Bioavailability and Bioequivalence (BABE) General Concept and overview Bioavailability a) Is a measurement of the rate and extent (amount)

to which the active ingredient or active moiety becomes available. b) Is also considered as a measure of the rate and extent of therapeutically active drug that is systemically absorbed. Bioequivalence drug products A generic drug product is considered bioequivalent to the reference drug product if both products are pharmaceutically equivalents and its rate and extent of systemic drug absorption (bioavailability) do not show a statistically significant difference when administered in the same dose of the active ingredient, in the same chemical form in a similar dosage form, by the same route of administration and under the same experimental conditions. Generic drug product a) The generic drug product requires an Abbreviated New Drug Application for approval by the United States Food and Drug Administration and may be marketed after patent expiration of the Reference drug product. b) The generic drug product must be a therapeutic equivalent to the Reference drug product but may differ in certain characteristics including shape, scoring configuration, packaging, and excipients (including colors, flavors, preservatives, expiration date and minor aspects. Pharmaceutical Equivalents a) Are drug products that contain the same therapeutically active ingredients), same salt, ester or chemical form; are of the same dosage form; and are identical in strength and concentration and route of administration. b) Pharmaceutical equivalents may differ in characteristics such as shape, scoring, configuration, release mechanisms, packaging, and excipients (including colors, flavouring, preservatives) Reference drug product Is usually currently marketed brand name product with a full New Drug Application and is usually approved by the FDA. Therapeutic equivalent drug products Are pharmaceutical equivalents that can be expected to have the same clinical effect and safety profile when administered to patients under the same conditions specified in the labelling. Therapeutic equivalent drug products a) The products are safe and effective b) The products are pharmaceutical equivalent c) The drug products are bioequivalent d) The drug products are adequately labelled e) The drug products are manufactured in compliance with CGMP regulations Pharmaceutical alternatives Are drug products that contain the same therapeutic moiety but are different salts, esters, or complexes or are different dosage form; or strengths

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Bioavailability and Bioequivalence Determination May be determined directly using plasma drug concentration versus time profiles, urinary drug excretion studies, measurements of an acute pharmacological effect, clinical studies, or in vitro studies. 1. Acute pharmacological effects a) Onset time- The time of the drug administration to the MEC b) Intensity The intensity of the pharmacological effect is proportional to the number of receptors occupied by the drug up to a maximum pharmacological effect. c) Duration of Action- The time for which the drug concentration remains above the MEC. d) Therapeutic Window The drug concentration range between the MEC and MTC *MEC minimum effective concentration *MTC minimum toxic concentration 2. Plasma Drug concentration - Time for peak plasma concentration relates to the rate constants for systemic drug absorption and elimination. a) Peak Plasma concentration - The plasma drug concentration at Tmax relates to the intensity of the pharmacological response. 3. Area under the plasma drug concentration versus time curve relates to the amount or extent of drug absorption. The amount of systemic dug absorption is directly related to the AUC. The AUC is usually calculated by the trapezoidal rule and is expressed in units of concentration multiplied by time. 4. Urinary Drug Excretion a. The cumulative amount of active drug in the urine is directly related to the extent of systemic drug absorption b. The rate of drug excretion in the urine is directly related to the rate of systemic drug absorption. c. The time for the drug to be completely excreted corresponds to the total time for the drug to be systemically absorbed and completely excreted after administration. 5. Clinical Response a. Can be used to measure bioavailability quantitatively; however they are less precise than other methods and are highly variable because of individual differences in drug pharmacodynamics and subjective measurements. RELATIVE AND ABSOLUTE BIOAVAILABILTY Relative Bioavailability 1. Is the systemic availability of the drug from a dosage form as compared to a Reference standard given by the same route of administration. 2. Is calculated as the ratio of the AUC for the dosage form to the AUC for the Reference dosage form given in the same dose. 3. A relative bioavailability of 1 (or 100%) implies that drug bioavailability from both dosage forms is the same but does not indicate the completeness of systemic drug absorption.

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Absolute Bioavailability (F) 1. Is the fraction of drug systemically absorbed from the dosage form 2. Calculated as the ratio of the AUC for the dosage form given orally to the AUC obtained after intravenous (IV) drug administration (adjusted for dose) 3. A parenteral drug solution given by IV administration is considered to have 100% systemic absorption (i.e., F= 1) 4. An F value of .80 (or 80%) indicates that only 80%bof the drug was systemically available from the oral dosage form. Bioequivalence Studies - Are performed to compare the bioavailability of the generic drug product

Study Design
1. Fasting Study 2. Food Intervention Study 3. Multiple dose (steady state) Study Fasting Study 1. Bioequivalence studies are usually evaluated by a single dose, two period, two treatments, two sequences, open label, randomized cross over design, comparing equal doses of the test (generic) and Reference (brand) products in fasted, adult, healthy subjects. 2. Both male and female subjects may be used in the study 3. Blood sampling is performed just before the dose (zero time) and at appropriate intervals after the dose to obtain an adequate description of the plasma drug concentration versus time profile. Multiple Dose (Steady State) Study 1. Required for oral extended (controlled) release drug products in addition to a single dose fasting study and food intervention study. 2. Three consecutive trough concentrations (Cmin) on three consecutive days should be determined that the subjects are at steady state. 3. The last morning dose is given to the subject after an overnight fast with continual fasting for at least 2 hours following dose administration. Blood sampling is performed similarly to the single dose study. Waivers of an in-vivo bioequivalence study (Biowaivers) A comparative in vitro dissolution (drug release) study between the test and reference products may be used in lieu of an in vivo bioequivalence study for some immediate release (conventional) oral drug products. No Bioequivalence study is required for certain drug products given as a solution such as oral, parenteral, ophthalmic, or other solutions. DRUG PRODUCT SELECTION Generic Drug Substitution a) Is the process of dispensing a generic drug product in place of the prescribed drug product. b) The substituted product must be a therapeutic equivalent, approved by the FDA, expected to produce the same clinical effect and safety profile as the prescribed drug. Prescribability a) Refers to the, measurement of average bioequivalence in which the comparison of population means of the Test and Reference products falls within acceptable statistical criteria. b) Is the current basis for FDA approval of therapeutic equivalent generic drug products 3 |BABE

Switchability a) Refers to the measurement of individual bioequivalence, which requires knowledge of individual variability (intra subject variability) and subject by formulation effects. b) Assures that the substituted generic drug product produces the same response in the individual patient. Therapeutic substitution Is the process of dispensing a therapeutic alternative in place of the prescribed drug product. The substituted drug product is usually in the same therapeutic class and is expected to have a similar clinical profile. Formulary issues a) Formulary is a list of drugs. b) A positive formulary lists all drugs that may be substituted, whereas a negative formulary lists drugs for which the pharmacist may not substitute. c) A restrictive formulary lists only those drugs that may be reimbursed without justification by the prescriber; for drugs not listed in the restrictive formulary, the prescriber must justify the need for the no listed drug. The Orange Book a) Provides therapeutic evaluation codes for drug products b) A rated drug products are drug products that contain active ingredients and dosage forms that are not regarded as presenting either actual or potential bioequivalence problems or drug quality standards issues. c) B rated drug products are drug products for which actual or potential bioequivalence problems have not been resolved by adequate evidence of bioequivalence.

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