kinetics exam 3 Flashcards
During a multiple-dose schedule the more recent a missed dose is, the less the effect the omission has on the current plasma drug concentration.
A
True
B
False
false! according to slide 24, it will have a greater effect!
PLASMA CONCENTRATION-TIME COURSE
AFTER ONE ORAL DRUG ADMINISTRATION
onset of action = when the drug reaches the minimum effective concentration
peak time = the time it takes to reach the peak concentration
duration = the time in which the drug is above the minimum effective concentration
intensity = the window between the peak concentration and the minimum effective concentration
therapeutic window = the window between the minimum toxic concentration and the minimum effective concentration
predicted plasma drug con concentrations for multiple-dose regimen using the superposition principle
taking/giving the patient the same dose at certain time intervals and as a result will result in a total dose after adding the doses taken previous to the one given
towards a steady state
taking a dose at different time intervals will increase the concentration in the body and keep it at a steady state
tou symbol:
At a steady state, concentrations will rise and fall according to a repeating pattern as long as we continue to administer the drug at the same dose level and with the same time period between doses.
This repeated dosing period is often called the dosing interval and is abbreviated using the Greek letter tau (τ).
Predicting Plasma Drug Accumulation
It is assumed:
– that a first-order process eliminates the drug
– that early doses do not affect the pharmacokinetics of later doses
i.e. the pharmacokinetics of later doses are only superimposed (stacked on top of) on those of earlier ones (the principle of superposition)
- Also, the entire 0 Cpdt for a single dose administration is equal to nn+1Cpdt for any dosing interval at a steady state in a multiple-dosing case - so
- the area under the curve of the first dose is equal to the area under the curve of any dose interval at steady state
Predicting Plasma Drug
Accumulation II
Based on the principle of superposition, the concentration-time curve in a multiple-dosing case can be predicted from the concentration-time data of a single-dose administration
- *Ref Table 8.1; if a constant dose is given at constant periods, the plasma concentrations after each dose consist of the same data obtained after the single dose. For each time point, then, the predicted plasma concentration is the sum of the residual concentration resulting from each previous dose
- The prediction holds even if the dosing interval is not fixed
Situations In Which Superposition Would Not Be Valid
The drug does not follow linear kinetics see Table 9.1 for examples
- A Drug’s carrier system gets saturated (for instance, the drug is eliminated by a saturable enzymatic process and so follows Michaelis- Menten kinetics. Recall Vmax and KM)
- There is enzyme induction
- There is enzyme inhibition
- The patient’s disease condition changes significantly between doses
Drug Accumulation
Multiple dosing is intended to keep plasma drug levels within the therapeutic window - which is always the goal!
- The dose and the time between doses () may be adjusted to achieve this.
- Accumulation will not occur if a second dose is given at an interval longer than that required for the elimination of the previous dose
- A steady state should eventually be achieved during accumulation (Cmax and Cmin should remain the same from dose to dose)
- There is no accumulation if at steady state Cmax is the same as for (Cn=1)max for the first dose.
- For drug safety, Cmax should always be less than the minimum toxic dose
Drug Accumulation II
the drug accumulation index:
R = (Cinfinity)max/(Cn=1)max
R = D0/VD[1 - e^-ktou]/(D0/VD)
R = (1/1 - e ^-k(τ))
Thus, accumulation depends not on the dose, but on the dosing interval (which is tau) and the elimination rate constant which is k
- The time required to attain a steady state is dependent on the elimination half-life but is independent of dose or interval between doses
- Average steady-state Plasma Concentration =[AUC]t1^t2/ tau
Drug Accumulation III
The time required to attain one-half of the steady-state plasma levels (the accumulation t1/2):
t1/2acc = t1/2(1 + 3.3log (ka/ka-k))
- For IV infusion administration ka is rapid»_space;>k
t1/2acc = t1/2(1 + 3.3log(ka/ka))
i.e. for an IV-administered drug
t1/2acc = t1/2
Thus t1/2acc is dependent on the elimination t1/2 but not on dose or dose intervals
Drug Accumulation IV
The time needed to reach 90% and 99% steady-state concentrations is 3.3 t1/2 and 6.6 t1/2 respectively.
- The number of doses needed to reach steady-state is dependent on t1/2 and .
(specifically, it is for 99% steady state)
(6.6 x t1/2)/tau
interrelation of elimination half life, dosage interval, maximum plasma concentration, and the time to reach steady-state plasma concentration
table 8.3
Relation Between Loading Dose
and Accumulation Index
Maintenance Dose (DM ) = Loading Dose (DL) – Amount of Drug
Remaining at end of Dosing interval
DL = DM x (1/1-e^ktau)
You would recall the accumulation index
R = 1/(1 - e^ktau)
So the loading dose is the product of the maintenance dose and the accumulation index.
the dose of sulfisoxazole (Gantrisin, Roche) recommended for an adult female patient (age 26 years, 63 kg) with a urinary tract infection was 1.5 g every 4 hours. The drug is 85% bound to serum proteins. The elimination half-life of this drug is 6 hours and the apparent volume of distribution is 1.3 L/kg. Sulfisoxazole is 100% bioavailable.
a.Calculate the steady-state plasma concentration of sulfisoxazole in this patient.
b.Calculate an appropriate loading dose of sulfisoxazole for this patient.
c.Gantrisin (sulfisoxazole) is supplied in tablets containing 0.5 g of the drug. How many tablets would you recommend for the loading dose?
d.If no loading dose was given, how long would it take to achieve 95%–99% of steady state?
Drug Accumulation:
Repeated IV Injections
For a one-compartment open model following first-order
kinetics, after a single dose:
DB = D0e^-ktau
- So given that the interval between a first and second dose is
tau: DB = D0e^-ktau - The fraction of the dose remaining in the body:
f = DB/D0 = e^-ktau
Thus f depends on k and tau e.g. f is large if tau is small.
Drug Accumulation:
Amount of Drug in the Body
- The maximum amount of drug in the body:
Dmax = D0/(1-f)
Since the difference between the maximum and minimum amounts of drug in the body is equal to the administered dose (D0):
Dmin = Dmax - D0
Where F= fraction of dose absorbed (NB: for an IV dose F=1), the average amount of drug in the body at steady-state:
Dav = FD0/ktau
The respective concentrations can be determined by dividing the amounts by the apparent volume of distribution
A new drug is to be given by multiple IV bolus injections to a patient such that drug steady-state concentrations should be maintained between a maximum of 20 and a minimum of 1 mg/L.
Assume a one-compartment linear
the model applies to this drug in this concentration range. The elimination rate constant and apparent volume of distribution for this drug in this patient are 0.223 hr-1 and
40.6 L, respectively.
Calculate the dosing interval that will exactly achieve this concentration requirement.
Also, calculate the maintenance dose.
problem to solve! slide 22 of multiple dosages
table
table
Drug Accumulation: Plasma Level Equations
Cmax = C^0p/(1 - e^-ktau)
Cmin = (C^0pe^-ktau)/(1-e^-ktau)
Cav = (FD0/VDktau)
….
Drug Accumulation: Plasma Level Equations II
After administering n i.v.doses (time between doses), the plasma concentration at time t after the nth dose is given by:
CP = (D0/VD)(1-e^-nktau)
- At steady-state, e-nk approaches zero:
CP^infinity = D0/VD(1/1-e^ktau)e^-ktau
problem to solve
Non-Compliance:
Dose Skipped?
When a dose is missed, the concentration that should have been contributed by the missing dose ((D0/VD)e-ktmiss) is subtracted from the concentration at time t after the nth dose (given that time is time tmiss since that scheduled
dose). For i.v.:
CP = D0/VD[(1 - e^nktau/1 - e^ktau)e^-kt - e^-ktmiss]
Or at steady-state (where n is very large):
CP^infinity = D0/VD(e^-kt/ 1- e^-ktau) - D0/VD e^-ktmiss
NB: The more recent a missed dose is, the greater the effect it will have on the current plasma concentration.
- Missed doses greater than 5 half-lives later should be omitted because of their minimal impact