Topic 10

Question 1

Level A

Answer 1

• Level A correlation is one in which there is a predictive mathematical model for the relationship between the entire in vitro dissolution / release-time course and the entire in vivo response-time course (e.g., concentration-time profile or amount of drug absorbed-time profile)
• AXIS: % dissolved and % absorbed
• Strongest level

Question 2

Level B

Answer 2

• Level B correlation is one in which there is a predictive mathematical model for the relationship between summary measures that characterize the in vitro and in vivo time courses (e.g., mean dissolution times and mean absorption times)
• AXIS: MDT or MRT or MAT
• Medium level

Question 3

Level C

Answer 3

• Level C provides a mathematical model of the relationship between amount dissolved in vitro at a particular time and a measure of bioavailability
• AXIS: % dissolved @ 15 min and another single point (Cmax, Tmax)
• Weakest level

Question 4

Noyes-Whitney Eq.

Answer 4

= (D*A)/h * (Cs-C)

• D = diffusion rate constant
• A = surface area
• Cs = conc. of drug in stagnant layer (solubility)
• h = thickness of stagnant layer
• SINK conditions: C remains below Cs/3

Question 5

Agitation, Temp., Solubility, Salt form on RoD

Answer 5

• Agitation and Temp. both directly proportional to RoD (AFFECTS H)
• More soluble, quicker RoD (vice versa)
• Salt = ions, increase ability to go into solution, so increase RoD (AFFECTS Cs)

Question 6

Zero order vs First order

Answer 6

• ZERO order if straight line on regular graph paper (linear scale)
• FIRST order if straight line on semilog graph paper (most drugs follow first order dissolution profiles)

Question 7

IVIVC

Answer 7

• For rate and extent of abs. in vivo
• Can be surrogate to bioequivalence studies
• SUPAC (scale up post approval): minor post approval changes like site of manufacture, form change, new strength

Question 8

IVIVC IR formulations

Answer 8

• Not successful for obtaining good correlations, generally, bc in lab it can be a few minutes for dissolution but in body it can take hours due to permeability, food, gastric emptying
• A difference in sensitivity: dissolution test in vitro is more sensitive than in vivo profile

Question 9

IVIVC ER formulations

Answer 9

• Great success with IVIVC
• Release is prolonged so higher probability of RoD in vitro being correlated to in vivo
• Permeability, GE, motility contribute less to overall input

Question 10

Three KEY factors of ER products not behaving in vivo as predicted in vitro

Answer 10

• Transit times
• Permeability
• Drug degradation

Question 11

Transit Times and ER

Answer 11

• Variable between stomach/food/colon
• Colon has less SA/transporters/mucus
• Worry about safety/efficacy bc 1 patient can be getting a too low amount for it to work while another can be getting too much leading to toxicity
• Need a wide therapeutic window

Question 12

Permeability and ER

Answer 12

• Has to be permeable and abs. in colon for ER

Question 13

Drug Degradation and ER

Answer 13

• Colon is a rich region for microbiome, has bacteria that can break down drug
• F will decrease

Question 14

MDT Calc

Answer 14

• ZERO order: time at which 50% dissolved, or triangle area (B*H/2) / 100%
• FIRST order: MDT = 1/Kdiss (use half life off graph @ 50%, to find k)

Question 15

Ideal behavior characteristics in vivo

Answer 15

• Be readily absorbed in large intestine (non polar/unionized)
• Not be degraded by microflora in large intestine
• Remain in GI tract > 24 hr
• Not have physiological effect on large intestine
• Show linear elimination in vivo

Question 16

Briefly comment on gastrointestinal transit times and the use of 24-hour release products

Answer 16

The transit through the GI tract (large bowel/stomach) is highly variable. In many conditions, the mean transit time through the alimentary canal is less than 24 hours. Even under “normal” circumstances a shortened transit can occur. For these reasons, the ideal of 24-hour release products is not always realized in vivo.

Question 17

Discuss the consequence of a patient chewing your product, instead of swallowing it whole. The drug is then released quickly. What dose would the patient receive?

Answer 17

The product contains 4 times as much drug (100mg vs 25mg) as the conventional product. Rapid release of the total content could give rise to increased incidence of adverse events. This phenomenon is called “dose dumping”.

Question 18

Why do statisticians state that more subjects are needed in a bioequivalence trial when the 90% confidence interval is 0.78-1.29 in a trial with 24 subjects?

Answer 18

A larger number of subjects reduces the 90% confidence interval. Both the lower (0.78) and the upper (1.28) limits are outside the criteria used for bioequivalence (0.8/1.25). The ratio of the means of the measure may be one. To have statistical assurance this is so a larger number of subjects is needed.

Question 19

When is it likely that testing the same product (lot, etc.) against itself will not give a bioequivalent outcome? Do you think that you could conduct such a trial and that the outcome could show the products to be not equivalent?

Answer 19

When the intrasubject variability is high, declaration of bioequivalence may not occur unless a large number of subjects is used. It is extremely unlikely
that a test result would show the product to be not equivalent to itself in a well-controlled study.