Multiple-Dosage Regimens:
Repetitive Extravascular
Therapeutic Window : between MEC (minimum effective concentration) and MTC (minimum
toxic concentration).
• Css max should be lower than MTC and Css min should be equal or higher than MEC
• Maximum concentration is reached at t max. Minimum concentration is reached at the
end of the interval; at Tau Ʈ
IN TR O D U C T IO N
• Accumulation of drug
• New dose in given before total Tpeak..Tp: time needed to
elimination of the previous one
reach peak plasma
concentration, following
At SS… rate of absorption=rate of elimination
multiple doses
tmax: The time at which
maximum (peak) plasma
concentration occurs
following a single oral
dose
• Superposition principle
• First order kinetics of Ke
• Zero order drug input (Ka)
• Typical to single oral PK
F and Ka affect Cmax in direct proportion
Before steady state: B.SS
(during accumulation)
**** You must determine whether Cp is before or after SS by calculating number of doses to
reach ss (n) then determine if Cp is before or after this (n) ****
multiple dosing factor (r) : differs referring to dose number-n- variable
B.SS n = 1
for the first dose (n=1) …. No (r) value
The plasma concentration at any time during an oral or extravascular multiple-
dose regimen before SS, assuming a one-compartment model and constant doses and dose
interval:
e e
n = number of doses
= dosage interval
F = fraction of dose
r(e) : r(a) :
multiple dosing factor multiple dosing factor
absorbed
for elimination for absorption
t = time after
administration of n doses:
ex. 2hr after the 3rd re and ra should be calculated separately for
dose…t=2 each dose number (n)
B.SS n > 1 Cmax, Cmin calculation Before steady state:
Trough concentration: (C trough)
• the concentration of drug in the blood immediately before the
next dose is administered
• Cmin is the lowest concentration during a dosing interval.
• although this does not necessarily represent the :
lowest concentration To
during a dosing
calculate Ctrough: interval
Replace t by
trough
(tp)n: the time needed to reach peak plasma concentration
following multiple doses is given by: (tmax)n
(tmax)n
tmax: the time needed to reach peak plasma concentration following
single oral dose is given by: (tmax)
Can be used for the 1st
dose only in multiple oral
doses
(tp)n: (tmax)n
At steady state:
**** You must determine whether Cp is before or after SS by calculating number of doses to
reach ss (n) then determine if Cp is before or after this (n) ****
The index for measuring drug accumulation (R): accumulation ratio:
For elimination ….. R (e) : constant
For absorption …. R(a) : constant
Number of doses to reach SS (nSS) = 6.6 t1/2/t
Time to reach SS (tss) =4.32* t1/2
time to get to steady state can be represented as: tss
Number of doses to reach (fraction of) steady state… (n):
Time needed to reach (fraction of) steady state (nƮ):
* *
fss : Fraction of steady state conc. obtained after the nth dose is
given by:
* *
fcss
How: If fss = 0.4 after 7th dose…. This means 0.4 of Css is available after the 7th dose
At very large values of Ka (i. e. Ka/K≥ 10): in normal kinetics:
-
• The fraction ( f ) of the dose remaining in the body:
plasma concentration at any time during an oral or extravascular
multiple-dose regimen at SS:
R (e) : R (a) :
accumulation ratio accumulation ratio
for elimination for absorption
1 1
*R(e) - *R(a)
At SS: R
1 Should be >1
ss
2
= R(e)*R(a)
ss
ss
If the dose was administered in the elimination phase (no significant absorption
occurs) accumulation R ratio can be simplified into:
dose was administered in the elimination phase
At post absorptive phase… all become equal …..
= R(e)
The time at which maximum (peak) plasma concentration at SS
(tmax.ss) :
t(max.ss)
Ra
𝟏
𝐑(𝐞)
𝐑(𝐚))
t(max.ss)
The maximum drug concentrations ( ∞ Cmax ) can be obtained with the
following equation:
R (e)
The minimum drug concentrations ( ∞ Cmin ) can be obtained with the
following equation:
R (e)
The mean plasma level at steady state, ∞ Cav, is determined by a
similar method to that employed for repeat IV injections
The same for multiple oral
and Iv
No need for LD as t1/2 is short
3X: triple amount of dose
The least amount of dose As the highest interval
fraction ( f )
Medication adherence occurs when a patient takes their medications according to the prescribed dosage,
time, frequency, and direction
the extent to which a patient’s behavior corresponds with the prescribed medication dosing regime, including time,
dosing and interval of medication intake
Quantitatively:
In single dose : lower concentrations are obtained
Qualitatively: are the same
Quantitatively:
In multiple dose : higher concentrations are
obtained
1
2
3
4
1
Using
tmax
Using
2
3
nss = 11
So 7th dose is before SS
4
= R(e)*R(a)
