Multiple Dosage Forms

Question 1

What are the parameters of adjusting dosage regimens?

Answer 1

1. size of the drug dose
2. τ, the frequency of drug administration (ie, the time interval between doses)

Question 2

How do we predict Cp at any point in the dosage schedule?

Answer 2

If we know PK parameters for a single dose, the doses, and dosing intervals

Question 3

What is the key question for drug accumulation?

Answer 3

Will successive doses of the drug have any effect on the previous dose?

Question 4

What is the principle of superposition?

Answer 4

Assumes previous doses will not affect PK of subsequent doses

Blood levels after the second, third, or nth dose will overlay or superimpose the blood level attained after the (n-1)th dose.

〖𝐴𝑈𝐶〗0^∞ (1𝑠𝑡 𝑑𝑜𝑠𝑒)=〖𝐴𝑈𝐶〗(𝑡_1)^(𝑡_2 ) (𝑛𝑡ℎ 𝑑𝑜𝑠𝑒)

Question 5

What are the reasons superposition principle may not work (non-linear PK)?

Answer 5

1. changing pathophysiology in the patient
2. saturation of a drug carrier system
3. enzyme induction
4. enzyme inhibition.

Question 6

What are the assumption of drug accumulation?

Answer 6

1. The drug is eliminate by 1st order kinetics
2. The PK of the drug after a single dose are not altered after taking multiple doses

Question 7

What is the use for superposition principle?

Answer 7

used to predict drug concentrations after multiple doses given at either equal or unequal dosage intervals

Question 8

What happens if the drug is administered at a fixed dose and and dosage interval?

Answer 8

the amount of drug in the body will increase and then plateau to a mean plasma level higher than the peak Cp obtained from the initial dose

Question 9

Describe the process of giving repetitive equal dosing

Answer 9

1. plasma level–time curve plateaus and a steady state is obtained
2. At steady state, the plasma drug levels fluctuate between 𝐶_𝑚𝑎𝑥^∞ and 𝐶_𝑚𝑖𝑛^∞ .
   3, Once steady state is obtained, and 𝐶_𝑚𝑎𝑥^∞ and 𝐶_𝑚𝑖𝑛^∞ are constant and remain unchanged from dose to dose

Question 10

Describe drug accumulation at steady state?

Answer 10

Question 11

What is 𝐶_𝑚𝑎𝑥^∞ used for?

Answer 11

1. Evaluate drug accumulation
2. Determine drug safety (MTC)

Question 12

What is R?

Answer 12

1. Accumulation ratio
2. Ratio of 𝐶_𝑚𝑎𝑥^∞/Cmax (first dose)
3. 𝑅=1/(1−𝑒^(−𝑘𝜏) )

Question 13

What effects R index?

Answer 13

1. Elimination rate constant
2. Dosing interval
3. Independent of dose

Question 14

Interpret this graph?

Answer 14

Amount of drug in the body as a function of time. Equal doses of drug were given every 6 hours (upper curve) and every 8 hours (lower curve). ka and k remain constant.

Question 15

Describe the dosage rate between IV infusion and oral?

Answer 15

Dosage rate is the same

Cavg from oral will be equal to Css from infusion

Question 16

Describe the difference between oral and IV accumulation half-life?

Answer 16

Question 17

If rate constant decreases what happens to accumulation half-life?

Answer 17

Accumulation half-life increases

Question 18

Describe the factors of when plasma concentration reach steady state

Answer 18

1. constant dosing size
2. Shorter dosage interval
3. larger the dosing rate
4. higher the ss drug level

Question 19

What is paroxetine (paxil)?

Answer 19

An antidepressant drug with a long elimination half-life of 21hours

Well absorbed after oral administration and has a tmax of about 5 hours, longer than most drugs

Question 20

Describe Cmax of paroxetine?

Answer 20

After multiple dosing of 30 mg ofparoxetine for 30 days in one study ranged from 8.6 to 105 ng/mL among 15 subjects

Question 21

Why is dosing interval important?

Answer 21

1. Slow elimination may cause the plasma curve to peak slowly
2. tmax is affected by k and ka
3. Clinically it is important to achieve a stable steady-rate level in multiple dosing that does not undergoes or overdoes the patient

Question 22

What happens if you take a dose too early or late?

Answer 22

Contributes to variation. Individual variation in metabolism rate can also cause variable blood level

Question 23

What is a rapid IV injection?

Answer 23

The max dose in the body is the dose given

Question 24

What is the equation we use for IV bolus?

Answer 24

Question 25

What is the equation we use for repetitive iv injections?

Answer 25

For repetitive IV injections, we can further substitute time (t) with dosage interval (τ)

Question 26

How do we find fraction of dose in the body?

Answer 26

Question 27

What variable affect f?

Answer 27

k and tau

If tau increases f decreases

Question 28

How do you calculate Cmax?

Answer 28

Question 29

How do you calculate Cmin?

Answer 29

Question 30

How do you calculate Cavg?

Answer 30

Question 31

What is the preferable method of calculating Cavg?

Answer 31

Question 32

What is Cavg used for?

Answer 32

1. AN estimate of the mean plasma drug concentration at steady state
2. Often the target drug concentration for optimal therapeutic effect
3. Gives an indication as to how long this plasma drug concentration is maintained during the dosing interval (between doses)

Question 33

What factors affect Cavg?

Answer 33

1. AUC and tau
2. Reflect drug exposure after multiple doses

Question 34

What can drug exposure determine?

Answer 34

Drug safety and efficacy

Question 35

How is Cavg used in practice?

Answer 35

1. Reflects drug exposure after multiple doses (safety, efficacy)
2. Sample 2-3 points within dosage interval
3. From this we estimate AUC and calculate Cavg

Question 36

How is Cmin used in practice?

Answer 36

1. Trough method
2. Take sample immediately before next dose
3. Less robust than using AUC but only on sample needed

Question 37

Why don’t we use Cmax in practice?

Answer 37

More variability than Cmin

Question 38

What equations do we do to know the plasma concentration at any time?

Answer 38

Question 39

How do calculate concentration before steady state?

Answer 39

Question 40

How do we calculate concentration after steady state?

Answer 40