Biopharmaceutics, Generics, Compounding Flashcards
What is the biopharmaceutical definition of what we commonly call a drug?
complex mixture of ingredients making a “finished drug product”
What are the different components that a finished drug product is comprised of?
- Active pharmaceutical ingredient (API): aka “drug substance”; thing that actually causes the pharmacodynamic response
- everything else (“excipients”)
What are the main different routes of biopharmaceutics?
- oral
- parenteral (IM/SQ/IV)
- topical vs transdermal
- intra-mammary (IMM)
- Intranasal (IN)
- rectal
- Buccal
What is the dosage form of oral meds & what are some things to consider?
- solid (pills/tablets vs capsules), semi-solid (paste/suspension), oral soln, feed premix (powder/granular)
- when & where is API released? how much API gets absorbed? what happens when it is absorbed? expiry dates?
What is the dosage form of parenteral meds & what are some things to consider?
- usually soln (water-soluble), sometimes non-aqueous
- sterility? how do you “inject” it? will it be irritating?
What is the dosage form of topical/transdermal meds & what are some things to consider?
- cream, liquid, gels, patches
- intended for local effect only, or is systemic absorption desired? how long does it stay there?
What is the dosage form of intramammary meds & what are some things to consider?
- suspension
- stay in teat/udder or systemic absorption? milk residues?
What is the dosage form of intranasal meds & what are some things to consider?
- liquid, aerosolize/nebulize (convert liquid to fine particles)
- how to ensure it gets inhaled? where does it go in respiratory tract?
What is the dosage form of rectal meds & what are some things to consider?
- suppository
- not common in vet med
What is the dosage form of buccal meds & what are some things to consider?
- fast-dissolving tablet or paste
- absorbed through cheek epithelium, avoids 1st pass (hepatic) metabolism, but make sure it isn’t swallowed! (in theory this increases bioavailability)
what is point of these “excipients”? why not just administer the active pharmaceutical?
- just dosing the API wont maximize its efficacy or safety
What are some examples of how dosing just the API wont maximize its efficacy or safety?
- how much reaches systemic circulation? where & when does the API get absorbed, & for how long?
- stability of API (how long does it last in dose form)
- oral: API’s taste awful (bitter) or irritate GI mucosa
- parenteral: API is insoluble, or too rapidly absorbed
- topical: API may not stay on skin
- transdermal: API may not penetrate skin
What excipients do we add to oral pharmaceuticals & why?
- binding agent -> delays DISAGGREGATION (breaks down tablet) & DISSOLUTION (solubilizes API); both are necessary to permeate intestinal cell
- coating or capsule -> protect API from acid in stomach; decrease irritation in proximal GI tract; delay timing of absorption
- flavouring agent - increase palatability
What excipients do we add to parenteral injection pharmaceuticals & why?
- pH adjuster: make inj less irritating; increases solubility of API (smaller inj vol); enhances stability of API in soln
- salt or chelating agent: alters API solubility; determines how long before API is released; vasoconstriction (impact on absorption?)
- preservative : maintain sterility
3 big points in terms of formulating biopharmaceutics:
- formulation matters
- different forms of same API can have BIG difference
- messing w/ formulation changes drug product
What is a pioneer drug product?
innovators (original release)
What is a generic drug product?
copies of pioneer drugs
What is a compounded drug product?
when pharmacy makes up drug product but it’s not an approved formulation of drug
what is point of generic drugs?
- allows for more drug product availability
- more competition = decreased prices
- only once pioneer drug has expired
How come pioneer drugs are more expensive?
- v high cost for initial drug approval (have to perform all initial research & development (chemistry, clinical efficacy, & safety studies)
- patent allows for “exclusive marketing”
- when patent runs out - price typically drops
How come generic drugs are cheaper?
- “proven” safety & efficacy of pioneer drug
- are not required to reproduce efficacy & safety studies that pioneer did
What does generic drug need to be approved?
manufacturing & chemistry (Drug product quality):
- same requirements as pioneer drug
> potency (right strength or concentration)
> purity (API is legit, no excess impurities)
> stability, sterility, etc.
clinical efficacy & safety:
- generic drug must be same STRENGTH & DOSAGE FORM as demonstrate BIOEQUIVALENCE w/ pioneer product (it is assumed that equal plasma concentrations result in equal clinical efficacy & safety)
- if same strength, dosage form, & bioequivalent, generic & pioneer product are considered clinically interchangeable
What is bioequivalence (BE)?
when RATE & EXTENT of absorption of 2 PHARMACEUTICALLY EQUIVALENT formulations of drugs (pioneer & generic) are sufficiently similar, w/in ALLOWABLE LIMITS, when administered under similar experimental conditions
What does pharmaceutically equivalent mean?
- 2 drugs that contain IDENTICAL AMTS (strength or concentration) of IDENTICAL MEDICINAL INGREDIENTS, in COMPARABLE DOSAGE FORMS (ex: if pioneer drug is a tablet, generic version cannot be a suspension or solution
- does not necessarily contain same NON-MEDICINAL INGREDIENTS - provided they don’t influence absorption characteristics of active ingredient
How do you prove bioequivalence?
Blood-lvl study
- 2 grps, 2 treatments (compare generic & pioneer products)
- each animal gets both products w/ washout period in btwn (10x half-life to avoid drug carry-over into next period)
-dosing same animal 2x reduces inter-individual variability
- collect multiple blood samples over time (early time: enough to capture absorption/Cmax & later time: @ least 3x half-life beyond Tmax)
- determine plasma concentrations (REQUIRES VALIIDATED ANALYTICAL METHOD)
- concentration-time profiles & PK modelling to estimate:
>extent of internal exposure: AUC
>peak exposure: Cmax
>rate of exposure: Tmax
How do you interpret the results of blood-lvl study?
have lower & upper confidence intervals; if arm of lower is below 0.80, efficacy issue; if arm of upper is above 1.25, safety issue
What is compounding?
combining or mixing multiple ingredients (@ least 1 of which is a drug) to create a final product in an appropriate dosing form
why use compounded drugs?
- available formulations arent appropriate for specific patient (diluted formulations for v sm animals)
- improve client compliance (more palatable oral product; non-oral formulation)
- no approved drug product commercially available (requires bulk ingredient - “grey” zone; ex: cisapride)
COST IS NOT A VALID REASON
FDA rules on compounded drugs?
- used to treat an UNMET therapeutic need or reduce animal suffering
- dont cause harm to treated animal
- dont result in therapeutic failures
- dont result in violative drug residues (food animals)
PRICE IS NOT VALID REASON
Best to worst drug use order
approved (DIN) vet drug (on label) -> approved (DIN) vet drug (extra label) -> approved (DIN) human drug (ELDU) -> compounded drug: from approved (DIN) vet drug (ELDU) -> compounded drug: from approved (DIN) human drug (ELDU) -> compounded drug: from active pharmaceutical ingredients (ELDU)
What are some concerns associated w/ compounding?
- PURITY of compounded drug
- quality of drug
- drug that is present (is supposed to be there)
- no other drugs there (if not supposed to be there) - POTENCY of compounded drug
- “quantity” of drug
- ACCURACY w/ label quantity
- manufactured drugs: concentration must be w/in +/- 10% - stability of compounded form
- hydrolysis (if it comes dry - keep it dry)
- oxidation (light or oxygen exposure; pink or amber colour change)
- consistency (precipitates (organic vs aqueous solution); settling out)
- expiry (beyond use) date (25% of time left on original expiry date; water-based cmpds - 14 days, oil bases cmpds - 180 days, NOT APPROPRIATE & NOT FOR LONG) - pharmacokinetic changes due to formulation
- absorption (oral, transdermal)
- bioavailability
ex of potency compounding mistakes
- testing meloxicam (12/19 did not meet label claim)
- Biodyl injectable supplement (incorrect [selenium] -> 100x potency -> 21 dead Eq)
Ex of stability compounding mistake?
patients received epidural injs w/ preservative free methylprednisolone acetate leading to fungal meningitis
ex of pharmacokinetic changes in product due to changes in formulation?
- just b/c pharmacy can make gel or patch w/ API in it, does not mean that it will be absorbed
- some APIs will not permeate skin
- results can vary BTWN or even W/IN patients
- products not uniform btwn pharmacies or batch-to-batch w/in pharmacy
- explain transdermal products w/ client (HOW WILL YOU ASSESS EFFICACY?)
What to tell your clients about compounded drugs?
DO: - explain why you are prescribing cmpd’d drug (for this SPECIFIC patient, different strength or route or administration is necessary (compared w/ approved drug) or no approved drug is available)
- have method of assessing efficacy of compounded drug
- get INFORMED CONSENT from client & DOCUMENT IN MEDICAL RECORD
DO NOT: - call it a “generic version” or “same thing”
- use it strictly b/c it is cheaper
