Print Medical Pharmacokinetics #1

Clinical Pharmacokinetics

• Course information
• General goals
• Fundamental Hypothesis
• Typical clinical cases
• Interim summary
• What kinds of drugs do we monitor?
• Detailed goals
• Steady state
• Major pharmacokinetic parameters
• Pharmacokinetic models
• Formulae that must be recalled from memory

Course Information
(Pharmacokinetics section of pctx 610)

Opening Remarks

• Name: Gordon L. Coppoc, DVM, PhD
• Four hours of clnical pharmacokinetics -- Taste only!
  Greatly simplified with emphasis on concepts involved.
• For assistance: Office -- Lynn G182
  Door Open, come in
  Door Closed, make appointment with me before or after class
• Reference: Harveyetal92 Relevant parts of Chapter 1 and Chapter 2
  Goodman & Gilman's Pharmacology '96, pp 17-26.?
• Main Goal:
  To help you understand major concepts of clinical pharmacokinetics and to solve simple problems
• These materials on Internet
• 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 --PCTX 611 [html]"
• Experimental approach, please give me feedback

Pharmacokinetics Goals

General Goals

• Pharmacokinetics vs pharmacodynamics
• Diagnosis of toxicoses
• Establishing / adjusting dosage regimens
• Understanding withdrawal times for food safety

Detailed Goals

• 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

Fundamental Hypothesis

Statement of hypothesis

• Simplest statement
  • Predictable relationship between plasma (or serum) concentration of drug and its effect
• Fancier
  • Magnitude of desired clinical response and of toxicity are functions of the drug concentration at the site of action and that there is reasonably predictable relationship between plasma (or serum) drug concentration and the concentration at the site of action.

Key Figure

redrawn from Koch-Weser, 1973

Therapeutic Window

Variability of concentration as function of dose

• [Draw graph of theophylline plasma concentration vs dose showing large range of variability]
• Contrast to narrower range of effect as function of plasma concentration

Formula

Simple application 

• Draw figure of IV infusion to steady state
  • Use data below to establish first plateau
  • Draw in desired plateau
  • How adjust dose?
• Input data:
  • Desired Css = 20 mg/L
  • Measured Css = 10 mg/L
  • Dose rate = 30 mg/h
• New dose rate = ??
  •  

    New Rate = Old rate * {Desired Css / Measured Css) mg/h = mg/h * {(mg/L) / (mg/L)}

    60 mg/h = 30 mg/h * {20/10)

   

First- & Zero-Order Kinetics 

• Michaelis-Menten plot
• One MUST UNDERSTAND the significance of first- and zero-order kinetics
• In THIS SHORT TREATMENT of pharmacokinetics, we will deal ONLY with drugs at concentrations where they are eliminated by FIRST ORDER kinetics
•  

  Note: * Upper flat portion is the zero-order portion * velocity is in mass/time (NOT fraction); * Drug concentration is in mass/volume

Clinic Cases

• Case #1 Anticonvulsant
• Case #2, Gentamicin

Anticonvulsant case #1

FICTITIOUS CASE and DRUG

Date: 5/16/95
Name: Susie
Signalment: Female, 11 yrs
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 

Graphing the data

• 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

Questions about graph

• 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)

Questions regarding the significance of the data

• 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)

Areas of the graph

• 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

Questions about areas of the graph

• 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"?

Evaluation of the regimen

• Look at the observed concentrations in this case vis-a-vis the therapeutic window you have made
• Note that the "Susie" has not had seizures for 3 weeks

Questions about the dose regimen

• Should one change the dose and/or schedule for Susie?
• Why or why not?

Case #2 -- Gentamicin

 Date: 5/24/95
Name: John Doe
Signalment: male, 50 kg
History: Weak, transfusion 5/23/95
Current Status:improving
Dose: 4 mg/kg IV Dose Interval: 8 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 @ 8 h

Graphing the data

• 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 @ 8h )

Questions about the graph

• 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 anticonvulsant example
• Is this a first time dose? Can one tell?
• How were sample times probably chosen?
• What fluid was measured? Why?

Questions regarding the significance of the data

• The concentration is approximately 5 mcg/mL @ 1 hour, ... So what?
• The concentration is approximately 0.88 mcg/mL @ 8 hours, ... So what?
• How does the ratio of trough to peak compare to that in the anticonvulsant example?

Review of therapeutic window

• 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?)

Questions about "therapeutic window"

• 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.

Evaluation of the regimen

• Look at the observed concentrations in this case vis-a-vis the therapeutic window
• Note that the Mr. Doe was said to be "improving" -- What does this mean for advising physician?

Questions about the dose regimen

• Should one change the dose and/or schedule for Mr. Doe?
• Why or why not?

Summary

Summary

• 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