Module 1. Effect(s) of dose manipulation on plasma concentrations.

Objectives

**Having completed this exercise and based on pharmacokinetic constants and data, students should be able to:**

- Predict (estimate) changes in the
__magnitude__of drug effect(s) based on the dose administered. - Predict (estimate) changes in the
__duration__of drug effects based on the dose administered. - Determine whether
__accumulation__of a drug will occur with repeated administration. - Locate and label maximum, minimum, and average concentrations on a graph of plasma concentration versus time.
- (Visually) estimate the duration of effect from a graph of plasma concentration versus time.
- Describe how the dose
__independence__of a pharmacokinetic__model__enables prediction of concentrations resulting from dose adjustments.

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 do 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

Download dose.xlsx, the worksheet for this module. Depending on your settings, you may have to "enable editing" in order to make the changes suggested by the exercise.

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.

**Target concentrations**

- The Minimum Effective Concentration (MEC) of aspirin is approximately 10.0 μg/ml and produces mild analgesic effects. Identify this variable on the worksheet and on the graphs.
- The Minimum Toxic Concentration (MTC) of aspirin is is approximately 50.0 μg/ml and will produce toxic effects in some portion of dogs. Identify this variable on the worksheet and on the graphs.
- The pharmacokinetic goal of aspirin therapy (for pain relief) should be to maintain concentrations between the MEC and the MTC.
- When the spreadsheet loads, the graphs indicate that 10 mg/kg IV or PO provides modest analgesia for slightly less than 2 hours.

**Manipulate the dosage**

- When the spreadsheet loads all simulations are set to a dose of 10 mg/kg (Graph #1 overlaps #2, Graph #3 overlaps #4).
- Inspect the graphs.
- Graph #1 is typical for IV administration (Highest concentration at T=0, Concentrations ONLY fall.)
- Graph #3 is typical for non-IV (oral, IM, SC) administration (concentrations rise to a peak some time after administration)

- Double one IV and one PO simulation (change the dose to 20 mg/kg for #2 and #4).
- The simulations with the higher dose demonstrate higher concentrations.

**Inspect**

Calculated values

- Changing the dose does not change C
_{lt}, V_{z}, K_{a}, F, λ_{z}or T_{1/2}

Steady-State Concentrations (for repeated doses during therapy).

- T
_{max}does not change when the dose changes - C
_{max}, C_{ave}, C_{min}and AUC double when you double the dose. - Compare concentrations on the graphs (first dose) to the calculated steady-state values. Steady-state concentrations are only slightly higher than those of the first dose. This indicates a
__lack__of accumulation between the first dose and steady state for aspirin in dogs. - Calculate the time to reach steady state given this model. Steady state is reached during the first dose interval.

Graphs

- 20 mg/kg IV approaches but does not exceed the MTC (Upper)
- 20 mg/kg PO produces mid-range analgesic concentrations
- The duration of analgesic effect (time above MEC) is extended by just a bit more than an hour.

**Assess**

- The model described in this exercise was dose independent.
- Accumulation of aspirin did not occur at these dosages.
- Doubling doses doubled concentrations at all times during a dose interval.
- Durations of effect were extended by one half-life. They were not doubled.

Questions (Key)

- The model described in this exercise is dose independent. When dosage is changed in such a model, which of these
__does not change__(list all that apply)? C_{max}, C_{ave}, C_{min}, C_{lt}, V_{z}, T_{1/2} - Assume that moderate analgesia requires a plasma concentration of 30 μg/ml. Based on the information in this module and for a dog, can an oral dose regimen for aspirin be designed to produce moderate analgesia without toxicity for an entire 12 hour dose interval?
- According to the plasma concentrations, how long was mild analgesia maintained after a 10 mg/kg oral dose? after a 20 mg/kg oral dose?
- Which calculated value conveniently approximates the increase in the length of time achieved (duration of a particular effect) when increasing the dose from 10 to 20 mg/kg?