midterm 1.1 - bioavailability and bioequivalence studies

Measurement of the rate and extent of therapeutically active drug that reaches the general circulation from an administered dosage form

Bioavailability

Measurement of the concentration of the intact drug and its metabolite in the urine (Methods of bioavailability assessment)

Cumulative urinary drug excretion curve

Availability of the drug from a dosage form administered extravascularly (non-IV) compared with availability of drug after IV administration (Types of bioavailability)

Absolute bioavailability

Availability of the drug from a dosage form compared with that of a standard or relative to an established commercial preparation of proven clinical effectiveness (Types of bioavailability)

Relative bioavailability

Refers to pharmaceutical equivalents whose rates and extents of drug absorption are equal

Bioequivalent products

Same therapeutic or clinical objective; different API (Therapeutic equivalent or alternative)

Therapeutic equivalent

Same therapeutic or clinical objective; different color, scoring, flavor, etc. (Therapeutic equivalent or alternative)

Therapeutic alternative

Cimetidine and ranitidine are therapeutic __________

Equivalents

Aspirin and paracetamol (analgesic) are therapeutic __________

Equivalents

Aspirin and ibuprofen (anti-inflammatory) are therapeutic _________

Equivalents

Pharmacokinetics, pharmacodynamics, and comparative clinical trials are __________ studies

In vivo

Comparative dissolution studies are __________ studies

In vitro

Studies that aim to compare the bioavailability of the generic drug product with the branded/innovator product

Bioequivalence studies

Refers to the regulatory drug approval process when the application is approved based on equivalence other than through in vivo equivalence testing

Biowaiver

API is tested for __________ and __________ (SP)

Solubility, Permeability

Dosage form is tested for __________

Dissolution

Means that in vivo bioavailability and/or bioequivalence studies may be waived

Biowaiver

Biowaiver for solid oral dosage forms is based on dissolution test using pH __________, ___________, and ___________

1.2, 4.5, 6.8

System that provides a guide for predicting intestinal drug absorption

Biopharmaceutics classification system (BCS)

BCS predicts the in vitro pharmacokinetics of oral immediate release drug products based on their __________ and __________ (SP)

Solubility, Permeability

Highest dose strength is soluble in < 250 mL in water over a pH range of 1 to 7.5 (Class boundaries)

Highly soluble

Extent of absorption in humans is determined to be >90% of an administered dose, based on mass-balance or in comparison to an IV reference dose (Class boundaries)

Highly permeable

85% of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I and II in a volume of <900mL of buffer solution (Class boundaries)

Rapidly dissolving drugs

↑ solubility, ↑ permeability (BCS classification)

Class I

↑ dissolution, ↑ absorption (BCS classification)

Class I

Rate-limiting step for class I drugs

Dissolution

Metoprolol (BCS classification)

Class I

Diltiazem (BCS classification)

Class I

Verapamil (BCS classification)

Class I

Propranolol (BCS classification)

Class I

Formulation must control the release rate of the drug (BCS classification)

Class I

↓ solubility, ↑ permeability (BCS classification)

Class II

↓ dissolution, ↑ absorption (BCS classification)

Class II

Systems developed based on micronization and addition of surfactants (BCS classification)

Class II

Ketoconazole (BCS classification)

Class II

Nifedipine (BCS classification)

Class II

Mefenamic acid (BCS classification)

Class II

Phenytoin (BCS classification)

Class II

↑ solubility, ↓ permeability (BCS classification)

Class III

Rate-limiting step for Class III drugs

Permeability

Requires technologies in formulation that address low membrane permeability (BCS classification)

Class III

Cimetidine (BCS classification)

Class III

Captopril (BCS classification)

Class III

Acyclovir (BCS classification)

Class III

Neomycin B (BCS classification)

Class III

Peptides (BCS classification)

Class III

Proteins (BCS classification)

Class III

↓ solubility, ↓ permeability (BCS classification)

Class IV

Problematic when taken orally (BCS classification)

Class IV

Route of choice for Class IV drugs

Parenteral

Taxol (BCS classification)

Class IV

A modified version of BCS that is useful in predicting overall drug disposition

Biopharmaceutics drug disposition classification system (BDDCS)

High solubility, extensive metabolism (BDDCS class)

Class I

Low solubility, extensive metabolism (BDDCS class)

Class II

High solubility, poor metabolism (BDDCS class)

Class III

Low solubility, poor metabolism (BDDCS class)

Class IV

Refers to the process by which the drug is chemically converted in the body to a metabolite

Drug metabolism

Refers to the formation of polar compounds

Drug metabolism

Drug metabolism is also known as __________

Biotransformation

Main site of drug metabolism

Liver

The first pass effect __________ bioavailability

Decreases

The effect wherein drugs are metabolized before they are distributed to the rest of the body

First pass effect

Rapid metabolism of an orally administered drug before reaching the general circulation is termed __________ or __________ (FP)

First pass effect/Presystemic elimination

The most important enzyme system affecting drug metabolism

CYP450 enzyme system

CYP450 enzymes are responsible for __________

Oxidative biotransformation

CYP450 enzymes are __________ or __________ (MM)

Mixed-function oxidases, Monooxygenases

Caffeine, testosterone, R-warfarin (CYP enzyme)

CYP1A1

Acetaminophen, caffeine, phenacetin, R-warfarin (CYP enzyme)

CYP1A2

17β-Estradiol, testosterone (CYP enzyme)

CYP2A6

Cyclophosphamide, erythromycin, testosterone (CYP enzyme)

CYP2B6

Acetaminophen, tolbutamide, hexobarbital, S-warfarin, phenytoin, testosterone, R-warfarin, zidovudine (CYP enzyme)

CYP2C-family

Acetaminophen, caffeine, chlorzoxazone, halothane (CYP enzyme)

CYP2E1

Acetaminophen, codeine, debrisoquine (CYP enzyme)

CYP2D6

Acetaminophen, caffeine, carbamazepine, codeine, cortisol, erythromycin, cyclophosphamide, S- and R-warfarin, phenytoin, testosterone, halothane, and zidovudine (CYP enzyme)

CYP3A4

Introduction of a functional polar group (-OH, -COOH, -NH2, -SH) (Phase of drug metabolism)

Phase I (Functionalization)

4 polar groups (OCNS)

-OH, -COOH, -NH2, -SH

May be achieved by direct introduction of a functional group or modifying or unmasking existing functional groups (Phase of drug metabolism)

Phase I (Functionalization)

Involves direct introduction of functional group (Phase I reactions)

Hydration

Involves modifying or unmasking existing functional groups (Phase I reactions) (ORH)

Oxidation, Reduction, Hydrolysis

Attachment of small, polar, and ionizable endogenous compounds (Phase of drug metabolism)

Phase II (Conjugation)