Topic 9 (Revised)

Question 1

Advantages to the use of multiple doses for BA/BE evaluations

Answer 1

• Drug taken under conditions like those used in patients
• Shorter testing period (dosing interval)
• Less time points needed
• Plasma conc. is higher and more accurately assayed
• Data from patients for drugs that are toxic and can not be given to volunteers

Question 2

Disadvantages to the use of multiple doses for BA/BE evaluations

Answer 2

• Volunteers exposed to excess amount of drug over long time period
• Fluctuation does not indicate differences in rate abs. as well as single dose
• Assurance that steady state is achieved may be a problem
• Some subjects very likely to miss a dose or two, so not at steady state
• Greater incidence of adverse effects is more likely

Question 3

Modified Release Products

Answer 3

• Formulations where the rate and/or site of release of the active ingredient(s) is different from that of the immediate release dosage form
• Deliberate modification achieved by formulation design
• MR products may accomplish therapeutic objectives and/or convenience objectives (thereby improving adherence)
• 2 forms: delayed release, extended release

Question 4

Delayed Release

Answer 4

• Delayed-release dosage forms release drugs at a time later than immediately after administration
• Exhibit a lag time in their plasma concentration-time profiles
• Often have coatings (e.g., enteric) that delay release until it has passed through the stomach
• Typified by a delay before the plasma concentration begins to rise
• Patient education: do not chew or crush; delayed onset of action not useful in acute situations

Question 5

Delayed Release Issue

Answer 5

• Variability in lag time
• Lag time is often highly variable (both within subject and between subject)
• The product cannot be counted on for immediate onset of action or even for a specific time of onset
• Often require dosing on an empty stomach to reduce variability

Question 6

Extended-Release

Answer 6

• Designed to reduce the frequency of drug administration as compared to the use of an immediate-release dosage form

• Also designed to reduce the fluctuation (SWING) in the plasma concentration-time profile (and presumably adverse events) or to maintain a concentration that provides near constant drug response throughout the dosing interval
• Food Effects are common for extended release formulations

Question 7

Long Half-Life Drugs

Answer 7

• > 24 hours
• There is less need for modified-release products for long half-life drugs
• Given once every 12 or 24 hours, there is not that much fluctuation for immediate-release products
• Accumulation based on repeated administration because its half-life is greater than the dosing interval used

Question 8

Short to Intermediate Half-Life Drugs

Answer 8

• Between 2 - 24 hours
• Modified-release can help maintain a more constant plasma concentration
• A more consistent therapeutic response
• Allows a longer dosing interval to be used

Question 9

Very Short Half-Life Drugs

Answer 9

• < 2 hours
• Modified-release can be problematic because of the large dose needed to sustain levels for 6 or 8 hours
• Possibility of “dose dumping”, release of the total dose quickly, e.g., by chewing a modified-release product

Question 10

Pros of ER Formulations

Answer 10

• Sustained therapeutic blood levels of the drug
• Improved patient compliance
• Reduction in adverse side effects and improvement in tolerability

Question 11

Cons of ER Formulations

Answer 11

• Dose-dumping
• Less flexibility in dose adjustment
• If patient experiences an AE or allergy, cannot remove drug from system
• Less possibility for high dosage

Question 12

The smaller the ratio of t/t1/2…

Answer 12

the greater will be the extent of accumulation

Question 13

When the dosing interval equals the half life of the drug…

Answer 13

the Cav,ss will be about twice the average concentration after the first dose