Concepts

Understand and explain pharmacokinetic factors that determine the relationship between dose and plasma concentrations:

• Volume of distribution (Vz)
• Absorption rate constant
• Elimination Rate Constant

• Dose "Independent" pharmacokinetic behavior
• "Time 0" concentration for intravenous drugs
• Peak concentration (Cmax) for non-intravenous drugs
• Time to peak concentration (Tmax)
• Duration of effect

Significance

A veterinarian needs to appreciate the results of dose manipulation (in terms of plasma concentrations). Under normal circumstances doubling the dose doubles the plasma concentrations at all time points on the concentration versus time profile. This means that the pharmacokinetic constants did not change with a change in dose This is what is meant by "dose independent" pharmacokinetics. Certain misconceptions arise concerning the effect of increased dose on the duration of effect. It may seem logical to assume that doubling the dose of a drug will double its duration. In fact, doubling the dose of a drug usually extends its duration by one drug half-life.

Exercise

1) Pharmacokinetic variables on the worksheet are preset for a typical adult dog given an aspirin. Please note, the dose and interval were chosen for the purposes of this exercise and are not the only appropriate dose regimen for dogs.

2) All simulations

• The "Lower" Concentration is preset to 10.0. This represents a target plasma concentration for aspirin in order to produce mild analgesic effects.
• The "Upper" Concentration is preset to 50.0. This represents a plasma concentration that is likely to produce toxicity in some portion of the dogs treated with aspirin.

3)For simulations #2 and #4, change the dose to 20 mg/kg.

4) Review the calculated values at the bottom of the worksheet. Please note: The calculated steady-state values represent concentrations that will be acheived if the drug is given repeatedly at the dose and dose interval set on the worksheet.

5) Review the linear and log graphs of the simulations.

Questions

1) Which calculated values changed when you changed the dose? State the relationship between the dose and each of these parameters (one sentence or phrase)

2) Plasma concentrations for the 20.0 mg/kg dose remain double those of the 10.0 mg/kg dose throughout. Which graph type indicates shows that the RATIO of concentrations is the same for the two doses troughout the study?

3) What effect does doubling the dose have on the length of time concentrations remain above 10.0 µg/ml?

4) The weight setting doesn't have any effect on the shape of the curves or any of the calculated plasma concentrations. Why? (Hint: what is the relationship between the units for dose and the units for clearance and volume of distribution?)