Week 6- Bioavailability and Bioequivalence Pn. Khadijah Hanim Abdul Rahman School of Bioprocess Engineering Universiti Malaysia Perlis

Bioavailability and Bioequivalance Bioavailability- 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. For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.

Bioequivalence requirement. A requirement imposed by the FDA for in-vitro and/or in-vivo testing of specified drug products, which must be satisfied as a condition for marketing.

Bioequivalent drug products. describes pharmaceutical equivalent or pharmaceutical alternative products that display comparable bioavailability when studied under similar experimental conditions.

For systemically absorbed drugs, test drugs and reference listed drug- considered bioequivalence if: the rate and extent of absorption of the test drug do not show a significant difference from the rate and extent of absorption of the reference drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses

2. the extent of absorption of the test drug does not show a significant difference from the extent of absorption of the reference drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses. - and the difference from the reference drug in the rate of absorption of the drug is intentional, is reflected in its proposed labeling, is not essential in obtaining the effective body drug concentrations on chronic use, and is considered medically insignificant for the drug.

PURPOSE OF BIOAVAILABILITY STUDIES Bioavailability studies are performed for both approved active drug ingredients and therapeutic moieties not yet approved for marketing by the FDA. New formulations of active drug ingredients must be approved by the FDA before marketing. In approving a drug product for marketing, the FDA ensures that the drug product is safe and effective for its labeled indications for use. The drug product must meet all applicable standards of identity, strength, quality, and purity.

Bioavailability- considered as an aspect of drug product quality Links to in-vivo performance of drug product used in clinical trials- evidence of safety and efficacy pharmacokinetics parameters: rate and extent of systemic absorption, elimination half-life and rates of excretion and metabolism- established after single and multiple dose Data from in-vivo bioavailability- important to established recommended dosage regimens and drug labeling.

Summary: Bioavailability- to define the effect of changes in physicochemical properties of drug substance and effect of dosage form on pharmacokinetics of the drug. Bioequivalence- to compare the bioavailability of the same drug from various drug products. Bioavailability and bioequivalence- performance measures of drug product in-vivo.

Relative and absolute availability AUC (area under the drug concentration) time curve is used as a measure of the total amount of unaltered/active drug that reaches the systemic circulation. The AUC is dependent on the total quantity of available drug, FDO, divided by the elimination rate constant, k, and the apparent volume of distribution, VD. After IV, F=unity. After oral administration- F vary from 1 to 0.

Relative availability Relative (apparent) availability- availability of the drug from a drug product as compared to a recognized standard. For oral absorption drug- difficult to determine the availability- availability of drug in formulation is compared to availability of drug in a standard dosage formulation.

Relative Availability The relative availability of two drug products given at the same dosage level and by the same route of administration can be obtained using the following equation: B- product B- the recognized reference standard

Relative Availability When different doses are administered, a correcting the dose size The percent relative availability using urinary excretion data [Du]∞ - total amount of drug excreted in urine

Absolute Availability The absolute availability- drug is the systemic availability of a drug after extravascular administration (e.g., oral, rectal, transdermal, subcutaneous) compared to IV dosing. The absolute availability of a drug - generally measured by comparing the respective AUCs after extravascular and IV administration. This measurement may be performed as long as VD and k are independent of the route of administration.

Absolute Availability Absolute availability after oral drug administration using plasma data can be determined as follows: Absolute availability using urinary drug excretion data can be determined by the following:

Example: The bioavailability of a new investigational drug was studied in 12 volunteers. Each volunteer received either a single oral tablet containing 200 mg of the drug, 5 mL of a pure aqueous solution containing 200 mg of the drug, or a single IV bolus injection containing 50 mg of the drug. Plasma samples were obtained periodically up to 48 hours after the dose and assayed for drug concentration. The average AUC values (0-48 hours) are given in the table below. From these data, calculate (a) the relative bioavailability of the drug from the tablet compared to the oral solution and (b) the absolute bioavailability of the drug from the tablet. Drug Product Dose (mg) AUC (mg hr/mL) Standard Deviation Oral tablet 200 89.5 19.7 Oral solution 200 86.1 18.1 IV bolus injection 50 37.8 5.7

The relative bioavailability of the drug from the tablet is The absolute drug bioavailability from the tablet is

Methods for assessing bioavailability Direct and indirect methods In-vivo bioavailability- demonstrated by rate and extent of drug absorption- determined by comparison of measured Pharmacokinetics/ pharmacodynamic parameters, clinical observations, in-vitro studies- used to determine drug bioavailability from a drug product.

METHODS FOR ASSESSING BIOAVAILABILITY

Plasma drug concentration Systemic drug bioavailability- measurement of drug conc in blood, plasma or serum after drug administration tmax- time of peak plasma conc- time required to reach max drug conc after drug administration At tmax- peak drug absorption occurs: rate of drug absorption=rate of drug elimination Drug absorption still continues after tmax- slower rate Comparing drugs- tmax can be used as indicator of drug absorption rate tmax become smaller- absorption rate becomes more rapid.

Plasma Drug Concentration-time curve

Cmax- peak plasma drug concentration Cmax- indicates the drug is sufficiently systemically absorbed to provide therapeutics response. Cmax- provides warning of possibly toxic levels of drug

AUC- area under the curve AUC- measurement of extent of drug bioavailability AUC- total amount of active drug that reaches systemic circulation AUC- AUC from t=0 to t=∞, equal to amount of unchanged/active drug reaching general circulation divided by clearance.

AUC proportional to dose. E.g. single dose of drug is increased from 250- 1000 mg, the AUC also- 4 fold increase.

Urinary Drug Excretion Data Indirect method for estimating bioavailability Drug excreted in significant quantities as unchanged drug in urine. Du∞- cumulative amount of drug excreted in the urine- related directly to the total amount of drug absorbed

Relationship between cumulative amount of drug excreted in urine and plasma level-time curve: When drug is almost completely eliminated (point C), plasma conc approaches 0- Du∞ is obtained.

dDu/dt- rate of drug excretion. Most drugs- eliminated by 1st order process. Rate of drug excretion- dependant on 1st order elimination rate constant, k and plasma conc, Cp. (dDu/dt)max- at point B, (dDu/dt)min- at point A and C Thus, a graph comparing rate of drug excretion with respect to time should de similar shape as plasma level-time curve.

t∞- total time for the drug to be excreted. The slope of the curve segment A-B (from the graphs)- related to rate of drug absorption Point C- total time required after drug administration for the drug to be absorbed and completely excreted t=∞.

Bioequivalence studies Bioequivalent drug products- same systemic drug bioavailability- same predictable drug response Variable clinical responses among individuals- unrelated to bioavailability- due to differences in pharmacodynamicsof drug Difference in pharmacodynamics- differences in receptor sensitivity to the drug.

Bases for determining bioequivalence Bioequivalence- established if, in-vivo bioavailability of test drug product- does not differ significantly in rate and extent of absorption when administered at the same molar dose under similar experimental condition, either single dose or multiple dose.

DESIGN AND EVALUATION OF BIOEQUIVALENCE STUDIES Bioequivalence studies- to compare the bioavailability of generic drug product to brand-name product. Once bioequivalence established- likely both generic and brand-name dosage forms, produce the same therapeutic effect. The basic design for a bioequivalence study is determined by The scientific questions to be answered, The nature of the reference material and the dosage form to be tested, The availability of analytical methods, and Benefit–risk and ethical considerations with regard to testing in humans. For some generic drugs, the FDA offers general guidelines for conducting these studies

For bioequivalence studies- test and reference drug formulations must contain: Pharmaceutical equivalent drug In the same dose strength In similar dosage forms (e.g: Immediate/controlled release) The same route of administration

Analytical Methods Analytical method used in an in-vivo bioavailability or bioequivalence study- must be demonstrated to be: - accurate sufficient sensitivity with appropriate precision For bioavailability studies- both parent drugs and major active metabolites are studied For bioequivalence studies- parent drug is measured.

Reference Standard For bioequivalence studies: One formulation of drug is chosen as reference standard Reference drug product- should be administered by the same route unless an alternative route is needed.

Study Design Three different studies may be required for solid oral dosage forms, (1) a fasting study, (2) a food intervention study, and/or (3) a multiple-dose (steady-state) study.

Crossover Designs Subjects are selected at random Complete crossover design is usually employed- each subject receives the test drug product and reference product. E.g. Latin-square crossover designs- comparing 3 different drug formulations (A, B, C) Plans the clinical trial- each subject receives each drug product only once

All patients do not receive the same drug product on the same day and in the same order After each subject receives a drug product- blood samples are collected at appropriate time intervals Time intervals should be spaced- peak blood conc, total AUC and absorption/elimination phases may be well described.

Evaluation of the data Analytical Method Must be accurate, precision, sensitive and specific Only one method is implemented during bioequivalence study - Data- in tabulated and graphic form

Statistical Evaluation of the data Bioequivalence- determined using a comparison of population averages of bioequivalence metric, such as AUC and Cmax To established bioequivalence- calculated confidence interval should be between 80-125% (for ratio of the product averages). There must be no statistical difference between bioavailability of test product and reference product

Pharmacokinetic Evaluation of the data For single-dose studies (including fasting study/ food intervention study)- pharmacokinetic analyses include calculation for each subject: -AUC (AUC0-t), (AUC0-∞) -tmax and Cmax -k, t1/2 and other parameters may be estimated

Bioequivalence example No statistical differences for pharmacokinetics parameters. 90% confidence limit-within 80-125% of reference products The power test for AUC were above 99%- good precision of data The power test for Cmax was 87.9%- this parameter was more variable.

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