Bioavailability

What is biopharmaceutics? (1)

The study of inter-relationship of the physicochemical properties of the drug and the drug product based on the biological performance of the drug

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What is biopharmaceutics? (2)

Uses quantitative methods and theoretical models to evaluate the effect of the drug substance, dosage form and routes of drug administration on the therapeutic requirements of the drug and the drug product in a physiological environment

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How do drugs have an effect?

Drug release - absorption - drug in blood - elimination (excretion/metabolism) - drug in tissue (clinical effect)

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What is bioavailability? (1)

Description of rate/extent of which a drug when administered in a pharmaceutical dosage form becomes available at site of pharmacological effect

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What is bioavailability? (2)

Indicates measurement of rate/extent (amount) of therapeutically active drug that reaches the systemic circulation and is available at site of action

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Why is bioavailability important to pharmaceutical scientists?

Key performance indicator of efficiency of a formulation, variance (poor clinical response in certain individuals), expertise in pharmaceutical science, understand key concepts to solve OTC issues, choose formulations in clinical setting (hospital)

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Is bioavailability initially measured in vitro or in vivo?

In vivo

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What is pharmacokinetics?

What the body does to the drug. Assumes correlation of systemic drug concentration action. Easy to measure

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What is pharmacodynamics?

What the drug does to the body. Relevance of other parameters has to be ruled out. Difficult to measure

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Describe features of pharmacokinetics

Plasma concentration-time curves, net effects of drug release, stability, presystemic metabolism, absorption. Therapeutic window, varies between people/drugs, effect vs side effects, external influences

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What information does a pharmacokinetics drug provide?

Dosing level, duration, therapeutic window, dosing regimen, accumulation effects (systemic, active site, metabolites), bioavailability, use of urinary drug extraction/blood samples (no metabolites/robust analytic method)

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Which factors are considered in bioavailability?

Gender (avoid women of child bearing age, how many men/women), age, condition (healthy, fasted/fed), body weight

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Describe features of quantifying bioavailability

Plasma concentration-time curves. Absorption and elimination phases (Ka., Ke, Cp max, T max, AUC) - shows rate/extent

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What is absolute bioavailability (F)? (1)

Fraction of an administered dose which actually reaches the systemic circulation e.g. F = 1 when 3 mg is taken and 3 mg of drug is in the blood

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What is absolute bioavailability (F)? (2)

IV infusion has F = 1. F = (AUC ev/AUC iv). Can be divided by dose if in equivalent. F = (AUC ev/dose ev) / (AUC iv / dose ev). F = (Xu) abs / (Xu) iv where (Xu) is the total cumulative amounts of unchanged drug in urine

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What is relative bioavailability?

Availability of a drug product as compared to another dosage form or product of the same drug given in the same dose. RB = (AUC a/ AUC b) where A is test product and B is reference standard

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Which factors influence bioavailability?

Variations in absorption power, variations in pH of GI fluid, GE rate, intestinal motility, perfusion of GI tract, presystemic and first pass metabolism, age/sex/weight, disease states. Interactions with: food, fluid volume, other drugs

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How do formulations influence bioavailability?

Fast to slow: solutions, suspensions, capsules, tablets, coated tablets, CR formulations

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How do drugs and excipients influence bioavailability?

Particle size, crystalline structure, degree of hydration of crystal, salt/ester form. Amount of disintegrant, amount of lubricant, special coatings, nature of diluent, compression force

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What are bioequivalent drug products?

Pharmaceutical equivalents that have similar bioavailability (e.g. are not significantly different with respect to rate and extent of absorption) when given in the same molar dose and studied under similar experimental conditions

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Outline the phases in clinical trials (1)

Phase 1 (healthy volunteers, pharmacokinetics, side effects, dose effects). Phase 2 (patients/small group, pharmacodynamics, dose response). Phase 3 (patients/large group, proof of concept). Phase 4 (patients, after registration, widen market

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Outline the phases in clinical trials (2)

Bioequivalence studies, toxicological studies, pharmacokinetics during medicine development

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Describe the graph for bioequivalence

2 formulations, equivalent PK profile, less regulatory, hard to match exactly

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How can bioequivalence be determined? (1)

In vivo PK tests in humans. In vitro test correlated with an in vivo PK test in humans. In vivo test in animals correlated to a human in vivo PK test. In vivo human test using urinary metabolites. In vivo test in humans using pharmacodynamic measure

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How can bioequivalence be determined? (2)

Comparing clinical trial data (not recommended). In vitro test without a known IVIVC. List in order of acceptability to the FDA during drug submission

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Bioavailability

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