Pharmacokinetics lecture 11 Contents '''

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Pharmacokinetics lecture 11Contents ...

• Multiple dosing

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Accumulation
Much of previous dose still present
Previous dose almost fully eliminated
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Steady state
Amount eliminated 1 dose
Amount eliminated ltlt 1 dose
Amount eliminated lt 1 dose
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Concentrations at Steady State
Css,max Peak
Css (Average)
Css,min Trough
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Predicting Css
Fractional bioavailability
Individual dose size
Css F . D Cl . ?
Clearance Dosage
interval
e.g. If doses given twice daily, ? 12 hours.
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General equation

• The equation for predicting Css
• Css F.D
• Cl.?
• is very general
• Applicable to 1 or 2 compartment systems
• Applicable to any route of administration. If
• route is i.v., then F 1.0 and we could just
  use
• Css D
• Cl.?

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Example calculation
What daily dose of Lithium to achieve Css of 0.8
mMole/L, given that F 100
Cl 1.5 L/h Css F.D
rearranges to D Css.Cl.?
Cl.?
F D 0.8 mMole/L x 1.5 L/h
x 24 h 1.0
28.8 mMole
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Css,max and Css,min
For many purposes it is adequate simply to adjust
the average concentration to some target figure.
But, occassionally it is necessary to keep
Css,max and Css,min within certain limits. The
classic example is the aminoglycoside antibiotics
(e.g. gentamicin) where effectiveness is
associated with a Css,max greater than a certain
figure and toxicity is avoided by keeping Css,min
below a certain figure.
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Css,max and Css,min
Css,max D . 1 V 1 -
e-K? Css,min Css,max - D
V

• Unlike the equation for Css, these equations are
  not general. They are only applicable to
• Intravenous doses into
• One compartment systems

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Example calculationfor Gentamicin
Vol dis 17.5 Litres K 0.2 h-1 Dosing 80mg
three times daily (i.v.) Css,max should be
between 4-8 mg/L Css,min should be less than 2
mg/L Will the regime be satisfactory?
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Css,max D . 1 V 1 -
e-K? 80mg . 1
17.5L 1 - e-0.2h-1 x 8h
4.57mg/L . 1
1 - e-1.6 4.57mg/L .
1 1 -
0.202 4.57mg/L . 1
0.798
5.73mg/L
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Css,min Css,max - D
V 5.73mg/L - 80 mg
17.5L
5.73 - 4.57 mg/L 1.16 mg/L
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Will regime be satisfactory?
Requirement was ... Css,max should be between 4-8
mg/L Css,min should be less than 2
mg/L Prediction is ... Css,max will be 5.73mg/L
Css,min will be 1.16 mg/L Regime should be OK
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Loading dose
As with infusions, a loading dose may be required
to produce therapeutically effective blood levels
without delay.
With loading dose (extra large initial dose)
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Loading dose
The formula is similar to that for i.v. infusion,
except that we need to incorporate
bioavailability (F) in case the route is
extra-vascular. LD Target x Vol
F If route is i.v.,
can ignore F, as it will 1.0
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Loading dose -example
Wish to achieve immediate blood concentration of
50 µg/L Vol dis 200 Litres Route is i.v. LD
Target x V F 50 µg/L
x 200 L 1 10,000 µg
10 mg
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Divided doses
3 x 200 mg
2 x 300 mg
6 x 100 mg
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Changing the absorption rate constant
Ka 0.25h-1
Ka 1.5h-1
Ka 0.25h-1
Ka 1.5h-1
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Fluctuation in blood levels

• Degree of fluctuation is affected by
• Extent of dose division
• Greater division means less fluctation
• Release rate from the dosage from
• Slower release means less fluctuation

The final result will depend upon the balance of
these two factors.
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Fluctuating blood concentrationsAn example -
Theophylline
Simple tablets
Rapid release and absorption Tends to make blood
levels very fluctating Has to be off-set by
considerable dose division e.g. Nuelin
normally given as 3 or 4 daily doses
Modified release
Slower release and absorption Reduces
fluctuations in blood levels Can get away with
less dose division e.g. Nuelin SA can be given
as twice daily doses
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Terms with which you should be familiar ...
Accumulation Css (Pronounced C bar SS) Css,max
Css,min Dosage interval (?)
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What you should be able to do

• Describe accumulation and explain why a steady
  state is eventually achieved.
• Predict Css from F, D Cl and ? (etc).
• Predict Css,max and Css,min from D, V, K and ??
• Calculate a loading dose from Target, V F.
• Describe and explain the effects of changes to Ka
  and dose division upon the degree of fluctuation
  in blood drug concentrations.