterization and production of drug delivery devices that have dimensions between 1nm and 1000 nm • Nanotechnology can allow for: - Enhanced solubility and dissolution - Enhanced drug delivery - Decreased drug degradation - Decreased toxicity
What are nanomedicines?
• The majority of nanomedicines are administered parenterally • Include: ‒ Polymer-drug conjugates PEGylated proteins ‒ Antibody-drug conjugates ‒ Dendrimers ‒ Micelle systems ‒ Liposomes ‒ Microspheres and Nanoparticles
What are micelle systems?
• Use of surfactants to self-assemble into micelles • Polymeric micelles are specially designed micelles made from block copolymers ‒ Amphoteric molecules that contain: ◦ Hydrophobic section ◦ Hydrophilic section
How does the size of microspheres alter the release rate of the drug?
↓ size of microsphere = ↑ SA = ↑ rate of release of drug