For this pharmacokinetic model, which includes intermittent dosing and a distribution phase (but not absorption), we will consider daily IV injections of digoxin. The pharmacokinetics of digoxin are complicated. Both the volume of distribution and the elimination clearance depend on a patient's glomerular filtration rate. Additionally, digoxin has a narrow therapeutic range (0.5 - 2.0 ug/L depending on the clinical utility), which makes it very difficult to dose. There are many formulas to guide digoxin dosing and to predict pharmacokinetic parameters. We are going to use
Vf(L) = 3.8*(Body weight in kg) + 3.1*(Clcr as mL/min).
Cl(mL/min) = 0.8*(Body weight in kg) + (Clcr as mL/min); Cl(L/hour) = (Cl mL/min)(60 min/hour)/(1000 mL/L)
Our patient weighs 80 kg and you have estimated their creatinine clearance (Clcr) as 100 mL/min. Your therapeutic goal is an average [digoxin] ~ 1.0 ug/L. Using the above formulae, we can estimate the patient's Vd ~ 614 L and Cl ~ 9.84 L/hour for digoxin. What sort of maintenance dose do we require to maintain an average [digoxin] ~ 1.0 ug/L?
As we have done before, we utilize the equation for relating the rate of infusion and Cl to the steady state drug level, ratein = [digoxin]SS * Cl = 1.0 ug/L * 9.84 L/hour = 9.84 ug/hour. In a 24-hour day, the patient requires a maintenance dose of approximately 240 ug. But, how should this be divided? Once, twice or three times per day?
We need to calculate the elimination half-life, t1/2 = 0.693 * Vd / Cl = 0.693 * 614 L / 9.84 L/hour = 43 hours. Therefore, even if we dose digoxin once per day, this is still less than the expected elimination half-life and there should be minimal differences between peak and trough levels. All of the above has been set into the pharmacokinetic model below. For the moment we are going to ignore distribution phase, so ViF = 0.99. You should observe that it takes a long time to reach steady state, over one week. Obviously, we are going to require a loading dose. However, once steady state is reached, the patient's [digoxin] should be varying between 0.8 - 1.2 ug/L, which is what we want. Calculate an appropriate loading dose to bring the patient to 1.0 ug/L.
Loading dose = [digoxin] * Vd = 1.0 ug/L * 614 L = 614 ug. Try adding that to the model.
Now, let's see the consequences of digoxin's distribution phase. When digoxin is administered it first distributes in an initial (central) volume that is ~ 10% the final (central + peripheral) volume of distribution. Digoxin subsequently equilibrates with the peripheral volume with an apparent half-life ~ 30 minutes. Hence, we should set ViF = 0.1 and t1/2d = 0.5. Try changing ViF (t12d should already be set correctly). It might be useful to reduce the loading dose back to zero or change the starting time to 24 hours in order to better visualize what is going on.
The effect should be dramatic. Immediately after IV injection, the patient's digoxin level soars to ~ 4 ug/L. This is a dangerously toxic drug concentration. However, the patient does NOT experience any toxicity. This is because the sites of action for digoxin reside in the peripheral volume NOT in the central volume. However, we are measuring drug levels from the central volume (i.e. the blood). The peripheral volume never experiences the dramatic peaks in drug level. After 3 - 5 distribution half-lives, the central and peripheral drug concentrations have equilibrated and blood drug levels are representative of the effective concentration at drug active sites. In general, on should avoid drawing a blood sample for digoxin quantitation too soon after administration (< 2 hours for IV injection). In order to demonstrate the relationship between central and peripheral drug concentrations, the below model simulates both concentrations. In blue you should see the familiar plot of central drug concentrations and, in magenta, you can now also see the predicted drug concentration in the peripheral compartment.For demonstration of our final pharmacokinetic model, intermittent dosing with both absorption and distribution phases, we will continue with digoxin but now consider the effect of absorption with PO dosing. Digoxin is available in a number of oral formulations. We will consider tablets that are absorbed with an approximately one hour half-life and are 70% bioavailable. The closest dosage to our current 240 mg is a 250 mg tab. Hence, you need to set everything the same as our Model 5 example but change dose to 250, F to 0.7, and set t12a = 1.
The overall effect of delayed absorption is predictable: peaks are lower and later, troughs are a bit higher. We also note that 4 - 6 hours are required before the central and peripheral volumes equilibrate and blood levels are representative of the effective drug concentration at tissue active sites.