Multiple Dosage Forms Flashcards
What are the parameters of adjusting dosage regimens?
- size of the drug dose
- Ο, the frequency of drug administration (ie, the time interval between doses)
How do we predict Cp at any point in the dosage schedule?
If we know PK parameters for a single dose, the doses, and dosing intervals
What is the key question for drug accumulation?
Will successive doses of the drug have any effect on the previous dose?
What is the principle of superposition?
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.
γπ΄ππΆγ0^β (1π π‘ πππ π)=γπ΄ππΆγ(π‘_1)^(π‘_2 ) (ππ‘β πππ π)
What are the reasons superposition principle may not work (non-linear PK)?
- changing pathophysiology in the patient
- saturation of a drug carrier system
- enzyme induction
- enzyme inhibition.
What are the assumption of drug accumulation?
- The drug is eliminate by 1st order kinetics
- The PK of the drug after a single dose are not altered after taking multiple doses
What is the use for superposition principle?
used to predict drug concentrations after multiple doses given at either equal or unequal dosage intervals
What happens if the drug is administered at a fixed dose and and dosage interval?
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
Describe the process of giving repetitive equal dosing
- plasma levelβtime curve plateaus and a steady state is obtained
- At steady state, the plasma drug levels fluctuate between πΆ_πππ₯^β and πΆ_πππ^β .
3, Once steady state is obtained, and πΆ_πππ₯^β and πΆ_πππ^β are constant and remain unchanged from dose to dose
Describe drug accumulation at steady state?
What is πΆ_πππ₯^β used for?
- Evaluate drug accumulation
- Determine drug safety (MTC)
What is R?
- Accumulation ratio
- Ratio of πΆ_πππ₯^β/Cmax (first dose)
- π =1/(1βπ^(βππ) )
What effects R index?
- Elimination rate constant
- Dosing interval
- Independent of dose
Interpret this graph?
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.
Describe the dosage rate between IV infusion and oral?
Dosage rate is the same
Cavg from oral will be equal to Css from infusion
Describe the difference between oral and IV accumulation half-life?
If rate constant decreases what happens to accumulation half-life?
Accumulation half-life increases
Describe the factors of when plasma concentration reach steady state
- constant dosing size
- Shorter dosage interval
- larger the dosing rate
- higher the ss drug level
What is paroxetine (paxil)?
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
Describe Cmax of paroxetine?
After multiple dosing of 30 mg ofparoxetine for 30 days in one study ranged from 8.6 to 105 ng/mL among 15 subjects
Why is dosing interval important?
- Slow elimination may cause the plasma curve to peak slowly
- tmax is affected by k and ka
- Clinically it is important to achieve a stable steady-rate level in multiple dosing that does not undergoes or overdoes the patient
What happens if you take a dose too early or late?
Contributes to variation. Individual variation in metabolism rate can also cause variable blood level
What is a rapid IV injection?
The max dose in the body is the dose given
What is the equation we use for IV bolus?
What is the equation we use for repetitive iv injections?
For repetitive IV injections, we can further substitute time (t) with dosage interval (Ο)
How do we find fraction of dose in the body?
What variable affect f?
k and tau
If tau increases f decreases
How do you calculate Cmax?
How do you calculate Cmin?
How do you calculate Cavg?
What is the preferable method of calculating Cavg?
What is Cavg used for?
- AN estimate of the mean plasma drug concentration at steady state
- Often the target drug concentration for optimal therapeutic effect
- Gives an indication as to how long this plasma drug concentration is maintained during the dosing interval (between doses)
What factors affect Cavg?
- AUC and tau
- Reflect drug exposure after multiple doses
What can drug exposure determine?
Drug safety and efficacy
How is Cavg used in practice?
- Reflects drug exposure after multiple doses (safety, efficacy)
- Sample 2-3 points within dosage interval
- From this we estimate AUC and calculate Cavg
How is Cmin used in practice?
- Trough method
- Take sample immediately before next dose
- Less robust than using AUC but only on sample needed
Why donβt we use Cmax in practice?
More variability than Cmin
What equations do we do to know the plasma concentration at any time?
How do calculate concentration before steady state?
How do we calculate concentration after steady state?
