PCL201H1 Lecture Notes - Lecture 13: Therapeutic Index, Loading Dose, Pharmacokinetics

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11 Jan 2018
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PCL201
DOSING I PHARMACOKINETIC CONCEPTS
AND FORMLAS RELATED TO DOSING
I. Definition of Pharmacokinetics (Narrow)
Pharmacokinetics narrowly defined - is the study of the
time course of drug concentration and the factors affecting
it (i.e.,absorption, distribution, biotransformation &
excretion).
It is the basis of dosing.
2. Schematic Overview of Dosing
Drug Dose (what’s administered)
Drug Concentration in Plasma (what’s measured)
Drug Concentration at Site of Action (what’s crucial)
Intensity of Effect (what’s desired)
Note: Normally we use repeated drug doses to maintain
therapeutic blood levels for days, weeks or a lifetime.
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3. Overview of Concepts:
The clinical pharmacokinetics of dosing are based on three major
concepts - and the related mathematics. These are: i) the
therapeutic window (range of therapeutic concentrations of
doses); ii) the plateau principle; and iii) clearance.
i) The therapeutic window allows you to choose a steady
state blood concentration (Css) that is effective and safe.
ii) The plateau principal shows you how blood concentrations
will rise to the steady state concentration(Css) if you start without
a loading dose.
iii) Calculations related to clearance give you k (t1/2) and V,
which you need for dosing.
3. The Therapeutic Window ( = “Range of Therapeutic
Blood Concentrations”)
Concept: The Css you try to establish and maintain
depends on the therapeutic window.
The therapeutic window is a range of plasma concentrations
that are effective but now toxic.
The bottom of the therapeutic window is Cther the first
concentration high enough to produce theraptic effects.
(= therapeutic threshold)
The top of the therapeutic window is Ctox the first
concentration that is high enough to produce toxicity.
( = toxic threshold)
or not of
range of concentrations
you want to acheive
constant steady state
not
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Importance: The objective in dosing is to get blood
concentrations into the therapeutic window and keep them
there.
Figure 1: Therapeutic Window
Note: Cther and Ctox are approximate values, ascertained
empirically early in drug development.
Ctox would be determined for the first unacceptable drug
effect to appear - and would differ with each drug.
You don’t determine Cther and Ctox yourself. You can find a
“range of therapeutic concentrations” for various drugs in
reference works (e.g., Goodman and Gilman.)
The Css you try to obtain is often in the middle of the
therapeutic window.
Note: Therapeutic window is sometimes defined as a range of
doses rather than as a range of blood concentrations.
blood concentration versus time and two lines indicating Cther and Ctox
just depends on pharmacological texts
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