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Hello All:
We are conducting a study in humans to determine the effect of our
drug on the PK of digoxin. I understand that digoxin has an effect on
the ECG and would like to know if there is a published reference
available that would provide more details. Specifically, I would like
to know approximately when following the administration of digoxin,
should an ECG be planned to capture any changes (around Tmax, a few
hours after Tmax etc).
Thanks for your help.
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Conventional teaching is that plasma digoxin concentration does
not reach
equilibirium with heart muscle (and skeletal muscle) for up to 8 - 12
hr after
the last ingested po dose. Therefore, I teach that one should not
use plasma
digoxin concentration to explain alterations in the ECG unless the blood
sample was taken 12 hr after the last ingested dose.
Hope this is helpful............Dan Sitar
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Dear Girish:
The time course of a drug and its effect are always a dynamic
system. The best reference I know is from Reuning, Sams, and Notari:
Role of Pharmacokiinetics in Drug Dosage Adjustment 1. Pharmacologic
effect kinetics and apparent volume of distribution of digoxin. J
Clin Pharmacol, 1973, 13(4) 127-141. Their Figure 7 shows well that
after an IV dose, the plasma concentrations fall rapidly for about
4-5 hours, and then there is a bend, and thay fall much less rapidly.
On the other hand, both the tissue concentrations and the inotropic
effect (the Q - S2 interval) rise, peak, and fall pretty much
together, and neither correlates at all well with the plasma
concentration. They showed a very good corrrelation between the
computed ampount of digoxin in the peripheral (nonserum) compartment
and the inotropic effect.
It is because of their work that we developed such a model of
digoxin, and began to correrlate the patient's clinical response with
the computed amount of drug iin the peripheral compartment, and began
to select target goals (usually about 7 ug of glycoside/kg body
weight, for patients with CHF in sinus rhythm, up sometimes to 19 for
those with atrial fib or flutter) and computed dosage regimens to hit
such selected targets in the peripheral compartment. It has been of
great practical utility to us. We have incorporated this model into
our newer "multiple model" software for dosage design to hit such
targets with the least predicted weighted squared error (Jelliffe,
Schumitzky, Bayard et al: Model-Based, Goal Oriented, Individualized
Drug Therapy: Linkage of Population Modeling, new "Multiple Model"
Dosage Design, Bayesian Feedback, and Individualized Target Goals,
Clin. Pharmacokin, 34: 57-77, 1998. We have liked it a lot.
When to best observe the vayious responses? The peak effect, as
shown by Reuning and colleagues, comes about 4-5 hours after an IV
dose, and, with our model, about 7-8 hours after an oral dose. There
are about 4 D-optimal times after a dose to get serum samples - at
the peak serum conc, which is about 5 min after an IV infusion over
about 15 min, or at about 1.5 - 1.75 hours after an oral dose. Then
the trough is also useful, and these constitute the basic pair to get
the Vd of the central serum compartment and the Kel. The best
estimates of the rate constants out of the serum compartment and
back to it, seem to us to be obtained about 1/2 hr and 7 hrs after
the dose, and are what we have used.
Therefore, there is no single best time to get a serum
concentration to correlate with the effect. You need to make a
dynamic model of the process. I would start with a peak at 1.5 - 1.75
hrs after the dose, and a trough. I would measure the effect on the
EKG about 7 hours after the oral dose. If you are seeking to capture
changes in the PK of digoxin, then I would probably use all 4 samples
at the times shown above. There is NO correlation of effect with
serum concentrations, only with the overall central and peripheral
compartment model you make, and an absorptive compartment for oral
dosage, fitting the serum concentrations you measure. If it would
help to have a population model to use as a prior and then to do
Bayesian individual modeling, you might consider using our MM-USCPACK
software for this.
Many people have said to wait for a steady state, and to wait
until distribution is somplete after a dose, as that is when the
tissue compartment as an abstract whole will have a constant ratio
between its values and the serum concentrations. This is not
necessary, and actually greatly limits our ability to understand the
overall dynamics of the system. Principles of optimal experimantal
design have been well known for about 30 years, but for some reason
have not been applied in practice. The drug industry has used them
well to get the best parameter estimates for a model with the fewest
samples. You might look at D'Argenio, Optimal Sampling Times for
Pharmacokinetic Experiments, J. Pharmacokin Biopharmacol., 9:
739-756, 1981. There is also useful material on our web site
www.lapk.org, under Teaching Topics.
As to references about digitalis effect on the EKG, almost any
book would be useful, but I would stay away from Dubin. In my
opinion, it has many significant errors spread nonverbally in their
art work. I wrote my EKG book (Fundamentals of Electrocardiography,
Springer Verlag, 1990) specifically because of what I thought were
the many misconceptions spread through their art work, and because it
did not seem to teach any real understanding, only rote memory, but
that is all that many seem to want.
Hope this is useful. I look forward to talking with you more.
Roger Jelliffe
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