Multiple Oral Dose

Administration
Pedro Baratta
Multiple Oral Dose Administration
Multiple Oral Dose Administration
However Cpmin can be more easily determined
at t = 0 or t = t. Thus at t = 0 and n -> .

Plot Cp Versus Time after a Single Dose showing Possible Time of Second Dose
Multiple Oral Dose Administration
This can be further simplified if we assume that
the subsequent doses are given after the
plasma concentration has peaked and e-ka * t is
close to zero. That is the next dose is given
after the absorption phase is complete.
Cpmin then becomes:-
Multiple Oral Dose Administration
The relationship between loading dose and
maintenance dose and thus drug
accumulation during multiple dose
administration can be studied by looking at
the ratio between the minimum concentration
at steady state and the concentration one
dosing interval (t) after the first dose.
Multiple Oral Dose Administration
Which can be simplified to give:

We can further simplify Equation, if we assume

that ka >> kel:
then (ka - kel) approximatley equal to ka and
thus approximately = 1.
Multiple Oral Dose Administration
Another very useful concentration term for
the calculation of oral dosing regimens is the
average plasma concentration, , during the
dosing interval at steady state.
This term is defined as the area under the
plasma concentration versus time curve
during the dosing interval at steady state
divided by the dosing interval.
Multiple Oral Dose Administration
Multiple Oral Dose Administration
By integrating the equation for plasma
concentration at the plateau, between t = 0
and t = t gives:
Multiple Oral Dose Administration
An interesting result of this equation is that we get the same
average plasma concentration whether the dose is given as a single
dose every t dosing interval or is subdivided into shorter dosing
intervals.
For example 300 mg every 12 hours will give the same average
plasma concentration as 100 mg every 4 hours. Of course, the
difference between the maximum and minimum plasma
concentration will be larger in the case of the less frequent dosing.
For example F = 1.0; V = 30 liter; t1/2 = 6 hours or kel = 0.693/6 =
0.116 hr-1.
We can now calculate the dose given every 12 hours required to
achieve an average plasma concentration of 15 mg/L.
Multiple Oral Dose Administration

=
Multiple Oral Dose Administration
We could now calculate the loading dose

R = e-kel * [[tau]] = e-0.116 x 12 = 0.25

Multiple Oral Dose Administration
To get some idea of the fluctuations in plasma
concentration we could calculate the Cpmin
value.
Multiple Oral Dose Administration
Therefore the plasma concentration would
probably fluctuate between 7 and 23 mg/L
(very approximate) with an average
concentration of about 15 mg/L. [23 = 15 +
(15-7), i.e. high = average + (average - low),
very approximate!].
Multiple Oral Dose Administration
As an alternative we could give half the dose,
312 mg, every 6 hours give:-
Multiple Oral Dose Administration
The Cp would be the same

Thus the plasma concentration would fluctuate

between about 10.4 to 20 with an average of
15 mg/L.
Multiple Oral Dose Administration
Superposition Principle
Applies when all disposition processes are linear.
That is, distribution, metabolism, and excretion
(DME) processes are linear or first order. Thus,
concentrations after multiple doses can be
calculated by adding together the concentrations
from each dose. For example, calculate drug
concentration at 24 hours after the first dose of
200 mg. The second dose of 300 mg was given at
6 hours and the third dose of 100 mg at 18 hours.
Multiple Oral Dose Administration
Multiple Oral Dose Administration
Non-uniform dosing intervals
The calculations we have looked at consider that
the dosing intervals are quite uniform, however,
commonly this ideal situation is not adhered to
completely.
Dosing three times a day may be interpreted as
with meals, the plasma concentration may then
look like the plot in Figure 60. The ratio between
Cpmax and Cpmin is seven fold (8.2/1.1 = 7.45) in
this example.
Multiple Oral Dose Administration
Multiple Oral Dose Administration
However this regimen may be acceptable if
1) the drug has a wide therapeutic index
2) there is no therapeutic disadvantage to low
overnight plasma concentrations, e.g.,
analgesic of patient stays asleep.
 Exercicio 1
A drug is to be given orally every six hours to achieve an average concentration of 15
mg/L. Calculate the dose (F = 0.90) required if t1/2 = 11 hours and V = 23 L. Estimate the
peak and trough concentrations after steady state is reached.
Multiple Oral Dose Administration
t1/2 = 11 hr means the kel = 0.06 hr-1

Thus, Dose = 15 x 23 x 0.06 x 6 / 0.9 = 145 mg.

Give 150 mg to achieve a of 15.5 mg/L

Cpmin = (150 / 23) x (0.69 / (1 - 0.69)) = 12.8 mg/L

By rough estimation Cpmax can be calculated as 18.2 mg/L
(15.5 + (15.5 - 12.8))
 Exercicio 2 Exemplo IV
Calculate an appropriate dosing regimen for the
following male patient; age = 56 years, weight =
79 kg, serum creatinine = 2.0 mg/ 100 ml (mg%).
With this drug the kel is a function of creatinine
clearance; kel = 0.04 hr-1 with CLCr = 20 ml/min
and kel = 0.12 hr-1 with CLCr = 75 ml/min.
Apparent volume of distribution is calculated as
0.28 L/kg. Develop a dosing regimen to keep the
peak concentration close to but below 6 g/ml
and the trough concentration below 1.0 g/ml.
Multiple Oral Dose Administration

CLCR = (140 - 56) x 79 / (72 x 2.0) = 46.1 ml/min

By plotting kel versus CLCR it is possible to

interpolate a value of kel for the patient
Multiple Oral Dose Administration

From this graph or by calculations the kelpatient

= 0.0779 hr-1
Multiple Oral Dose Administration
R = Cpmin/Cpmax = 1/6 = e-kel*tau
Taking ln of both sides and solving for tau gives a value of 23.0 hr. Adjusting this
upwards (to avoid extending the concentration range) give a new tau value of 24
hours.
The new R value is now e-0.0779 x 24 = 0.154
Maintenance dose can be calculated from Cpmax * V * (1 - R) = 6 x 0.28 x 79 x (1 -
0.154) = 112 mg (probably give 100 mg which would produce a Cpmax of 5.34 mg/L
and Cpmin of 0.823 mg/L).
The required loading dose can be calculated as Cpmax * V = 6 x 0.28 x 79 = 133 mg
(125 mg would produce a Cpmax of 5.65 mg/L).