Phar431: Bioavailability/Bioequivalence (4/9/15)

Calculation of Bioavailability: Urinary drug excretion data may also be used to measure relative bioavailability, as long as the total amount of intact drug excreted in the urine is collected. How can the PERCENT RELATIVE AVAILABILITY using urinary excretion data be determined?

%Relative bioavailability = ( [Du]a / [Du]b ) x 100 Where [Du] is the total amount of drug excreted in the urine

Calculation of Bioavailability: The __________ is used as a measure of the total amount of unaltered drug that reaches systemic circulation

Area Under the Curve (AUC)

Which of the following conditions does NOT require special consideration for testing bioequivalency? A. drugs having high intrasubject variability B. drugs having half-lives of less than 8 hours C. drugs that are stereoisomers D. drugs that are intended for local effects

B. drugs having half-lives of less than 8 hours

Absolute availability, symbolized by the letter __, may be expressed as a fraction or as a percent by multiplying it by 100

F Note: -For IV, F=1 or 100% -For other routes, F<1 or <100%

Biopharmaceutics Classification System (BCS): Biowavers may be given by FDA for certain Class __ drugs.

for certain Class 1 drugs

A ___________ is dispensing a different brand or an unbranded drug product in place of the prescribed drug product. The substituted drug product contains the same active ingredient or therapeutic moiety as the same salt or ester in the same dosage form but is made by a different manufacturer (basically must be a pharmaceutical equivalent)

generic substitution For example, a prescription for Motrin brand of ibuprofen might be dispensed by the pharmacist as Advil brand of ibuprofen or as a nonbranded generic ibuprofen if generic substitution is permitted and desired by the physician. Does not require a physicians approval

Bioavailability Studies: When performing bioavailability testing, the data that is gathered is used to define what three major parameters?

1. The amount or proportion of drug absorbed from the formulation or dosage form 2. The rate at which the drugs was absorbed 3. The duration of the drug's presence in biologic tissue or fluid

What code is assigned to drug products requiring further FDA investigation and review to determine therapeutic equivalence? A. B* B. BE C. BT D. BX

A. B* The B* code signifies that the Agency will take no position regarding the therapeutic equivalence of the product until the Agency completes its investigation and review

Therapeutic Equivalence Evaluation Codes: -Two coding system designed by FDA Drug products that FDA considers NOT to be therapeutically equivalent to other pharmaceutically products are coded with the first-letter _____

B i.e. drug products for which actual or potential bioequivalence problems have not been resolved by adequate evidence of bioequivalence. Often the problem is with specific dosage forms rather than with the active ingredients. These are designated BC, BD, BE, BN, BP, BR, BS, BT, BX, or B*.

Quick Think: Two products MUST have the same bioavailability to be considered bioequivalent. A. True B. False

B. False, the two products must have SIMILAR bioavailabilities; they don't have to be the same

The _________ is identified by the FDA as the drug product on which an applicant relies when seeking approval of an Abbreviated New Drug Application (ANDA)

Reference Listed Drug (RLD) Note: the RLD is generally the brand-name drug that has a full New Drug Application (NDA)

Calculation of Bioavailability: ________ availability is the availability of the drug from a drug product as compared to a recognized standard

Relative (apparent) availability

Special Considerations for Testing Bioequivalency: Describe 5 special considerations for testing bioequivalency.

1. Drugs with high intrasubject variability Bioequivalence study based on parameters related to systemic bioavailability (AUC, Cmax , Tmax etc.) might require large number of subjects. e.g. Cyclosporine 2. Drugs with very long elimination half-lives A complete plasma drug concentration-time curve may be difficult to obtain. For these a parallel design can be used instead of crossover design Also a truncated (short-ended) plasma drug concentration-time curve (0-72 hr) may be more practical. e.g. Amiodarone has elimination half-life of 58 days. 3. Drugs that are stereoisomers Measurement of individual enantiomers may be important if each enantiomer will have different pharmacodynamic and pharmacokinetic properties. e.g. Citalopram and escitalopram. 4. Drugs intended for local effect. These drugs should not have systemic bioavailability as they are intended for local effect. e.g. Topical ointments, antacids etc. For these drugs a "surrogate" marker is needed for bioequivalence determination. e.g. For assessing bioequivalence of topical steroid hydrocortisone skin blanching can be used as "surrogate" marker. 5. Drugs with narrow therapeutic range. Additional testing may be required to ensure quality of drug products containing drugs with narrow therapeutic index. Examples of drugs with narrow therapeutic index are digoxin, warfarin, phenytoin, and theophylline.

Bioavailability Study Designs: Currently, three different studies may be required for SOLID ORAL DOSAGE forms. Name them

1. Fasting study 2. Food intervention study 3. multiple-dose (steady-state) study Note: proper study design and statistical evolution are important considerations for the determination of bioequivalence

Bioavailability testing is primarily done in one of two ways. Describe each way

1. measuring the plasma concentration of drug over time following one dose of the drug 2. measuring the cumulative amount of drug excreted in the urine over time

Therapeutic Equivalents -Drug products are considered to be therapeutic equivalents only if they are pharmaceutical equivalents and if they can be expected to have the same clinical effect and safety profile when administered to patients. In order for drug products to be therapeutic equivalents, they must meet what 5 criterion?

1. they are safe and effective 2. they are pharmaceutical equivalents 3. they are bioequivalent 4. they are adequately labeled 5. they are manufactured in compliance with Current Good Manufacturing Practice regulations.

Therapeutic Equivalence Evaluation Codes: -Two coding system designed by FDA Drug products that the FDA considers to be THERAPEUTICALLY EQUIVALENT to other pharmaceutically equivalent products and coded with the first letter _______

A i.e. (1) there are no known or suspected bioequivalence problems. These are designated AA, AN, AO, AP, or AT, depending on the dosage form; or (2) actual or potential bioequivalence problems have been resolved with adequate in vivo and/or in vitro evidence supporting bioequivalence. These are designated *AB*.

Pharmaceutical equivalents must also meet the same content uniformity, disintegration times, and/or dissolution rates A. True B. False

A. True

Pharmaceutical substitution generally requires the physician's approval. A. True B. False

A. True

The process of dispensing a pharmaceutical equivalent product for the prescribed drug product is known as: A. generic substitution B. pharmaceutical substitution

A. generic substitution

Therapeutic Equivalence Evaluation Codes: -Two coding system designed by FDA When actual or potential bioequivalence problems have been resolved with adequate in vivo and/or in vitro evidence supporting bioequivalence, these are designated as _____

AB

The ___________ bioavailability of drug is the systemic availability of a drug after extravascular administration (e.g., oral, rectal, transdermal, subQ) compared to IV DOSING.

Absolute bioavailability Note: the absolute availability of a drug is generally measured by comparing the respective AUCs after extravascular and IV administration

The process of dispensing a pharmaceutical alternative for the prescribed drug product is known as: A. generic substitution B. pharmaceutical substitution

B. pharmaceutical substitution

The ___________ System, developed by Amidon in 1995, is based on the aqueous solubility of the drug and the permeability of the drug through the GI tract

Biopharmaceutics Classification System (BCS) -divided into 4 classes (Class 1, Class 2, Class 3, and Class 4) -For regulatory purposes, drugs are classified according to the BCS in accordance the solubility, permeability, and dissolution characteristics of the drug

Bioequivalence: For systemically absorbed drugs, the test (generic) and reference listed drug (brand-name) shall be considered bioequivalent if: A. 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 B. the extent of absorption of the test drug does not show a significant difference from the extent of absorption of the reference drug C. Both A and B

C. Both A and B

According to the Biopharmaceutics Classification System (BCS), which of the following types of drugs belong to Class 3? A. drugs having high solubility and high permeability B. drugs having low solubility and high permeability C. drugs having high solubility and low permeability D. drugs having low solubility and low permeability

C. drugs having high solubility and low permeability Note: Class 1: drugs having high solubility and high permeability Class 2: drugs having low solubility and high permeability Class 3: drugs having high solubility and low permeability Class 4: drugs having low solubility and low permeability

Quick think: Diazepam HCl 50 mg was formulated in both spansules and pulvules. Both products proved to have similar efficacy and bioavailability when a clinical trials was conducted. They can be categorized as: A. pharmaceutical alternative B. pharmaceutical equivalent C. therapeutic equivalent

C. therapeutic equivalent -In order to be pharmaceutically equivalent, they would have to have identical dosage forms -in order to be a pharmaceutical alternative, they would be different esters, salts, or complexes of diazepam

Which of the following is TRUE regarding drug products that are assigned a bioequivalence category of A? A. they are drug products for which the data reviewed by the FDA are insufficient to determine therapeutic equivalence B. they are drug products containing active ingredients that have been identified by the FDA as having documented bioequivalence problems C. they are drug products that contain active ingredients for which no in vivo bioequivalence issue is known or suspected D. they are drug products that are currently under regulatory review by the FDA

C. they are drug products that contain active ingredients for which no in vivo bioequivalence issue is known or suspected

Biopharmaceutics Drug Disposition Classification System (BDDCS): -Wu and Benet have proposed a modification of the BCS system known as BDDCS which takes into account drug metabolism and transporters in the GI tract for drugs that are orally absorbed. For BCS Class __ drugs (class 1 or class 2?), transporter effects are more important.

Class 2 drugs Note: For BCS Class 1 drugs, transporter effects are minimal

What code is assigned to specific drug products for which the data that have been reviewed by the FDA are insufficient to determine therapeutic equivalence? A. B* B. BE C. BT D. BX

D. BX

Which of the following drugs do NOT need special consideration for evaluation of bioequivalency? A. drugs with high intrasubject variability B. drugs with very long elimination half-lives C. drugs that are stereoisomers D. drugs that have a wide therapeutic index

D. drugs that have a wide therapeutic index Note: drugs that have a narrow therapeutic index would need special consideration for evaluation of bioequivalency

Which of the following is FALSE regarding a pharmaceutical equivalent drug product? A. must contain the same active ingredient B. must be in the same dosage form C. must have the same amount of active ingredient D. must have the same excipients

D. must have the same excipients Pharmaceutically equivalent drug products are formulated to contain the same amount of active ingredient in the same dosage form and to meet the same or compendial or other applicable standards (ie, strength, quality, purity, and identity), but they may differ in characteristics such as shape, scoring configuration, release mechanisms, packaging, excipients (including colors, flavors, preservatives), and expiration time.

Drug products that are pharmaceutically equivalent must: A. contain the same active ingredient B. be in the same dosage form and use the same route of administration C. have the same strength or concentration D. A and B only E. A, B, and C are correct

E. A, B, and C are correct

Practice Problem: Deymycin is a new antibiotic developed to treat acute bacterial exacerbation of chronic bronchitis. A single IV dose of 250 mg was given to a patient and the following plasma data were obtained: Time--Concentration: 1.o hours--92.3 mcg/mL 2.0 hours--85.2 mcg/mL 4.0 hours--72.6 mcg/mL 8.0 hours--52.7 mcg/mL 24.0 hours--14.7 mcg/mL 48.0 hours--2.1 mcg/mL Determine the value of AUC

For IV Bolus: AUC = Cp0/ke 1. Solve for ke: Cpt = (Cpo)(e^-ket) ln (Cpt/Cpo)/-t = ke ke = ln (85.2/92.3) / -1 ke = 0.08 2. Solve for Cpo using same equation: Cpt = (Cpo)(e^-ket) Cpo = Cpt/ (e^-ket) Cpo = 92.3/ (e^-(0.08)(1)) Cpo = 99.99 mcg/mL 3. Solve for AUC: AUC = Cpo/ke AUC = 99.99/0.08 *AUC = 1250 mcg*hr/mL*

Area Under the Curve (AUC): What equation is used to determined the area under the curve (AUC) for drug administered intravenously (IV)?

For IV drugs: [AUC] = Dose/ (ke x Vd)

Calculation of Bioavailability: The relative availability of two drug products given at the SAME dosage level and by the same route of administration can be obtained using which equation?

For SAME dosage level: Relative Bioavailability =[AUC]a / [AUC]b

Area Under the Curve (AUC): What equation is used to determined the area under the curve (AUC) for ORALLY absorbed drugs?

For orally absorbed drugs: [AUC] = FDose/ (ke x Vd)

Practice Problem: Rosencillin is a new drug for the treatment of asthma. A 100 mg dose given via the ORAL route (oral bioavailability=38%) produces an AUC0 of 245 mcg/ml*hr. The elimination rate constant is 0.1 hr^-1. What is the volume of distribution of rosencillin?

Given: F=0.38 AUC0= 245 mg/L*hr k=0.1 hr^-1 Dose = 100 mg For oral route: AUC0 = (F)(dose) / (ke)(Vd) Rearrange equation and solve for Vd: Vd = (F)(dose) / (ke)(AUC) Vd = (0.38)(100) / (0.1)(245) *Vd = 1.55 L*

How is absolute bioavailability calculated when using the area under the curve (AUC)?

Note: this measurement may be performed as long as Vd and ke are independent of the route of administration

_______ is defined as dispensing a drug product that is a therapeutic alternative to the prescribed product. For example. amoxicillin is dispensed for ampicillin, or acetaminophen is dispensed for aspirin.

Therapeutic substitution Note: therapeutic substitution requires a physician's consent

Calculation of Bioavailability: The relative availability of two drug products given at the DIFFERENT dosage level and by the same route of administration can be obtained using which equation?

When DIFFERENT doses are given: Relative Bioavailability= { [AUC]a / DOSE-a} / { {AUC]b / Dose-b} Note: RB has no units

Calculation of Bioavailability: Xarelto (rivaroxaban), a factor Xa inhibitor, is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. A 20 mg immediate release tablet produced an AUC0 of 127.9 mg hr/L. A 25 mg dose of the extended release tablet (currently in production) produced an AUC0 of 154.5 mg hr/L. A 10 mg dose of rivaroxaban given IV produces an AUC0 of 300 mg*hr/L. What is the relative bioavailability of extended release tablets as compared to immediate release tablets?

When DIFFERENT doses are given: Relative Bioavailability= { [AUC]a / DOSE-a} / { {AUC]b / Dose-b} Relative Bioavailability = ( 154.5 / 25) / (127.9 / 20) RB = 0.95

Calculation of Bioavailability: Xarelto (rivaroxaban), a factor Xa inhibitor, is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. A 20 mg immediate release tablet produced an AUC0 of 127.9 mg hr/L. A 25 mg dose of the extended release tablet (currently in production) produced an AUC0 of 154.5 mg hr/L. A 10 mg dose of rivaroxaban given IV produces an AUC0 of 300 mg*hr/L. What is the absolute bioavailability (%) of the immediate release tablets of rivaroxaban?

absolute bioavailability= ( 127.9/20) / (300/10) x 100 absolute bioavailability = 21.6%

Pharmaceutical __________ are drug products that contain the same therapeutic moiety but as DIFFERENT salts, esters, or complexes.

alternatives -For example, tetracycline phosphate or tetracycline hydrochloride equivalent to 250 mg tetracycline base are considered pharmaceutical alternatives. Different dosage forms and strengths within a product line by a single manufacturer are pharmaceutical alternatives (eg, an extended-release dosage form and a standard immediate-release dosage form of the same active ingredient. -FDA currently considers a tablet and capsule containing the same active ingredient in the same dosage strength as pharmaceutical alternatives

_________ is the process of dispensing a pharmaceutical alternative for the prescribed drug product. For example, ampicillin suspension is dispensed in place of ampicillin capsules, or tetracycline hydrochloride is dispensed in place of tetracycline phosphate.

pharmaceutical substitution