Clinical Pharmacokinetics 9: 136-156 (1984)

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Clinical Pharmacokinetics of Amiodarone

Roberto Latini, Gianni Tognoni and Robert E. Kates
Istituto di Ricerche Farmacologiche 'Mario Negri', Milano, and Division of
Cardiology, Stanford University School of Medicine, Stanford

Summary Amiodarone is an iodinated benzofuran derivative with recognised antiarrhythmic ac-

tivity in man. As yet, its pharmacokinetic behaviour has not been satisfactorily charac-
terised. Specific and sensitive high-pressure liquid chromatographic methods have become
available only recently and this partly explains the scarcity of pharmacokinetic data on
the drug.
Available evidence suggests that absorption of amiodarone following oral administra-
tion is erratic and unpredictable; oral bioavailability ranges from 22 to 86%. The drug is
eliminated largely by metabolism; less than 1% of the dose is excreted unchanged in the
urine. Biliary excretion may have a role in the overall elimination of the drug. Desethyl-
amiodarone is the only metabolite positively identified in the plasma of patients receiving
treatment with amiodarone; no data are available on its possible pharmacological activity.
Since it is a highly lipophilic drug, amiodarone is extensively distributed into tissues.
Adipose tissue and skeletal muscle accumulate large amounts ofthe drug during long term
treatment. Myocardium/plasma ratios of amiodarone are high both in man and in ani-
mals; peak concentrations in the myocardium are reached within halfan hour after admin-
istration of an intravenous bolus to dogs. Placental transfer of amiodarone has been dem-
onstrated in humans, while its blood profile is not modified by dialysis treatment. In vitro
protein binding of amiodarone has been reported to be 96.3 ± 0.6%.
The plasma half-life of amiodarone after single-dose administration has been reported
to be in the range of3.2 to 79.7 hours. However, after withdrawal oflong term amiodarone
treatment the half-life is as long as 100 days. Total body clearance ranges from 0.10 to
0.77 L/min after single-dose intravenous administration, and the apparent volume of dis-
tribution ranges between 0.9 and 148 L/kg.
Amiodarone disposition kinetics in patients with cardiac arrhythmias are not different
from those in healthy volunteers. However, the possible effects of liver and cardiac failure
on the drug's kinetics have not been studied.
Amiodarone potentiates the anticoagulant effect of warfarin, probably by inhibition of
its metabolism. Increases of steady-state concentrations of digoxin, together with the ap-
pearance of signs of digitalis toxicity, have been reported when amiodarone was given to
patients receiving long term treatment with digoxin. Amiodarone has also been shown to
interact with other antiarrhythmic agents such as quinidine and procainamide.
The time of onset of action of amiodarone after a single intravenous dose ranges be-
tween 1 and 30 minutes and its duration of effect between 1 and 3 hours. During long
term oral treatment, the therapeutic effect is observed after a delay of 2 to 21 days and
can last more than 1 month after withdrawal of therapy. The time course of amiodarone
electrophysiological effects after intravenous bolus administration to dogs follows its myo-
cardial concentrations.
Pharmacokinetics of Amiodarone 137

The plasma steady-state concentration of amiodarone found to be effective in man

rangesjrom 0.4 to 11.99 pglml; however. even ifno therapeutic range has yet been defined.
there is good agreement on keeping steady-state levels between 1.0 and 2.5 pg/ml in patients
treated for arrhythmias.
Clinically relevant extracardiac side effects have been reported. such as corneal de-
posits. thyroid dysfunction. peripheral neuropathy. pulmonary fibrosis and. less import-
antly. liver toxicity. Many of these side effects seem related to the dose and duration of
amiodarone therapy. but information on their relationship to drug plasma concentrations
is not available.

Amiodarone was initially developed and mar-
keted as an antianginal agent (Charlier et aI., 1968;
Facquet et aI., 1969; Vastesaeger et aI., 1967), but
has more recently been employed successfully as
an antiarrhythmic drug. Based on in vitro studies,
it has been categorised as a class 3 agent (Singh,
1983; Singh and Vaughan Williams, 1970). It pro-
longs the action potential duration in the atrial and
ventricular myocardium, with a minor effect on the
rate of phase 4 depolarisation. The popular use of,
and considerable interest in, this compound is due
to its high efficacy in the treatment of supraven-
tricular, junctional and ventricular rhythm dis-
turbances (Marcus et aI., 1981; Podrid and Lown,
1981).
Amiodarone has unique pharmacokinetic prop-
erties, with a very long biological half-life, up to
more than 100 days. Following the development
of reliable high-pressure liquid chromatography
(HPLC) methods for the determination of amio-
darone concentrations in biological fluids and in
tissues, studies have been conducted to evaluate its
absorption and disposition characteristics. As yet
however, the pharmacokinetic behaviour of amio-
darone is still not satisfactorily characterised. Its
protein binding, metabolism and the relationship
between short and long term pharmacokinetics are
not well elucidated.
The drug's pharmacodynamic characteristics
pose major unsolved problems. The definition of
a therapeutic range, the explanation of the large
differences in time to its onset of action between
intravenous (l to 30 minutes) and oral adminis-
tration (2 to 21 days) [Rosenbaum et aI., 1976;
Ward et aI., 1980], and the qualitative differences
in its electrophysiological effects between intraven-
ous and long term oral administration are among
those issues awaiting further clarification (Coutte
et aI., 1976).
Due to the limited human data on the phar-
macokinetic and pharmacodynamic characterisa-
tion of amiodarone, animal data are also discussed
in order to help clarify and support the limited hu-
man findings,
1. Physicochemical Properties
Amiodarone is a benzofuran derivative with a
molecular weight of 645.32 (fig. 1); amiodarone free
base is 39.3% iodine by weight. The oral formu-
lation contains the chlorohydrate salt of amioda-
rone; a 200mg tablet contains 75mg of iodine.
The physicochemical characteristics of amio-
darone have been recently described in detail by
Bonati et ai. (1983a). The drug is amphiphilic with
both hydrophilic (tertiary amine) and hydrophobic
(benzofuran and di-iodinated benzene ring) por-
tions. It is highly soluble in chloroform and poorly
soluble in water (Singh, 1983), which makes it dif-
ficult to perform in vitro experiments. Its acid-base
constant (pKa) is 6.56 and its maximum lipid so-
lubility range is from pH 3.5 to 5.5 (Bonati et aI.,
1983a).
2. Analytical Methods
The first published attempt to assay the con-
centration of amiodarone in biological samples was
that of Broekhuysen et ai. (1969). These investi-
gators used 13lI-Iabelled amiodarone. They meas-
Pharmacokinetics of Amiodarone
ured total radioactivity and made no attempt to
separate unchanged drug from metabolites or lib-
erated 1311. In other subjects they simply measured
total iodine excretion in the urine after admini-
stering the unlabelled drug. The main pitfall of both
methods is their lack of specificity, which limits
the interpretation of the results obtained. Though
efforts were made to correct for decay, the short
half-life of 131 I further limits the usefulness of this
method.
More recently, several HPLC methods for
measuring amiodarone and its metabolites in bio-
logical samples have been reported (table I). The
first HPLC method reported was that of Flanagan
et al. (1980). This method involved an extraction
of amiodarone into di-isopropyl ether at a pH of
4.5. The ether was injected into a silica column and
amiodarone was separated from other components
using a methanol-diethyl ether-perchloric acid mo-
bile phase. This method is sensitive to a lower limit
of SO ng/ml and is specific for unchanged amio-
darone, but, in its last version (Storey and Holt,
1982), amiodarone and desethylamiodarone (DEA),
Amiodarone
Desethylamiodarone (DEA)
Fig. 1. Chemical structures of amiodarone and its principal me·
tabolite.
138
a major amiodarone metabolite, could be meas-
ured at plasma concentrations as low as 2 ng/mi.
Other methods have involved extraction at differ-
ent pH values and with different solvent systems.
The extraction of DEA is more efficient at a pH
of 7.4.
Other chromatographic systems involving re-
versed phase separation have been reported. Both
normal and reversed phase systems are suitable for
the separation and simultaneous measurement of
amiodarone and DEA. Four reported methods in-
clude procedures for extraction and analysis of
amiodarone in tissues (Latini et aI., 1983; Lesko et
ai., 1981; Plomb et al., 1983; Riva et ai., 1982a).
Despite their methodological differences, all the
methods reported in table I fulfil basic require-
ments of sensitivity and specificity, which allow
comparison of the data generated.
3. Fundamental Pharmacokinetic
Properties of Amiodarone
3.1 Absorption and Bioavailability
The available evidence suggests that absorption
of amiodarone following oral administration is er-
ratic and unpredictable. The time to reach peak
plasma concentrations has been reported to vary
from 2 to 12 hours (table III). A lag time ranging
from 0.4 to 3 hours and an oral absorption lasting
as long as 15 hours were found in healthy volun-
teers given 400mg of amiodarone orally (Holt et
ai., 1983). Oral bioavailability has been reported to
be highly variable, ranging from 22 to 86% (An-
astasiou-Nana et aI., 1982; Andreasen et ai., 1981;
Holt et ai., 1983; Riva et aI., 1982b). The large dif-
ferences in bioavailability might account, at least
in part, for the variability in steady-state concen-
trations observed during long term oral therapy (see
section 3.4.2).
The low solubility of amiodarone in aqueous
solution might be a reason for its unpredictable ab-
sorption. Moreover, the relatively high extraction
ratio (0.49) found in isolated perfused rat livers
(Riva et aI., 1982a) suggests a first-pass effect which,
if substantiated, could be partly responsible for the
low and variable bioavailability.
Pharmacokinetics of Amiodarone 139

Table I. HPLC methods for analysis of amiodarone and desethylamiodarone (DEA)

HPLC column Sensitivity Simultaneous Reference

(ng/ml) measurement
[cv%)a of DEA

Normal phase 50 Yes Flanagan et al. (1980, 1982)

(silica) [2.2 b/6.9 C]

Reversed phase 100 No Andreasen et al. (1981)

(C-18) [7.1/10.0J

Normal phase 50 Yes Lesko et al. (1981)

(silica) [2.6/4.9J

Reversed phase 20 Yes Riva et ai. (1982a), modified by Latini et al.,

(C-8) [5.7/10.6) (1983)

Normal phase 100 Yes Anastasiou-Nana et al. (1982)

(?) (?)

Normal phase 2 Yes Storey and Holt (1982)

(silica) [2.9/4.3J

Reversed phase 25 Yes Plomp et al. (1983)

(C-18) [1.9/3.8]

a Coefficient of variation
b Within days CV%.
c Between days eV%.

3.2 Metabolism and Excretion
The metabolism of amiodarone has not been
completely characterised_ Several potential metab-
olites have been analysed (Flanagan et aI., 1982),
but only DEA (fig. 1) has been positively identified
in the blood of patients during long term oral treat-
ment. This metabolite accumulates to steady-state
concentrations which are comparable to those of
the parent drug (Heger et aI., 1983; Holt et aI.,
1983). The significance of its presence in relation
to amiodarone therapeutic and adverse effects is
now considered speculative.
Recently, DEA has been reported to accumulate
in red blood cells to an extent greater than that of
amiodarone; red blood cell/plasma concentration
ratios of 1.30 to 1. 76 for DEA and 0.38 to 0.48 for
amiodarone have been reported in patients treated
long term with amiodarone doses of 200 to 600
mg/day (Heger et a!., 1983). Under similar con-
ditions, Holt et a!. (1983) have found a mean blood/
plasma concentration ratio for amiodarone of O. 73
± 0.06. This should obviously be taken into ac-
count when comparing drug concentration values
reported in studies which use analytical methods
based on whole blood or plasma, respectively. In
1 patient, DEA has been measured in blood im-
mediately after the ingestion of a single 8g dose of
amiodarone taken in an unsuccessful suicide at-
tempt (Bonati et aI., 1983b). DEA blood levels
stayed around 200 ng/ml for the 2-week observa-
tion period, while amiodarone had dropped below
50 ng/ml in 5 days. Holt et al. (1983) have recently
shown that DEA reaches concentrations compar-
able to amiodarone within 3 to 5 days after an
intravenous bolus of the parent compound and dis-
appears from plasma in parallel with amiodarone,
at least up to 58 days. This probably means that
amiodarone elimination is the rate-limiting step.
Studies in normal subjects and patients with
cardiac arrhythmias have evaluated the extent of
excretion of amiodarone in urine after oral admin-
istration. Riva et a!. (l982b) collected urine for 72
hours after administering single 150mg intraven-
Pharmacokinetics of Amiodarone 140

ous doses to 3 normal subjects. No unchanged
amiodarone was detected. These same investiga-
tors collected 24-hour urine samples from patients
who were being treated long term with amioda-
rone, and similarly found no unchanged drug.
Anastasiou-Nana et al. (1982) collected urine for
24 hours after administering single intravenous
doses (150mg) to normal subjects; they analysed
the urine for unchanged drug, metabolite and io-
dine content. Neither amiodarone nor DEA was
detected in the urine, and an amount of iodine
equivalent to only 0.5% of the content of the ad-
ministered dose was found.
More recently, Haffajee et al. (1983) had the
same results when they gave a single dose of 800mg
ments of iodine content, these investigators con-
cluded that 5% of a dose is excreted unchanged in
the urine. This observation requires further study,
since urine was collected for only 2 hours, and total
iodine, not unchanged drug, was measured.
Broekhuysen et al. (\969) administered single
intravenous doses ofamiodarone labelled with 1311
to 2 subjects. Urine was collected for 24 hours and
analysed for 1311. Less than 0.7% of the admini-
stered radioactivity was found in this 24-hour urine
fraction. These investigators also examined the re-
covery of total iodine in the faeces of a separate
pair of subjects to whom amiodarone was admin-
istered for 1 month (300 mg/day). In this study,
131 1 was not employed, and no attempt was made

of amiodarone orally to 8 patients and collected to distinguish between amiodarone, metabolites, or

urine for 24 hours.
The data of Andreasen et al. (1981) differ from
those reported by others in that they were able to
measure amiodarone in urine collected for the first
2 hours after administration of a single 400mg
intravenous dose to 2 subjects. Based on measure-
free iodine. It was reported that a significant por-
tion of the administered iodine was recovered in
the faeces. Whether this was a result of excretion
of amiodarone in the bile, reported also in 1 sub-
ject by Andreasen et al. (1981), or a consequence
of poor bioavilability was not considered.

Amiodarone concentration (1"9/9 or 1'9fml)

10 20 30 40 50110 120
Adipose ~------~------~------~~------~------~~!I~----~
tissue pJ2§32J2l:2:JIT§2Jl2ZI2ElJIZEZIEI::S;;;ZITITiSIZ;§§2IBEIEISZIml§] \:}, ":"""':·"""""""'}"""I
Lung
Bile
Pancreas
Liver
Heart
Kidney
Aorta
Thyroid
Muscle
Blood
g
~--~---r---'----'----rl---.I----r---,----r--~--~lrl---r---.--
5 10 15 20 25 30 35 40 45 50 120 125
Tissue/blood ratiO

Fig. 2. Blood/tissue ratiOS of amiodarone in autoptic material of a patient treated long term.
Pharmacokinetics of Amiodarone
Two studies have dealt with amiodarone and
DEA elimination in patients requiring long term
haemodialysis. The disappearance rate in plasma
of the two compounds was not altered by dialysis
periods; moreover neither amiodarone nor DEA
could be measured in the dialysate (Bonati et aI.,
1983c; Harris et aI., 1983).
Amiodarone and DEA were also measured in
samples collected 8 to 12 hours after administra-
tion in 10 patients receiving long term therapy. The
mean urinary concentration of amiodarone was 29
ng/ml, that of DEA 149 ng/ml, while plasma con-
centrations were 2.08 and 1.48 Itg/ml, respectively
(Harris et aI., 1983).
3.3 Distribution
3.3.1 Tissue Uptake
The characteristics of amiodarone distribution
in man are not well delineated.
Broekhuysen et ai. (1969) gave 100mg of 131 1_
amiodarone intravenously to 1 subject and meas-
ured the regional isotope distribution by total body
scanning. Analyses were performed daily for 6 days
following administration. The radioactivity was
observed to decrease in lung, liver, heart, and kid-
ney, while it remained almost constant in limbs
and steadily increased in the thyroid gland.
When a single dose of 1311-labelled amiodarone
was given orally to a patient during long term
amiodarone therapy, 131 1 accumulated in the limbs;
however only a transient accumulation followed by
a rapid decay of radioactivity was evident in the
thyroid gland. These data suggest that amiodarone
accumulates extensively in the skin, subcutaneous
fat and/or muscle. When iodine content was meas-
ured at post mortem in tissues from 3 patients who
had been treated long term with amiodarone, adi-
pose tissue and skeletal muscle were found to be
the main reservoirs of amiodarone (Broekhuysen
et aI., 1969). Using a specific HPLC assay, Haffajee
et ai. (1983) analysed postmortem samples from
patients who had been treated long term with
amiodarone. They found high concentrations of
unchanged drug in adipose tissue, lung and liver.
A profile of the blood/tissue ratios of amioda-
141
rone in various organs at post mortem in a patient
treated long term with a low dose (200 mg/day)
maintenance regimen is shown in figure 2 (Mag-
gioni et aI., 1983). Holt et ai. (1983) reported post-
mortem data from 9 patients who died on amio-
darone; liver and fat had the highest concentrations,
followed by lung, lymph node, myocardium, skel-
etal muscle, thyroid gland and brain in decreasing
order. Interestingly, DEA concentrations in all tis-
sues, except in fat, were higher than those of amio-
darone. Harris et ai. (1983) obtained a liver biopsy
for diagnostic purposes from a patient treated with
amiodarone long term. The concentrations of
amiodarone and of DEA in the hepatic tissue were
1020 and 5050 Itg/g, respectively. High concentra-
tions of amiodarone (734 ltg/g) and of DEA (2551
ltg/g) were measured in lung biopsy samples from
a patient with pulmonary toxicity and similar con-
centrations were found in 1 without pulmonary
toxicity at post mortem (Heger et aI., 1983). This
tendency of DEA to accumulate in tissues more
than amiodarone is in agreement with the higher
red blood cell/plasma ratio of this compound as
described above (see section 3.2).
In some cases it was possible to measure amio-
darone and its metabolite in specimens obtained,
during cardiac surgery, from patients on amioda-
rone. Myocardium accumulation ratios in the range
of 20 to 60 for amiodarone and of 100 to 260 for
DEA have been reported in 21 patients as a whole
(Debbas et aI., 1983; Marchiset et aI., 1983). No
attempt was made to separate atrial from ventric-
ular concentrations.
Studies in Animals
More extensive studies ofamiodarone uptake in
tissues have been carried out in animal models.
Iodine was measured in tissues of mice, rats, rab-
bits and dogs treated long term with amiodarone
(Broekhuysen et aI., 1969); the highest concentra-
tions were found in liver, lungs, spleen, adrenals,
adipose tissue and myocardium. One report de-
scribed the tissue accumulation of iodine in rats
during long term oral amiodarone administration
(Broekhuysen et aI., 1969). In this 24-day study, no
further accumulation of iodine was observed after
Pharmacokinetics of Amiodarone 142

the third day. While there was considerable vari-
ability in the data, it appeared that steady-state was
achieved within 3 days.
A later study (Riva et aI., 1982a), using an HPLC
assay, reported the distribution of amiodarone in
rats after intravenous bolus administration. Dif-
ferences in both rate and extent of uptake were
noted for the tissues analysed. The brain showed
the lowest concentrations of amiodarone, while
amiodarone accumulated extensively in fat. The fat
contained the highest concentrations among all the
tissues analysed at the end of the study (16 hours
after administration of amiodarone) [fig. 3]. Adi-
pose tissue seems to behave as a reservoir or depot
for the drug, and its role might become important
during long term treatment.
The kinetics of distribution of amiodarone into
the myocardium has been extensively studied in

.-.
1000 0-0 Adipose tissue
0----0 Kidney
A-A Liver

.--.
Heart
6----6 Skeletal muscle
Brain
Blood

100

c:
o
~
E
2l
c:
8
Q)
:>
II>
.~
:c-o
o
:is
Q)
c:
o ,
iii
"8
·E '.
« 0.10

-'f- - -- -t- - - ___ _

-·-·-t

O.Ol.L...-.,......---,-----r----r-----.---------------r-
2 4 6 8 16
Time (h)

Fig. 3. Blood and tissue concentrations of amiodarone after intravenous bolus administration (50 mg/kg bodyweight) to rats (after
Riva et al., 1982a; reproduced with permission).
Pharmacokinetics of Amiodarone {43

the dog (Latini et aI., 19&3). The uptake is rela-
tively fast; the peak is reached between 10 and 30
minutes after an intravenous bolus (fig. 4), and the
myocardium/plasma partition ratio is very high
(mean = 89). A puzzling difference was found when
the animals were treated long term with oral drug;
the partition coefficient at steady-state was then less
than half that after single-dose administration
(mean = 34). Other authors have also reported the
myocardial uptake of amiodarone in rabbits and
dogs to be very high (Kannan et aI., 1981).
Some ultramicroscopic studies on tissues after
prolonged amiodarone treatment, both in rats and
man, suggest that the molecule (or a metabolite)
interacts with constituents of the cell membrane,
namely the phospholipids, causing alterations par-
ticularly evident in the Iysosomes (Bockhardt et ai.,
1978; Lullmann et ai., 1980; Meier et aI., 1979).
The histological characteristics of the lesions and
the biochemical effects closely resemble those
caused by other amphiphilic compounds. Many of
these substances have been shown, in experimental
animals, to alter the phospholipid content of tis-
sues, causing a phospholipidosis (LiiHmann et aI.,
1975). This particular interaction of amiodarone
with cell constituents might be a factor contribut-
ing to some of its side effects and to its long-lasting
accumulation in body tissues.
amiodarone in the newborn at birth were 0.15 and
0.34 ~g/ml for amiodarone and DEA, respectively;
newborn/mother ratios for amiodarone and DEA
in plasma were 0.27 and 0.53.
Recently, two other reports have appeared. In
one, amiodarone was given to a woman in the last
3 weeks of pregnancy; the transplacental passage of
amiodarone and DEA was found to be of the order
of 10% and 2591 , respectively (Pitcher et aI., 1983).
A similar passage was described in another case
treated with amiodarone towards the end of preg-
nancy (McKenna et aI., 1983). Treatment with
amiodarone was continued while the mother was
breast feeding the infant. Amiodarone and DEA
were present in the milk at higher concentrations
than in the mother's plasma. The estimated daily
ingestion of amiodarone and DEA by the breast-
fed infant was around 1.5 and 0.6 mg/kg body-
weight, respectively. No effects attributable to
amiodarone were noticed in the newborn.
100
0;
0;
"- 0
0 lJ,
f--lJ,----~_
~ 10 --lJ,- -_ A--"' __ A~b.
..=,
I

3.3.2 Protein Binding

c
0 "\
~
0
In vitro experiments using ultracentrifugation
have shown that the bound fraction ofamiodarone 'c"
0
1.0
\
0
0
0
\
to plasma proteins is 96.3 ± 0.6%. Such high bind- 0,

.,e'"
c 0'0
ing does not seem to be responsible, however, for .....0 ,
the reported potentiation of warfarin activity, as ~ o-o_o~
E
no displacement of warfarin was found (at least <t 0.1
in the in vitro situation) and different binding
sites could be demonstrated (Neyroz and Bonati,
1984).
0.01 +----.--r-.--,---..---r--
o 60 120 180 240 300 360
3.3.3 Placental Transfer and Secretion into Time (minutes)
Breast Milk
Transplacental passage of amiodarone and DEA
Fig. 4. Plasma (0) and myocardial (6) concentrations of amio-
has been shown in I patient treated with amio- darone after intravenous bolus administration (5 mg/kg body-
darone during the last trimester of pregnancy (Can- weight) to a dog. The lines represent the computer best fit of
delpergher et aI., 1982). Plasma concentrations of data (after Latini et al., 1983; reproduced with permission).
Pharmacokinetics of Amiodarone 144

Table II. Pharmacokinetic parameters of amiodarone after intravenous bolus administration

Dose Terminal tv, Cl Vd last measurable No. of Reference

(mg) (h) (lIm in) (l/kg) sample subjects

150 17.4 0.60 12.9 32-40 hours 3 (volunteers) Riva et al. (1982b)
[12.1-20.7] [0.49-0.72]" [9.3-17.2]"

150 4.3 0.2 1.3 7 hours 8 (volunteers) Anastasiou-Nana et al.

[3.2-6.2] [0.12-0.291b [0.9-2.21b (1982)

400 '" 11 16-24 hours 7 (patients) Andreasen et al. (1981)

300 16.1 0.45 11.7 24 hours 3 (patients) Riva et al. (1982b)

[11.6-19.61 [0.21-0.771 [6.9-21.0)

400 24.8 days 0.14 65.8 58 days 6 (volunteers) Holt et al. (1983)
[9.3-44.1] [0.10-0.19] [18.3-147.71

Dose Dose
a Cl = ; Vd =
AUCo _ , AUCo _ 00 • f3

Dose
b Cl = 0.693 x Vd x 1/60; Vd = --
Co

Abbreviations: Cl = total body clearance; Vd = apparent volume of distribution; tv, = half-life.

3.4 Blood/Plasma Kinetics Much shorter 'terminal' half-lives (mean 4.3

The kinetics of amiodarone in blood or plasma
has been studied in healthy volunteers, patients
with cardiac arrhythmias, and experimental ani-
mals.
3.4.1 Intravenous Administration
A summary of the reported pharmacokinetic
parameters of amiodarone determined after intra-
venous bolus administration is given in table II.
Amiodarone was given intravenously to healthy
volunteers and patients with supraventricular
tachycardia by Riva et al. (l982b). The mean ki-
netic parameters did not differ between the 2
groups; both the apparent volume of distribution
and total blood clearance were quite high. A com-
parison with results from other studies can be made,
taking into account that in this case the drug was
measured in whole blood, and that the blood/
plasma ratio is 0.73 (Holt et aI., 1983). The dis-
appearance of amiodarone in blood was biexpo-
nential with a mean half-life of 16.8 hours.
hours) were reported by Anastasiou-Nana et al.
(1982); the apparent volume of distribution and
total piasma clearance were also much lower. A
short sampling period of only 7 hours may account
for some of the discrepancies between this and other
studies.
Andreasen et al. (1981) administered amioda-
rone both intravenously and orally to patients. The
plasma disappearance curves often had secondary
peaks, between 4 and 12 hours after administra-
tion, which did not allow a reliable estimate of the
kinetic parameters (fig. 5). These peaks were ten-
tatively attributed by the authors to enterohepatic
circulation of amiodarone.
Recently, using a very sensitive HPLC assay
(Storey and Holt, 1982), amiodarone and DEA
could be measured in the piasma of 6 healthy
volunteers up to 58 days after a 400mg intravenous
bolus (Holt et al., 1983). A long terminal phase with
an average half-life of 25 days could be shown in
plasma. These values are more consistent with the
long washout half-lives estimated after long
Pharmacokinetics of Amiodarone 145

term treatment, and document the existence of a
slowly equilibrating compartment (possibly adi-
pose tissue).
3.4.2 Oral Administration
Data from single- and multiple-dose oral studies
with amiodarone are summarised in table III.
Irregular plasma concentration-time curves and
variability in the time to peak concentrations and
in absolute bioavailability were reported by 4
groups (Andreasen et aI., 1981; Haffajee et aI., 1983;
Kannan et aI., 1982; Riva et ai. 1982b). Similarly,
elimination half-lives after single doses were also
highly variable, ranging from 3 to 80 hours, with
no differences between patients and volunteers. The
erratic and long lasting absorption (Haffajee et ai.,
1983; Holt et ai., 1983; see also section 3.1) ac-
count to a considerable extent for the high varia-
bility reported.
During long term administration, amiodarone
accumulates in the blood or plasma. Steady-state
was not reached for at least 30 days (Andreasen et
aI., 1981), with a 2- to 3-fold increase occurring
from day 1 to day 30. More irregular patterns of
accumulation were reported in 3 patients by Riva
et al. (l982b).
Two studies have reported significant correla-
tions between amiodarone daily dose (mg/kg) and
its steady-state concentrations in small groups of
patients (Haffajee et aI., 1983; Staubli et ai., 1983).
However, the variability is too large to make ac-
curate predictions. A relationship between total ad-
ministered dose and steady-state concentrations has
been reported in larger numbers of patients (Bop-
pana et aI., 1983; Heger et aI., 1983; Siddoway et
aI., 1983).
The profile of the steady-state blood concentra-
tions of amiodarone and DEA in a controlled ef-

100 100

10 10
E
t;;
..=,
c:
0

~c:
(I)
0
c: ,,,......... -e...•...• _ _____
0

•
0
to
E
•
•
t/)
to
a. 0.1 0.1
Q)
c:
e
to
"0
0
'E
« 0.01 I I I I I 0.01 I I
0 4 8 12 16 20 24 0 4 8 12 16 20 24
Time (h) Time (h)

Fig. 5. Plasma concentrations of amiodarone after oral (---) and intravenous ( - ) bolus administration (400mg) to 2 patients (after
Andreasen et al .• 1981; reproduced with permission).
Pharmacokinetics of Amiodarone 146

Table III. Pharmacokinetic parameters of amiodarone (mean and range) after single- and multiple-dose oral treatment (single doses
except where specified)

Dose Time to peak Bioavailability Terminal tv. Last measurable No. of Reference
(mg) (h) (%) sample after subjects
amiodarone

200-400 4.5 17.1h 30h 5 (volunteers) Anastasiou-Nana et al.

[3-6) [10.2-25.0J (1982)
400 2.3 58 35.9h 50h 3 (volunteers) Riva et al. (1982b)
[2-3) [22-86J [12.1-79.7)

400 7.3 42 "" llh 16-24h 7 (patients) Andreasen et al. (1981)

[4.2-12.0) [29-80]

300 13.7 days 37 days 1 (patient)a Andreasen et al. (1981)

daily

400 8 9.2h 24h 3 (patients) Riva et al. (1982b)

[6-10] [6.9-12.8]

1400-1800 4.9 7.2h 24h 6 (patients) Kannan et al. (1982)

[3-6.2] [3.0-16.9)

400-800 29 days 60 days 4 (patients)" Kannan et al. (1982)

daily [20-58)

200-400 4.5 34 17.1h 30h 8 (patients) Anastasiou-Nana et al.

[3-6] [23-50] [11.7-24.0] (1982)

200-1200 52 days 70 (patients)" Harris et al. (1981)

daily

400 35 6 (volunteers) Holt et al. (1983)

[22-46)

200-600 52.6 days 138 days 8 (patients)" Holt et ai. (1 9S3)

daily [26-107]

800 5.2 4.6h 8 (patients) Haffajee et al. (1983)

[3-7)

200-1600 19.3 days 180 days 3 (patients)" Haffajee et al. (1983)

daily [13-30)

200-600 41.1 days 12 (patients)" Staubli et al. (1983)

daily [21-78J

a Long term treatment.

ficacy study of Lown class 3 and 4 patients receiv-
ing 400 and 200 mg/day over two 28-day periods,
respectively, is shown in figure 6 (Italian Collab-
orative Group on Amiodarone, 1984).
In 6 patients treated long term with amiodarone
who received a single oral dose of 13lI-labelled
amiodarone, the washout of the radioactivity from
the body had a mean half-life of 28 days (Broek-
huysen et al., 1969). Several groups have studied
the time course of disappearance of amiodarone
from blood following discontinuation of long term
oral therapy (Andreasen et aI., 1981; Haffajee et aI.,
1983; Harris et al., 1981; Holt et al., 1983; Kannan
et al., 1982; Staubli et a!., 1983). Amiodarone half-
lives during the washout period ranged from 14 to
107 days. This is definitely longer than that re-
Pharmacokinetics of Amiodarone
ported after most single-dose administrations and
more consistent with the slow disappearance rate
of the therapeutic effects described in many clinical
studies (Nademanee et al., 1982a; Rosenbaum et
al., 1974, 1976).
The observed discrepancy can be due to time-
dependent kinetics of amiodarone and/or to ana-
lytical limitations. During long term oral treat-
ment, the body clearance of amiodarone may
decrease (possibly due to impairment of liver
function) [Holt et al., 1983; Siddoway et al., 1983].
It is also likely that in many single-dose studies the
assay for amiodarone was not sensitive enough to
allow for an accurate characterisation of the ter-
minal half-life (Storey and Holt, 1982). This big
difference between half-lives calculated after single
and multiple doses makes pharmacokinetic pre-
dictions impossible.
The pharmacokinetics of amiodarone in coex-
isting disease states such as liver and cardiac fail-
ure have not yet been studied; the same is also true
for the effect of age on the drug's disposition.
4. Pharmacokinetic Drug Interactions
Relatively few reports have appeared dealing
with amiodarone interactions with other drugs.
There are two interactions which probably have a
pharmacokinetic basis: one with warfarin and the
other with digoxin. Both of these were documented
for the first time in 1981.
4.1 Warfarin
Potentiation of the anticoagulant effect of war-
farin has been reported by a number of authors
(Hamer et aI., 1982; Martinowitz et al., 1981; Rees
et aI., 1981; Serlin et at, 1981).
Several patients have experienced serious side
effects due to excessive hypocoagulability, which
necessitated either a drastic reduction in the dose
of warfarin or suspension of amiodarone. The time
course of onset of this interaction was highly vari-
able, ranging from 1 to 28 days; in most cases, the
delay Was longer than 6 days. Moreover, the po-
147
tentiation of warfarin lasted 2 to 16 weeks after
discontinuing amiodarone administration.
Warfarin concentrations in plasma were meas-
ured in 1 patient. The total plasma warfarin con-
centration increased after amiodarone therapy was
started. By the fourth day of concomitant admin-
istration, the warfarin concentration had doubled
and the prothrombin time tripled. However, pro-
tein binding of warfarin was unchanged, since the
free fraction remained constant (Serlin et al., 1981).
These findings have more recently received sup-
port from the in vitro study of Neyroz and Bonati
( 1984) who showed that amiodarone does not dis-
place warfarin from its binding sites (see also sec-
tion 3.3.2). Inhibition of warfarin metabolism by
amiodarone or a direct depression of vitamin K-
dependent coagulation processes are more likely
(Hamer et al., 1982; Richard et al., 1983). Poten-
tiation of acenocoumarol and heparin action by
amiodarone has also been reported (Richard et al.,
1983).
4.2 Digoxin
An interaction between digoxin and amioda-
rone has been reported by several groups (Achilli
et aI., 1981; Furlanello et al., 1981; Moysey et al.,
1981; Nademanee et al., 1982b). In 1 study, a sharp
increase in digoxin plasma concentrations after
administration of amiodarone was observed in 7
patients (Moysey et al., 1981). This rise was ac-
companied by the appearance of extracardiac dig-
oxin side effects (neurological and gastrointes-
tinal). The 2 drugs are highly taken up by the
myocardium and, since the onset ofthe interaction
was very fast (within I day), displacement of dig-
oxin from cardiac muscle by amiodarone was sug-
gested as the mechanism (Moysey et al., 1981).
In another study, a positive correlation between
amiodarone and digoxin steady-state concentra-
tions was reported in 33 patients (Furlanello et al.,
1981). However, no signs of digitalis toxicity were
observed. Achilli et al. (1981) could not show any
change in digoxin steady-state concentrations or ef-
fects in 5 patients who were given amiodarone con-
comitantly for 30 days.
Pharmacokinetics of Amiodarone 148

Day Amiodarone
dosage 58 patients

.
o

2 deaths (ventric-
ular fibrillation,
day 11 and 28)
."

48 patients
•
8 drop-outs

~,.

35 responders
.
13 non-responders

A = 0.80 ± 0.38 A = 0.91 ± 0.34

DEA = 1.23 ± 0.52 DEA = 1.20 ± 0.99
28

."
,-
" i 1 " I
1 death (ventric- 24 responders 10 non-responders
ular fibrillation,
day 56) A = 0.67 ± 0.31 A = 0.68 ± 0.47
DEA = 1.26 ± 0.05 DEA = 1.26 ± 0.66
56

10 responders

A = 0.97 ± 0.62
DEA =1.52 ± 1.58
84

Fig.6. Efficacy profile of amiodarone in a multicentre controlled study (Italian Collaborative Group on Amiodarone, 1984). Steady-
state blood concentrations (,ug/ml) of amiodarone (A) and desethylamiodarone (DEA) in responders and non-responders are shown.
Pharmacokinetics of Amiodarone
4.3 Other Drugs
Recently, amiodarone has also been reported to
increase the steady-state concentrations of quini-
dine (Tartini et aI., 1982), procainamide and N-
acetylprocainamide in 23 patients (Saal et aI., 1982).
Interactions with other antiarrhythmic agents
have been reported to cause 'torsade de pointes'
(Marcus, 1983).
5. Relationship Between the Pharmaco-
kinetics and Pharmacodynamics of
Amiodarone
The scarcity of reliable data, already noted for
the pharmacokinetics of amiodarone, is even more
relevant when one tries to understand the phar-
macodynamic characteristics of amiodarone in re-
lation to its kinetics.
5.1 Time Course of Antiarrhythmic Action
Since the early use of this drug, its peculiar time
course of action during long term oral administra-
tion has been noted. Rosenbaum et al. (1974, 1976)
evaluated the time of onset of action of amioda-
rone in 263 patients who were being treated for
various arrhythmias. Despite the administration of
loading doses (600 to 800 mg/day), the onset of
effect ranged between 4 and 8 days. Once a thera-
peutic effect was achieved, it was shown to last for
more than I month after discontinuation of amio-
darone administration. A longer duration was as-
sociated with longer treatment. Another group
(Ward et aI., 1980) reported a time course of onset
of action ranging between 2 and 21 days in patients
with various types of arrhythmias.
Kaski et al. (1981) studied 20 patients with sus-
tained, recurrent, symptomatic ventricular tachy-
cardia and observed a mean time of onset of 9.5
days, with a maximum of 16 days. The protection
from relapse after therapy was discontinued lasted
up to 90 days. Rakita and Sobol (1983) were able
to progressively decrease the time to achieve con-
trol of ventricular arrhythmias with amiodarone,
from a mean of 17 days to 10 days, by increasing
149
the loading dose regimen up to 1400mg of drug for
4 weeks. The high variability obtained is probably
due to differences between patients, dose regimens,
and methods of evaluation of therapeutic effect.
Nademanee et al. (l982c) studied arrhythmia
suppression, change in QTc and change in rT3 in
18 patients. Continuous measurements of the latter
2 variables, which relate to the drug's therapeutic
action, facilitated a better definition of the time
course of amiodarone action. The time of onset
ranged from 14 to 21 days, the maximum effect
being reached after 2 to 5 months of therapy. When
amiodarone was stopped, in 9 patients, arrhyth-
mias returned after 2 to 20 weeks, at which time
both QTc and rT3 also returned to baseline.
The efficacy profile of amiodarone in the Italian
Collaborative Study mentioned above (section
3.4.2; fig. 6) is suggestive of a dose-effect relation-
ship in responders; however, the study failed to
document a blood concentration-effect relation-
ship for both amiodarone and/or DEA (Italian
Collaborative Group on Amiodarone, 1984).
Coumel and Fidelle (1980) reported data from
135 children (fig. 7) treated with amiodarone for
various arrhythmias. A slightly different course of
action was observed in children. The time of onset
tended to be shorter (mean 4.1 days) than in adults.
After withdrawal of amiodarone, relapses of chronic
arrhythmias also occurred earlier than in adults.
These differences between children and adults
might be due to a faster clearance of the drug by
the children.
A few authors have reported on the onset and
duration of action of amiodarone after a single
intravenous bolus (Cabasson et aI., 1976; Coutte et
aI., 1976; Holt et aI., 1982; Touboul et aI., 1976).
The effects measured were either a modification of
electro physiological parameters or suppression of
arrhythmia. A very rapid (1 to 30 minutes) onset
was observed and the duration of effect was short
(1 to 3 hours). This rapid onset of action after an
intravenous bolus has prompted some authors to
use intravenous loadings before starting long term
oral treatment. Preliminary experiences show a
more prompt antiarrhythmic action (Holt et aI.,
1982; Mostow et ai., 1983). On the other hand,
Pharmacokinetics of Amiodarone 150

other studies have shown that the electrophysio-
logical effects of intravenous amiodarone also differ
qualitatively from long term oral administration.
Surface ECG after intravenous bolus administra-
tion shows prolongation of the P-R interval, but
no change of QTc, which is always increased dur-
ing long term oral treatment (Nademanee et ai.,
1981; Pritchard et aI., 1975; Singh et aI., 1976).
Effective refractory periods of the atrium and
ventricular and H-V interval were not found
to change after intravenous administration, but
were significantly prolonged after long term
oral administration (Coutte et aI., 1976; Wellens
et aI., 1982).
Pharmacokinetic differences could explain some
of the above discrepancies. The delay in onset after
oral administration might be due to a slow uptake
of the drug into the myocardium or any effector
site. The slow accumulation of DEA, or of another
active metabolite, during long term therapy is an-
other hypothesis to be considered. However, the
relationship between amiodarone pharmacokinet-
ics and its time course of action in man has not
yet been elucidated.
In a recent study in dogs (Latini et aI., 1982), it
was shown that the time course of amiodarone
electrophysiological effects after intravenous bolus
administration follows its myocardial concentra-
tions better than its blood concentrations. The ex-
trapolation of this observation to long term oral
therapy is only speculative.
In 9 patients, QTc prolongation was found to
correlate with plasma slightly better than with
myocardial concentrations of amiodarone (Debbas
et at, 1983). This probably means that tissue con-
centrations of the drug at steady-state do not add
any further information to the understanding of its
pharmacodynamics.

15
a;
II
E-
li)
CD
II)
10
'"
0
'0
...
Q)
.0
E
j
z 5

Time (days)

Fig. 7. Onset of antiarrhythmiC action of amiodarone in 91 children on long term oral treatment (after Coumel and Fidelle, 1980;
reproduced with permission).
Pharmacokinetics of Amiodarone 151

Table IV. Blood steady-state concentrations of amiodarone vs pharmacological-therapeutic effects

Arrhythmia Concentration (/Lg/ml) No. of Reference

patients
non- responders
responders

Atrial fibrillation 1.2-3.0 8.8 7 Andreasen et al. (1981)

Ventricular tachycardia 0.92-11.99 10 Nademanee et al. (1982a)

Ventricular tachycardia 0.44-4.10 10 Saksena et al. (1982)

Ventricular extra systoles and tachycardia < 1.5 > 1.5 22 Mostow et al. (1982)

Ventricular extrasystoles and tachycardia 0.84 1.05 10 Giani et al. (1983)

Atrial tachyarrhythmias 0.4-0.6 9 Haffajee et al. (1980)

Ventricular tachyarrhythmias 0.6-1.2 17 Haffajaa at al. (1980)

Atrial fibrillation 1.02 1.02-2.73 16 Staubli at al. (1983)

Ventricular extrasystoles

Ventricular tachycardia 0.68-0.80 0.67-0.97 58 Italian Collaborative Group on

Amiodarone (1984)

Atrial tachyarrhythmias 1.7 ± 0.7 8 1.5 ± 0.6" 54 Haffajae et al. (1983)

Ventricular tachyarrhythmias 1.9 ± 0.7 8 1.8 ± 0.7" 68 Haffajaa et al. (1983)

a Mean ± SO

5.2 Therapeutic Drug Monitoring
Considerations
The relationship between amiodarone steady-
state blood concentrations and its therapeutic
action has been investigated in several studies.
The currently available data are summarised in
table IV.
A plasma concentration range between 0.5 and
2.5 ~g/ml seems to be the most generally observed
in treated patients who respond to the drug. How-
ever, efficacy has been shown for amiodarone
plasma concentrations as low as 0.1 and as high as
11.9 ~g/ml.
Besides the variability in the drug assay meth-
ods, the broad spectrum of arrhythmias treated
(both type and severity) is a major confounding
factor. Lower dose regimens (200 to 400 mgjday)
tend to be used with success for supraventricular
arrhythmias, while higher dosages (400 to 1000 mgj
day) are employed for life-threatening arrhythmias.
No systematic study has been carried out to de-
termine whether these differences in dosage are
based on real differences in the dose-response re-
lationships for different arrhythmias. Haffajee et
al. (1983) reported a range of effective concentra-
tions of amiodarone in supraventricular tachycar-
dias of 0.5 to 2.8 ~gjml, as compared with 0.4 to
3.3 ~gjml in ventricular arrhythmias. No differ-
ence in amiodarone plasma concentrations was seen
between responders and non-responders (Haffajee
et a\., 1983; Italian Collaborative Group on Amio-
darone, 1984; Staubli et aI., 1983), even if the re-
sponse could be shown to vary with plasma con-
centrations in individual patients.
In trying to establish the significance of amio-
darone blood level monitoring in clinical practice,
one must take into account 2 other factors. Firstly,
the uptake ofamiodarone into myocardium is very
high (partition ratio with plasma between 22 and
134) and quite variable (Latini et ai., 1983), and
this might have some pharmacodynamic rele-
Pharmacokinetics of Amiodarone
vance. Secondly, the role of DEA, which is present
in blood at concentrations as high as amiodarone
during long term treatment, is currently not known.
5.3 Adverse Effects
For many years the therapeutic index of amio-
darone was considered very broad (Marcus et aI.,
1981; Nademanee et aI., 1981; Simpson, 1979); se-
rious side effects and cardiac toxicity were rarely
reported to occur in patients treated long term.
However, in the last 2 years there has been growing
concern about the drug's long term toxicity due to
the frequency of appearance of serious side effects.
These initially may not manifest until after more
than 1 year of therapy (Harris et aI., 1983; Heger
et ai., 1981; Marchlinski et aI., 1982; Sobol and
Rakita, 1982; Waxman et ai., 1982).
Harris et ai. (1983) classified the reported side
effects of amiodarone based on their hypothetical
relationship with dose and duration of therapy.
Elevations of serum aminotransferases are dose re-
lated. Almost all patients receiving 600 mg/day or
more show increased liver circulating enzymes. The
same authors were able to find a correlation be-
tween amiodarone blood concentrations at steady-
state and aminotransferase concentrations.
Corneal microdeposits and facial pigmentation
are classified as both dose- and duration-related.
Effects on the thyroid gland, which could be con-
sidered the most clinically relevant because of their
high incidence (with an estimated average of around
13%) and their implications for therapeutic behav-
iour (Beck-Peccoz et ai., 1983), are complex and
not easily related to either dose or duration of
therapy. The reported effects on the peripheral
nerves are even less satisfactorily documented and
explained, but do not seem to be dependent on dose
and duration of treatment.
The relationship between amiodarone and the
observed pulmonary toxicity is not clear, even
though it has been shown to occur in several
patients on high doses of the drug (Heger et ai.,
1981; Marchlinski et aI., 1982; Sobol and Rakita,
1982). The protective effect of corticosteroid
administration needs to be confirmed, and at pres-
152
ent cannot satisfactorily be related to a mechanism
of toxicity (Zaher et aI., 1983). The report of a su-
icide attempt with 8g ofamiodarone which was fol-
lowed by an uneventful clinical course seems to
exclude acute toxicity for the most likely target or-
gans -liver, heart and thyroid (Bonati et aI., 1983b).
Due to the suspected relationship of the most
serious side effects with amiodarone dose, Wax-
man et aI. (1982) suggested a maximum safe main-
tenance dosage of 600 mg/day. The unusually high
incidence of side effects associated with high doses
(Heger et aI., 1981), and the relatively low toxicity
with low dose regimens (Italian Collaborative
Group on Amiodarone, 1984), could be seen as
support for this recommendation.
Attempts to use plasma concentrations to pre-
dict side effects has not yielded anything more than
general recommendations. In most cases, an upper
limit of 2.0 to 2.5 ILg/ml for safe treatment with
amiodarone is suggested (Boppana et aI., 1983;
Haffajee et aI., 1983; Mostow et aI., 1982). Re-
cently, it has been suggested that the red blood cell
uptake of amiodarone and DEA correlates better
with some adverse effects than do plasma concen-
trations (Heger et aI., 1982). However, this finding
has not been supported by a more recent paper from
the same group (Heger ct aI., 1983).
6. Perspectives and Future Research
From the studies reviewed above, we conclude
that much has still to be done before the clinical
pharmacokinetics of amiodarone can be satisfac-
torily defined. Several areas need further attention.
These include:
1. Oral bioavailability, which is highly variable,
has not been studied in a sufficient number of
patients. Whether single- and multiple-dose bio-
availability are the same needs to be determined,
taking into account the possibility of a time-de-
pendent kinetics.
2. The implications of the high degree of pro-
tein binding of amiodarone should be evaluated in
interaction studies specifically in those few patients
who require combined antiarrhythmic therapy.
3. The current understanding of the metabol-
Pharmacokinetics of Amiodarone
ism and excretion of amiodarone is incomplete.
Only the monodesethyl derivative (DEA) has been
positively identified in the blood of patients.
Recently, a new metabolite, the di-N-desethyl de-
rivative has been identified in the myocardium of
dogs treated with mUltiple doses of amiodarone
(Latini et al., 1984). Whether other metabolites are
also present and which of them have some
pharmacological activity awaits further research.
4. Since amiodarone is often used in very sick
patients, the effects of main organ failure (heart and
liver) on its disposition kinetics need to be eval-
uated.
5. The overall consideration of available data
does not support a positive correlation between
blood or plasma concentrations of amiodarone (or
its metabolite, DEA) and antiarrhythmic efficacy.
6. The relationship between dose and duration
of therapy and therapeutic effects should be further
evaluated in larger studies, allowing for proper
stratification of patients with comparable types and
severity of arrhythmias, with the specific aim of
identifying the minimum effective loading and
maintenance doses and thus providing the best
benefit/risk profile.
A more stable relationship seems to be estab-
lished between dose and duration of treatment and
side effects, with the notable exception of those seen
on the thyroid gland, which appear to be dose- and
duration-independent.
In conclusion, amiodarone has been shown by
many independent groups to be a very powerful
antiarrhythmic agent, with unique features. Its
pharmacokinetics and pharmacodynamic behav-
iour have not been adequately studied, despite the
fact that it has been used clinically for more than
10 years in many countries. Amiodarone remains
an open challenge for the combined efforts of
clinical pharmacologists, clinicians, and endocri-
nologists seeking reliable predictive indicators of
boHr efficacy and safety.
Acknowledgements
This work was partially supported by the Italian CNR
Grant on Clinical Pharmacology and Rare Diseases. Dr
Latini is the recipient of a Merck Sharp and Dohme
International Fellowship in Clinical Pharmacology.
153
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Authors' address: Dr Roberto Latini, Laboratory of Clinical
Pharmacology, Istituto di Ricerche Farmacologiche 'M. Negri',
Via Eritrea 62, 20 I 57,Milano (Italy).

5th International Meeting of the

International SOciety for Developmental Neuroscience

Physiological and Pharmacological Control of

Nervous System Development
Date: 24-28 June 1984
Venue: Chieti, Italy

Includes: symposia, round tables, lecture, workshop and poster sessions,

For further information, please contact the organising secretariat:

Fondazione Giovanni Lorenzini,
Via Montenapoleone 23,
20121 Milan,
ITALY.