Course Information
(Pharmacokinetics section of BMS 444)
- Name: Gordon L. Coppoc, DVM, PhD
- Dr. Mary Ann Elchisak is professor in charge of the
course
- First two weeks -- clinical pharmacokinetics
- For assistance: Office -- Lynn G182
Door Open, come in
Door Closed, make appointment with me before or after
class
- Reference: VPT95, Ch 3,
pp 18-36.
- Main Goal:
To help you understand and to use clinical
pharmacokinetics
- See Internet for more information
- On SVM computers, click on "Netscape"
- Then on successive menus in "netscape"
"Schools of Purdue University" -->
"Veterinary Medicine" -->
"Departments" --> "Basic Medical
Sciences" --> "Course Syllabi" -->
"Clinical Pharmacokinetics -- BMS444 [html]"
- EASIER: type the following into the web browser locator:
www.vet.purdue.edu/bms/courses/pkin
- Experimental approach, please give me feedback
Send suggestions /
questions
Last modified: 8/19/96 glc
Send suggestions /
questions
Last modified: 8/18/96 glc
- Pharmacokinetics vs pharmacodynamics
- Diagnosis of toxicoses
- Establishing / adjusting dosage regimens
- Understanding withdrawal times for food safety
- Understand terms
- Steady State
- First- & Zero-order kinetics /
Michaelis-Menten plots
- Loading Dose / Volume of Distribution
- Clearance
- Ke (Elimination Rate) & Half-Life
- Bioavailability
- Compartment modeling
- One compartment model
- Two (and more) compartment models
- Adjust dose
- Be able to establish new dose regimens:
- Be able to account for dose forms available
- Be able to predict, at steady state, the Peak and
Trough concentrations
- Timing of samples
- Withdrawal time -- primarily for veterinary students
- Be able to describe significance of withdrawal
times
- Be able to predict theoretical withdrawal time
given key parameters
- Be able to describe effects of changes in dose
regimen on withdrawal time
Send suggestions /
questions
Last modified: 09 Sep 1996 20:33 glc
Date: 5/16/95
Name: Kissie
Signalment: Canine, Female, 11 yrs, 12 pounds
History: Seizures started 12/94. Medications started 4/95.
Chemistry panel normal
Current Status: No seizures since started current dose
regimen
Dose: 12 mg (elixir), PO Dose Interval: 12 h
Time on Dose:3 weeks
Serum Concentration #1: 20.2 mcg/mL @ 2 h #2: 19.9
mcg/mL @ 12 h
- Plot data from case on arithmetic graph paper
- make "y" axis 0 to 50 (mcg/mL serum)
- make "x" axis 0 to 14 (hours)
- Plot 2 hr concentration = 20.2 mcg/mL
- Plot 12 hr concentration = 19.9 mcg/mL
- What fluid was measured? Why?
- How were sample times chosen?
- Does the concentration change much during the dose
interval?
- During this dose interval, will the concentration more
than likely go | higher
| lower
| than the reported values?
- What might the "curve" look like if one had all
the data?
Draw a light dotted line representing your
notion of the curve's shape
- Given the two concentrations and sample times, predict
whether this drug is eliminated |
rapidly or slowly |.
- [scan ] What you should have
produced
- [drawing][scan] Graph of phenobarbital
concentration versus time
(scan is figure 1, Ravis et al, AJVR
45:1283-1286, 1984)
- The concentration is approximately 20.2 ug/mL at 2 hours
... So what?
- The concentration is approximately 19.9 ... So what?
- How does serum/plasma drug concentration relate to
effect?
- Procainamide
concentration vs effect (Koch-Weser73: , 5th
Int. Cong. Pharmacol. Pharmacology and Future of Man.
Problems of Therapy, Vol. 3, 1973)
- Draw two heavy horizontal lines across graph --
one at 20 ug/mL -- Label it Minimum Effective
Concentration (MEC)
one at 40 ug/mL -- Label it Minimum Toxic
Concentration (MTC)
- Write "often toxic" above the 40 ug/mL line
- Write "insufficient effect" below the 20 ug/mL
line
- What name might one give to the "middle" area
of the graph?
- How might one establish the "minimum toxic" and
"minimum effective" concentrations?
- Are these concentrations "absolute"?
- Look at the observed concentrations in this case
vis-a-vis the therapeutic window you have made
- Note that the "Kissie" has not had seizures for
3 weeks
- Should one change the dose and/or schedule for Kissie?
- Why or why not?
Send suggestions /
questions
Last modified: 8/20/96 glc
Date: 8/9/95
Name: SweetPea
Signalment: Canine, Female, 10 yrs, 5.3 pounds
History:CBC / Chem / VA ---> WNL
Current Status: Improving
Dose:8 mg, PO Dose Interval: 12 h
Time on Dose:2 weeks -- started on 6/14/95, then owners
stopped. Started again 2 weeks ago.
Serum Concentration #1: 10.2 mcg/mL @ 11 h #2: none
submitted
- Plot data from case on arithmetic graph paper
- May use same graph as did for Case #1, if wish
- make "y" axis 0 to 50 (mcg/mL serum)
- make "x" axis 0 to 14 (hours)
- plot concentration #1 (10.15 mcg/mL @ 11 h)
- Note: there is no concentration #2
- Does this value more nearly approximate a
"peak" or a "trough"?
- Will the concentration go lower during this dose
interval?
Given what you know about the speed at which
phenobarbital is eliminated what is your prediction?
- How was this sample time probably chosen?
- Is it ideal? ...practical?
- Will it introduce significant error in dose adjustment?
- The concentration is approximately 10.2 mcg/mL at 11
hours ... So what?
- Is the concentration within the target concentration
range?
- Is "SweetPea" still having seizures?
- Should the dose be adjusted?
- How might you adjust the dose?
- Desired trough concentration is 20 mcg/mL serum
- Measured "trough" concentration was 10.2 mcg/mL
serum
- Setup simple proportion formula
| New dose = Old dose x (Conc desired / Conc
measured) |
- Do the calculation
- New dose regimen is approximately 16 mg q12h
- What does q12h mean? bid? q6h? q1d? q1m?
- Will this new regimen result in the drug concentration
being in the therapeutic window for the entire dose
interval?
- Look at plot for case #1 and predict on the graph paper a
Peak for this animal?
- Why can we get away with using only one measurement for
phenobarbital in some cases?
- When would it be crucial to know the approximate peak
concentration?
Concentration at the trough is approximately half the normally
recommended minimum. Because SweetPea is still having seizures,
advise increasing dose to 15 mg q12h. If this produces excessive
sedation and/or incoordination for more than 3 to 4 days, the
evening dose should be decreased to 7.5 mg. After two to three
weeks on the new dose, advise submitting a "trough"
sample for analysis if SweetPea is still experiencing seizures.
- Why might sedation and / or incoordination last only 3 to
4 days?
- Why not just decrease both AM and PM doses instead of
only one?
(Hint: what dose forms are there for the medication?)
- Why wait two to three weeks to submit another sample?
Send suggestions /
questions
Last modified: 8/20/96 glc
Date: 5/18/95
Name: Yukon
Signalment: Canine, Male, 10 yrs, 88 pounds
History:Epileptic for 7-8 years -- last 2 weeks has break
through seizures and liver enzymes are elevated
Current Status: Seizures are occurring more often -- 2
last Wednesday
Dose:180 mg, PO Dose Interval: 12 h
Time on Dose:1 year
Serum Concentration #1: 48.4 ug/mL @ 3 h #2: none
submitted
- Plot data from case on arithmetic graph paper
- May use same graph as did for Case #1 & 2, if
wish
- make "y" axis 0 to 50 (mcg/mL serum)
- make "x" axis 0 to 14 (hours)
- plot concentration #1 (48.4 mcg/mL @ 3 h)
- Note there is no sample #2
- Is this value closer to the "peak" or to the
"trough"?
On what do you base this estimate?
- Will the concentration go lower during this dose
interval?
Given what you know about the speed at which
phenobarbital is eliminated what is your prediction about
how much lower?
- How was this sample time probably chosen?
- Is it ideal? ...practical?
- Will it introduce significant error in dose adjustment?
- The concentration is approximately 48.4 mcg/mL at 3 hours
... So what?
- Is the concentration within the target concentration
range?
- Is "Yukon" still having seizures?
- Normally recommended maximum concentration is 40 mcg/mL
- Should the dose be decreased for Yukon?
- If yes, use same proportion as before, BUT...
- Setup simple proportion formula
| New dose = Old dose x (Conc desired / Conc
measured) |
- Do the calculation
- What is rationale for decreasing the dose?
- What is the probability that phenobarbital alone (at
tolerable doses) will ever stop the seizures in Yukon?
- How important would it have been to know the trough
concentration in this case?
Concentration at "peak" (48.4 mcg/mL) is clearly
above the maximum recommended level of 40 mcg/mL. Because the
seizures are not being controlled at this dosage and because the
liver enzymes are already elevated (a sign of potential
hepatotoxicity), it is unlikely that phenobarbital will be
satisfactory as a sole agent. Advise considering reducing dosage
by 1/3 and adding KBr to the regimen.
Send suggestions /
questions
Last modified: 09 Sep 1996 20:33 glc
Date: 5/24/95
Name: Allie's 95 cria
Signalment: Llama, Female, born 5/20/95, 29 pounds
History:Cria weak, FPT (plasma transfusion 5/23/95)
Current Status:improving
Dose:27.3 mg IV Dose Interval: 12 h
Time on Dose:since 5/22/95 at 8 PM
Serum Concentration #1: 5.0 mcg/mL @ 1 h #2: 0.9
mcg/mL @ 12 h
- Plot data from case on arithmetic graph paper
- make "y" axis 0 to 20 (mcg/mL serum)
- make "x" axis 0 to 14 (hours)
- Plot concentration #1 (5.0 mcg/mL @ 1 h)
- Plot concentration #2 (0.9 mcg/mL @ 12h )
- Is this the highest the concentration is likely to be (or
have been) during this dose interval?
- Will the concentration go lower during this dose
interval?
- Draw your idea of what might the "curve" look
like if one had all the data?
- Does the concentration change much during the dose
interval?
- What does this change indicate about the "rate of
elimination" -- fast? slow?
Note contrast relative to phenobarbital.
- Is this a first time dose? Can one tell?
- How were sample times probably chosen?
- What fluid was measured? Why?
- The concentration is approximately 5 mcg/mL @ 1 hour, ...
So what?
- The concentration is approximately 0.88 mcg/mL @ 12
hours, ... So what?
- How does the ratio of trough to peak compare to that in
the phenobarbital example?
- Draw horizontal lines across graph at --
- 12 mcg/mL
- 5 mcg/mL
- 1 mcg/mL
- Write "often toxic" above the 12 mcg/mL line,
the MTC
- Write "insufficient effect" below the 5 mcg/mL
line, the MEC
- Write "need to drop below" below the 1 mcg/mL
line, (another MTC?)
- Where is the therapeutic window in this graph?
- What is the meaning of the "need to drop below"
statement
- How might his relate to toxicity of gentamicin
- Are these concentrations "absolute"?
- Note: this is the traditional understanding of ideal
gentamicin dosage regimens. New concepts will be
presented in the chemotherapeutic section.
- Look at the observed concentrations in this case
vis-a-vis the therapeutic window
- Note that the "cria" was said to be
"improving" -- What does this mean for advising
the veterinarian?
- Should one change the dose and/or schedule for the Llama
cria?
- Why or why not?
Send suggestions /
questions
Last modified: 8/20/96 glc
- Primary hypothesis of target concentration strategies
- Why we use plasma/serum for sampling
- Drug concentration (C) vs Time (t) plots -- proper
graphing
- Minimum Effective Concentration (MEC)
- Minimum Toxic Concentration (MTC)
(added concept of "need" to have low trough in
some cases)
- Therapeutic Window; Target Concentration Range
(related concept of "Therapeutic Index")
- Dosage adjustment -- simple cases --> Simple
proportion
- Assumptions for "simple" dose adjustment
- Dose interval (T) stays same
- No significant change in animal's handling of the
drug
- Kinetic processes not dose dependent
- Need to pay attention to whether it is peak or trough
that you are adjusting!
- Importance of need for knowing "peak" and
"trough" concentrations depends on the drug
New concept: OSCILLATION during dosage interval (more
later)
- Best times to take samples
Send suggestions /
questions
Last modified: 09 Sep 1996 20:33 glc
- Think about safety margins
Example: penicillin G versus gentamicin
- Think of ease of "bioassaying" the drug in the
patient, i.e., presence of easily detectable and rapid
response
Example: anticonvulsant versus anesthetic agent
- What if signs of too little and too much drug are
similar?
Example: digoxin
- When interindividual variation is much greater
in
DOSE vs PLASMA CONCENTRATION than in
PLASMA CONCENTRATION vs EFFECT!
Send suggestions /
questions
Last modified: 8/18/96 glc
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questions
Last modified: 12 Nov 1996 15:01 glc
