BIOPHAR - Drug Product Performance In-Vivo: Bioavailability and Bioequivalence

DRUG PRODUCT PERFORMANCE

• refers to how a drug is released from its formulation, leading to the availability of the drug in the body (bioavailability)

BIOAVAILABILITY STUDIES

• are a type of drug product performance study that investigates how changes in the physical and chemical properties of the drug substance, the formulation of the drug, and the manufacturing process of the drug product can impact its performance in the body
• establishes a connection between the in vivo performance of a new drug product and the original formulation used in clinical studies to assess its safety and effectiveness

BIOEQUIVALENCE STUDIES

• compare the bioavailability of the same active pharmaceutical ingredient between two drug products -- the test product and a reference product
• evaluate whether the test product is equivalent to the reference product in terms of bioavailability

GENERIC DRUG PRODUCT

• is a version of a drug that has been approved by the FDA as being equivalent tot he reference listed drug, which is usually the brand-name drug
• do not undergo extensive clinical safety and efficacy studies
• focus on demonstrating pharmaceutical equivalence, bioequivalence, and therapeutic equivalence to the reference drug

BIOAVAILABILITY AND BIOEQUIVALENCE

serves as indicators of the drug product's performance in the body

ABSOLUTE BIOAVAILABILITY

• is a measure of the fraction of an administered drug that reaches the systemic circulation unchanged
• it is calculated by comparing the area under the plasma concentration-time curve (AUC) after oral administration to the AUC after intravenous administration

RELATIVE BIOAVAILABILITY

• is a measure of the fraction of a drug that reaches the systemic circulation unchanged after administration of two different dosage forms or formulations of the same drug
• it is calculated by comparing the AUC after administration of one dosage form or formulation to the AUC after administration of another dosage form or formulation

DIRECT METHODS

• involve measuring the concentration of the active ingredient or active moiety in biological fluids, such as blood or plasma, following administration of the drug product (direct measure of the drug's absorption into the systemic circulation)
• high accuracy, sensitivity, and reproducibility

INDIRECT METHODS

• involve comparing the pharmacodynamic response or clinical effects of the drug product
• assess the biological effects of the drug rather than directly measuring its concentration
• evaluating the drug's effect on the body, such as changes in blood pressure or heart rate
• have limitations in terms of accuracy and sensitivity compared to direct methods

PHARMACODYNAMIC (PD) ENDPOINTS

• measure the effect of a drug on a specific biological response or outcome
• focus on demonstrating a dose-response relationship and ensuring that the selected dose reflects the rising phase of dose-response curve

CLINICAL ENDPOINTS

• involve evaluating the comparative clinical effects of different drug products using predetermined _ in a specific patient population
• least accurate, least sensitive to differences in bioavailability, and the most variable
• ex: symptom relief, disease progression, survival rates, or other relevant clinical outcomes

IN VITRO STUDIES

• specifically comparative drug release / dissolution studies
• involve measuring the rate at which a drug is released from different formulations under specific conditions

BIOWAIVER

in certain cases, comparative dissolution profiles of different dose strengths of a solid oral drug product, such as immediate-release tablets, can be used to obtain a _ from conducting additional in vivo bioequivalence studies

STANDARD CROSS-OVER DESIGN

subjects receive a single dose of both the test and reference products on separate occasions (random assignment is done)

WASHOUT PERIOD

• between administration of the two products
• allows elimination before next administration and minimizes any residual effects

HIGHEST STRENGTH RECOMMENDATION

• any potential differences in bioavailability are more likely to be detected at higher doses

SAMPLE SIZE AND STATISTICAL POWER

• the number of subjects in the study should be sufficient to achieve appropriate statistical power

ANALYSIS OF PHARMACOKINETIC PARAMETERS

• ex: AUC and Cmax
• capture drug's absorption, distribution, metabolism and excretion characteristics

CONFIDENCE INTERVAL

• 90% _ of the geometric mean ratio for Cmax and AUC are entirely within the predefined bioequivalence limitis
• ensures that the differences between the test and reference products are within an acceptable range