In-class - Bioequivalence PDF

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PharDSci 518 – Pharmaceutics II – 2021 Bioequivalence April 6, 2021 Breakout group instructions:  Work together as a group to solve the following problems.  Nominate one person from your group to login to Socrative and respond with your answers and verify their correctness. To login to Socrative, go to https://b.socrative.com/login/student/ and enter in the room name announced. Next, enter your group’s name.  Make your own individual key. Each student will need to upload a completed copy of the worksheet at the end of class. Case 1: Bioavailability 1. Which of the following pharmacokinetic parameters can be used to evaluate the rate of absorption? Select all that apply. ___ Cmax ___ Tmax ___ AUC 2. Which of the following pharmacokinetic parameters can be used to evaluate the extent of absorption? Select all that apply. ___ Cmax ___ Tmax ___ AUC Four formulations of a drug are noted in the table to the right. Use this data to answer the following questions. You will not be expected to complete calculations on assessments. 3. What is the absolute bioavailability of the oral solution?

Dosage form IV solution Oral solution Oral capsule Oral tablet

Dose 60 mg 200 mg 200 mg 200 mg

AUC (mg.h/l) 450 720 680 665

4. If the oral solution is considered the reference product, what is the relative bioavailability of the oral capsule against the oral solution?

5. Would the capsule or the tablet have better relative bioavailability when compared to the oral solution as a reference product?

PharDSci 518 – Pharmaceutics II – 2021 Case 2: Bioequivalence studies 6. True or false, bioequivalence studies evaluate the absolute bioavailability of a dosage form.

7. Which of the following most appropriately defines bioequivalence? a. The fraction of the dose of intact drug that reaches systemic circulation. b. The absence of a significant difference in the rate and extent of drug absorption. c. The extent of absorption of drug following an extravascular dose in comparison to an IV dose. 8. A drug is documented to be highly water soluble, to have rapid dissolution, have high permeability, and to have a wide therapeutic window. Which of the following methods can be utilized to determine if an immediate release dosage form containing this drug is bioequivalent to another product? Select all that apply. ___ In vivo pharmacokinetic studies in healthy volunteers ___ In vivo pharmacodynamic studies ___ Clinical trials in diseased patients ___ In vitro dissolution testing 9. A drug is characterized as poorly water soluble and highly permeability. Which of the following methods can be utilized to determine if a dosage form containing this drug is bioequivalent to another product? Select all that apply. ___ Pharmacokinetic studies in healthy volunteers ___ Pharmacodynamic studies ___ Clinical trials in diseased patients ___ In vitro dissolution testing 10. True or false, bioequivalence testing is generally done through a randomized crossover pharmacokinetic study in healthy volunteers. 11. To determine bioequivalence from an in vivo pharmacokinetic study, which of the following PK parameters needs to be statistically similar between the test formulation and the reference formulation? Select all that apply. ___ AUC ___ Cmax ___ Tmax ___ CL

The figure to the right represents data for an in vivo pharmacokinetic bioequivalence study. The figure graphically shows the means and the 90% confidence intervals of the AUCs of four generics in comparison to the brand name product. Use it to answer the following questions.

PharDSci 518 – Pharmaceutics II – 2021 12. Which of the generics could be considered bioequivalent to the innovator product? Select all that apply. ___ Generic A ___ Generic B ___ Generic C ___ Generic D 13. Which of the generics could be considered bioinequivalent to the innovator product? Select all that apply. ___ Generic A ___ Generic B ___ Generic C ___ Generic D 14. Which of the generics have inconclusive data to show either bioequivalence or bioinequivalence? Select all that apply. ___ Generic A ___ Generic B ___ Generic C ___ Generic D The results of two in vivo pharmacokinetic bioequivalence studies are shown below. In the first study, Dosage form A was compared to the brand name product. In the second study, Dosage form B was compared to the brand product. Use this data to answer the below questions. Dosage form A compared to brand Dosage form B compared to brand (test/reference (test/reference (test/reference (test/reference AUC) Cmax) AUC) Cmax) Subject 1 Subject 1 120% 115% 110% 105% Subject 2 Subject 2 120% 105% 150% 120% Subject 3 Subject 3 110% 112% 60% 80% Subject 4 Subject 4 110% 108% 130% 120% Subject 5 Subject 5 90% 80% 90% 95% Subject 6 Subject 6 110% 120% 110% 110% Average Average 108% 110% 107% 105% 90% CI 90% CI 87 to 129% 103% to 117% 97% to 116% 95% to 115% Compare the results of dosage form A and dosage form B. Which formulation had more variability? How do you know? 15.

16. Is Dosage Form A bioequivalent to the brand name product? How do you know?

17. Is Dosage Form B bioequivalent to the brand name product? How do you know?

PharDSci 518 – Pharmaceutics II – 2021 Case 3: Pharmaceutical equivalents and pharmaceutical alternatives 18. Bristol Myers Squibb and Barr both Tablet by Bristol manufacture warfarin sodium tablets. Myers Squibb Based upon the information available in Active ingredient Warfarin sodium the table to the right, are these two Dosage form Tablet tablets considered pharmaceutical Route Oral equivalents? Why or why not? Strength 5 mg a. Yes, they contain the same active Shape Round ingredient. Excipients FD&C Yellow No. 6 b. Yes, they are both tablets. Lactose Magnesium Stearate c. Yes, they contain the same active Starch ingredient, dosage form, route, and strength. c. No, they contain different excipients. d. No, they are different shapes.

Tablet by Barr Warfarin sodium Tablet Oral 5 mg oval FD&C Yellow No. 6 Hypromellose Lactose Magnesium Stearate Pregelatinized Starch

19. Information about Wellbutrin SR and Aplenzin are noted below. Which of the following best describes these two Wellbutrin SR Aplenzin medications? Active ingredient Bupropion hydrochloride Bupropion hydrobromide a. Pharmaceutical Dosage form; Route Tablet, extended release; oral Tablet, extended release; oral equivalents Strength 100 mg 174 mg b. Pharmaceutical alternatives c. Therapeutic equivalents d. Bioequivalents 20. To be therapeutic equivalents, drug products must be which of the following? Select all that apply. ___ Pharmaceutical equivalents ___ Pharmaceutical alternatives ___ Bioequivalent 21. True or false, Drug products classified as therapeutically equivalent can be substituted with the full expectation that the substituted product will produce the same clinical effect and safety profile as the prescribed product. Case 4: TE Codes 22. If the first letter of a therapeutic equivalence code is “A,” what does this mean? a. Drug products are considered therapeutically equivalent. b. Drug products are not considered therapeutically equivalent.

23. If the first letter of a therapeutic equivalence code is “B,” what does this mean? a. Drug products are considered therapeutically equivalent. b. Drug products are not considered therapeutically equivalent. 24. If a drug product is rated AB, what does this mean? a. The product has no issues with bioequivalence. b. The product has met necessary bioequivalence standards. c. The product is not considered to be therapeutically equivalent.

PharDSci 518 – Pharmaceutics II – 2021 25. If a drug product is rated BP, what does this mean? a. The product has insufficient data to determine bioequivalence. b. The product has documented bioequivalence problems. c. The product has potential bioequivalence problems. 26. Fill out the below table to summarize the TE codes listed in the learning objectives. TE code Meaning No issues with bioequivalence Product has insufficient data to determine bioequivalence Meets necessary bioequivalence standards Product has documented bioequivalence problems Product has potential bioequivalence problems

Case 5: Determining therapeutic equivalence 27. Are these products therapeutically equivalent? Use the table from the Orange Book below to help you.  Coumadin® (warfarin sodium) 2 mg oral tab by Bristol Myers Squibb  Warfarin sodium 2 mg oral tab by Barr Active Ingredient

Proprietary Name

Appl No

Product Number

Dosage Form

Route

Strength

TE Code

RLD

RX

WARFARIN SODIUM

COUMADIN

N009218

13

TABLET

ORAL

2MG

AB

RLD

RX

WARFARIN SODIUM

WARFARIN SODIUM

A040145

2

TABLET

ORAL

2MG

AB

Mkt.Status

RS

Applicant Holder BRISTOL MYERS SQUIBB PHARMA CO BARR LABORATORIES INC

Approval Date Approved Prior to Jan 1, 1982 26-Mar-97

a. Yes, these two products are therapeutically equivalent. b. No, these two products are not therapeutically equivalent.

28. Are these products therapeutically equivalent? Use the table from the Orange Book below to help you.  Proventil-HFA® (albuterol) 0.09 mg/inhalation metered dose inhaler by 3M  Ventolin HFA® (albuterol) 0.09 mg/inhalation metered dose inhaler by GlaxoSmithKline Mkt.Statu s

Active Ingredient

Proprietary Name

RX RX

ALBUTERO L SULFATE ALBUTERO L SULFATE

PROAIR HFA PROVENTIL-HFA

Appl No N02145 7 N02050 3

Product Numbe r

1 1

Dosage Form AEROSOL , METERED AEROSOL ,

Route

Strength

INHALATION INHALATION

EQ 0.09MG BASE/INH EQ 0.09MG BASE/INH

TE Code

RL D

R S

AB2 AB1

RL D RL D

R S R S

Applicant Holder

TEVA 3M

Approva l Date 29-Oct04 15-Aug96

PharDSci 518 – Pharmaceutics II – 2021

RX

ALBUTERO L SULFATE

VENTOLIN HFA

N02098 3

1

METERED AEROSOL , METERED

RX

ALBUTERO L SULFATE

PROAIR RESPICLICK

N20563 6

1

POWDER, METERED

INHALATION

INHALATION

EQ 0.09MG BASE/INH EQ 0.090MG BASE/INH

BX

RL D

R S

GLAXOSMITHKLINE

19-Apr01

RL D

R S

TEVA

31-Mar15

a. Yes, these two products are therapeutically equivalent. b. No, these two products are not therapeutically equivalent.

29. Two made up HFA inhalers of albuterol are noted in the table below. Are these two products therapeutically equivalent based on this information?  EasyBreathe HFA  FreshAir HFA Mkt.Status

Active Ingredient

Proprietary Name

Appl No

Product Number

RX

ALBUTEROL SULFATE

PROVENTIL-HFA

N02050 3

1

RX

ALBUTEROL SULFATE

EasyBreathe HFA

N02222 2

1

RX

ALBUTEROL SULFATE

FreshAir HFA

N02333 3

1

Dosage Form AEROSOL , METERED AEROSOL , METERED AEROSOL , METERED

Route

Strength

TE Code

RLD

RS

Applicant Holder

Approval Date

INHALATION

EQ 0.09MG BASE/INH

AB1

RLD

RS

3M

15-Aug96

INHALATION

EQ 0.09MG BASE/INH

BX

CPPS

29-Oct20

INHALATION

EQ 0.09MG BASE/INH

BX

CPPS

15-Aug20

a. Yes, these two products are therapeutically equivalent. b. No, these two products are not therapeutically equivalent.

30. Are these products therapeutically equivalent? Use the table from the Orange Book below to help you.  Albuterol 2 mg/5 mL oral syrup by Teva  Albuterol 2 mg/5 mL oral syrup by Lannett Co Inc Mkt.Status RX RX

Active Ingredient ALBUTEROL SULFATE ALBUTEROL SULFATE

Proprietary Name ALBUTEROL SULFATE ALBUTEROL SULFATE

Appl No A07341 9 A07810 5

Product Number

Dosage Form

Route

1

SYRUP

ORAL

1

SYRUP

ORAL

Strength EQ 2MG BASE/5ML EQ 2MG BASE/5ML

TE Code AA

RLD

RS

Applicant Holder

Approval Date

RS

TEVA

30-Mar-92

LANNETT CO INC

27-Dec-06

AA

a. Yes, these two products are therapeutically equivalent. b. No, these two products are not therapeutically equivalent.

31. Are these products therapeutically equivalent? Use the table from the Orange Book below to help you.  Glumetza® (metformin HCl) 500 mg oral extended release tablets by Santarus (N021748)  Metformin HCl 500 mg oral extended release tablets by Mylan Pharmaceuticals Inc (A200690) Mkt.

Active Ingredient

Proprietary Name

Appl No

Product

Dosage

Route

Strength

TE

RLD

RS

Applicant Holder

Approval

PharDSci 518 – Pharmaceutics II – 2021 Status Number

RX

METFORMIN HYDROCHLORIDE

METFORMIN HYDROCHLORIDE

A203755

1

RX

METFORMIN HYDROCHLORIDE

METFORMIN HYDROCHLORIDE

A076706

1

Form TABLET, EXTENDE D RELEASE TABLET, EXTENDE D RELEASE

Code

Date

ORAL

500MG

AB3

ACTAVIS LABORATORIES FL INC

ORAL

500MG

AB1

APOTEX INC

1-Aug16 14-Dec04

500MG

DISCN

METFORMIN HYDROCHLORIDE

GLUCOPHAGE XR

N021202

1

RX

METFORMIN HYDROCHLORIDE

METFORMIN HYDROCHLORIDE

A200690

1

RX

METFORMIN HYDROCHLORIDE

METFORMIN HYDROCHLORIDE

A076873

1

RX

METFORMIN HYDROCHLORIDE

GLUMETZA

N021748

1

TABLET, EXTENDE D RELEASE TABLET, EXTENDE D RELEASE TABLET, EXTENDE D RELEASE TABLET, EXTENDE D RELEASE

ORAL

**Federal Register determination that product was not discontinued or withdrawn for safety or efficacy reasons**

ORAL

500MG

AB2

BRISTOL MYERS SQUIBB CO MYLAN PHARMACEUTICALS INC

ORAL

500MG

AB1

SANDOZ INC

14-Dec04

ORAL

500MG

AB3

SANTARUS INC

3-Jun-05

RLD

RLD

13-Oct00 1-Aug12

a. Yes, these two products are therapeutically equivalent. b. No, these two products are not therapeutically equivalent.

32. Are these products therapeutically equivalent?  Sinemet (carbidopa/levodopa) 25/100 mg oral tablet by Merck Sharp Dohme (N017555)  Carbidopa/levodopa 25/100 mg oral extended release tablet by Mylan (A075091) Active Ingredient

Proprietary Name

RX

CARBIDOPA; LEVODOPA CARBIDOPA; LEVODOPA CARBIDOPA; LEVODOPA CARBIDOPA; LEVODOPA CARBIDOPA; LEVODOPA

SINEMET CARBIDOPA AND LEVODOPA CARBIDOPA AND LEVODOPA CARBIDOPA AND LEVODOPA CARBIDOPA AND LEVODOPA

RX

CARBIDOPA; LEVODOPA

RX

CARBIDOPA; LEVODOPA

Mkt.Status

RX RX RX RX

Appl No

Product Number

Dosage Form

Route

Strength

TE Cod e

RLD

AB

RLD

N017555

3

TABLET

ORAL

A077120

2

ORAL

A076212

1

A076521

1

TABLET TABLET, EXTENDED RELEASE TABLET, EXTENDED RELEASE

A073589

1

TABLET

ORAL

25MG; 100MG 25MG; 100MG 25MG; 100MG 25MG; 100MG 25MG; 100MG

CARBIDOPA AND LEVODOPA

A090324

2

TABLET

ORAL

25MG; 100MG

AB

CARBIDOPA AND LEVODOPA

A075091

2

TABLET, EXTENDED RELEASE

ORAL

25MG; 100MG

AB

ORAL ORAL

RS

Applicant Holder MERCK SHARP AND DOHME CORP

AB

APOTEX INC

AB

APOTEX INC IMPAX LABORATORIES INC MAYNE PHARMA LLC MYLAN PHARMACEUTICALS INC MYLAN PHARMACEUTICALS INC

AB AB

Approval Date Approved Prior to Jan 1, 1982 2-Jun-08 16-Jun-04 14-May-04 28-Aug-92

28-Sep-09

21-Apr-00

a. Yes, these two products are therapeutically equivalent. b. No, these two products are not therapeutically equivalent.

Case 6: Wellbutrin XL generics The below data is from the original bioequivalence study that was submitted to the FDA for generic approval of Budeprion XL (manufactured by Impax labs) as a therapeutic equivalent of Wellbutrin XL. (From http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm153270.htm )

PharDSci 518 – Pharmaceutics II – 2021

As Ratio (Test/ 90% Confidence reference) interval Fasting AUC 0.98 0.919 – 1.044 Cmax 0.89 0.803 – 0.982 Fed AUC 1.08 1.014 – 1.154 Cmax 1.1 1.034 – 1.18 noted in the plasma concentration time profile to the right, differences in the Tmax between the two formulations exist. Wellbutrin XL 150 mg had a Tmax of approximately 5-6 hours while Budeprion XL 150 mg had a Tmax of 2-3 hours. Parameter

33. Would these two products be considered bioequivalent to each other? a. Yes, AUC is within the appropriate range. b. Yes, Cmax is within the appropriate range. c. Yes, both Cmax and AUC are within the appropriate ranges. d. No, Tmax is not within the appropriate range.

The above data was collected in healthy volunteers that were administered the 150 mg doses of bupropion. Because of an association between high dose bupropion and seizures, the FDA allowed the generic manufacture to extrapolate the data from the 150 mg dose study to that of a 300 mg dose. As a result, a pharmacokinetic bioequivalence study was not completed prior to approval of Bupropion XL 300 mg in 2006 as equivalent to Wellbutrin XL 300 mg. By 2007, the FDA received numerous post-marketing reports in which patients switched from Wellbutrin XL to the generic Budeprion XL experienced undesirable effects including either a lack of efficacy or an increase in side effects. By the end of 2007, the FDA recommended to the generic manufacturer that a clinical pharmacokinetic study of the 300 mg dose be completed; however, this study was ultimately terminated due to low enrollment. As a result, the FDA completed their own bioequivalence study. The data below is from that bioequivalence study conducted by the FDA. (From NEJM – Withdrawal of Generic Budeprion for Nonbioequivalence)

Parameter AUC Cmax

Ratio (T referenc 0 0