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7 - Multiple Oral

1. Multiple dosing regimens aim to maintain drug concentrations between the minimum effective concentration and minimum toxic concentration through repetitive dosing. 2. Before steady state is reached, drug accumulation occurs as the dose interval is shorter than the drug's elimination half-life, resulting in increasing plasma concentrations with each successive dose. 3. At steady state, the rate of drug absorption equals the rate of elimination and plasma concentrations remain constant due to balanced drug accumulation from repeated dosing.

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88 views

7 - Multiple Oral

1. Multiple dosing regimens aim to maintain drug concentrations between the minimum effective concentration and minimum toxic concentration through repetitive dosing. 2. Before steady state is reached, drug accumulation occurs as the dose interval is shorter than the drug's elimination half-life, resulting in increasing plasma concentrations with each successive dose. 3. At steady state, the rate of drug absorption equals the rate of elimination and plasma concentrations remain constant due to balanced drug accumulation from repeated dosing.

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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)

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