Model Independent Pharmacokinetics

Introduction

Have been using this approach so far in this course

Treats body as black box, making no assumptions

Monitor Inputs, Outputs, and Concentration in Plasma

Basic equation of pharmacokinetic dose calculations

Dosing rate = Clearance * Css
(mg/hr = L//hr * mg/L)

Css = concentration of drug in plasma at steady state.This works well for IV infusion. For repeated bolus dosing, the OSCILLATIONS in concentration that give rise to peaks and troughs.
Css(ave) = Average drug concentration at steady state. Corresponds to the Css of IV infusion.
On can replace Css in the formula above with Css(ave) as a first approximation
Css(max) = peak concentrations at steady state
Css(min) = trough concentrations at steady state

Comments on the formula:

... fine for every-day, simple dose adjustments where one has "measured" peaks and/or troughs
... cannot predict peaks or troughs
... cannot use it to extrapolate concentrations to estimate "withdrawal times"

Calculations

Estimating dosing rate

Use formula

Dosing rate = Clearance * Css
(mg/hr = L//hr * mg/L)

Get estimate of CLEARANCE from literature for this drug

Find desired STEADY STATE CONCENTRATION from literature

Aim for middle of therapeutic range
Assume Css(ave) corresponds to Css
Css is knowable only for intravenously infused drugs

Multiply to find DOSING RATE

Determine optimal DOSING INTERVAL
(usually from literature as first approximation)

Multiply DOSING RATE * DOSING INTERVAL to get DOSE

Are PEAKS and TROUGHS in the therapeutic window?
If not adjust regimen by decreasing interval
(Note: Need information in "compartmental models" to estimate peaks and troughs

Questions

Will giving the drug at the computed rate immediately produce a therapeutic concentration?

Do you need to know the Vd to use this formula?

Do you need to know the size of the animal to use this formula?
Indirectly, YES. The CLEARANCE must be the whole animal clearance for the animal in question OR
Clearance must be normalized to a relative mass, e.g., L/hr/kg of body weight.
Many times you will have to do conversions since the literature often (usually) expresses the CL in a similar form.