Eur J Clin Pharmacol (1988) 35:681-684
© Springer-Verlag 1988
The Relative Systemic Availability of Ivermectin
After Administration as Capsule, Tablet, and Oral Solution
G. Edwards 1, 2, A. Dingsdale 1, N. Helsby 1, M. L'E. Orme 1, and A. M. Breckenridget
1 Department of Pharmacology and Therapeutics, The University of Liverpool, Liverpool
2 Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, UK
Summary. Administration of 12-mg doses of iver-
mectin (H2Bla) to 12 healthy volunteers in the form
of tablets, capsules, and alcoholic oral solution
showed the solution to have approximately twice
the systemic availability as either of the solid forms,
as evidenced both by the maximum concentrations
of drug attained in plasma and by the correspond-
ing areas under the plasma concentration vs time
curves. However, the two solid formulations
showed similar systemic availability.
Key words: ivermectin; bioavailability, pharmaco-
kinetics
Invermectin is a chemical modification of one of
the avermectins, a series of naturally-occurring mac-
rocyclic lactones produced by the actinomycete
Streptomyces avermitilis. Ivermectin, composed of
dihydroavermectins Bla ( > 80%) and Bib (~<20%),
is a broad-spectrum agent active against animal
endo- and ectoparasites, but most notably appears
to have great potential in the treatment of human
onchocerciasis, for which single oral doses of
100-200 gg-kg 1 are effective against microfilariae
of Onchocerca volvulus(White et al. 1987). The vari-
ous clinical trials of ivermectin have not provided
pharmacokinetic information, particularly the rate
and extent of its absorption. The aim of the present
study was to estimate the relative systemic avail-
ability of a single oral dose of ivermectin when
given as capsules or tablets, compared with the ad-
ministration of an identical dose as an oral solution.
EuropeanJournal of ~B~@D@@~
Methods
Study Design
This was an open, balanced, three-period cross-over
study in 12 healthy non-smoking men, ages
18-50 years, weight 60-80 kg, who received each of
three treatments: A. Ivermectin (12mg) as an oral
solution (20ml) in aqueous ethanol (40% v/v);
B. Ivermectin (12 rag) as two 6 mg tablets; C. Iver-
mectin (12 rag) as two 6 mg capsules. Each subject
was randomly assigned to a treatment sequence
such that two subjects received the drug according
to each of the six possible treatment sequences.
Treatments were given after an overnight fast, and
there was a washout period of at least thirteen days
between each treatment. The study protocol was ap-
proved by the Ethics Committee of the Mersey Re-
gional Health Authority.
Subjects
Each subject gave his written informed consent. A
physical examination was made and an ECG per-
formed before and after the study. The subjects were
monitored throughout the study for possible adverse
effects. Safety was also assessed by the measurement
of standard haematological and biochemical indices
before and after each treatment and the values were
compared with the reference range.
Blood Sampling
Blood samples (20 ml) were taken from a forearm
vein via a heparinized cannula immediately before
682
and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36, 48, and 72 h
after each drug administration. Samples were col-
lected into heparinized tubes which were cen-
trifuged immediately (1000 x g for 15 min) and the
plasma removed and kept at - 2 0 ° C until assayed.
Analysis of Ivermectin in Plasma
In this assay only the H2Bla component was quan-
tified. Concentrations of H2Bla in plasma were
determined by reverse-phase HPLC with fluores-
cence detection by a modification of the method of
Chiou et al. (1987). The plasma (0.5 ml) was put
into a 15 ml capacity glass tube fitted with a Teflon-
lined screw cap, and to it was added the internal
standard, a monosaccharide derivative of ivermec-
tin (30 ng; 30 pA) as a solution in methanol (Merck,
Sharp, and Dohme, Rahway, NY, USA. After a fur-
ther addition of methanol (maximum 1.0 ml), vortex
mixing (30s), and centrifugation (3000rpm for
10 rain) the upper layer was decanted into a second
tube. To this was added water (1.0 ml) and ethyl
acetate (5.0 ml) followed by vortex mixing (30 s)
and centrifugation (2000 rpm for 10 min). The or-
ganic layer was removed, the extraction procedure
repeated, and the combined organic phases evap-
orated to dryness under a stream of nitrogen at
45°C. The residue was resuspended in ethyl acetate
(0.1 ml) and the derivatizing reagent (dimethyl-
formamide 0.9 ml, 1-methyl imidazole 0.2 ml, acetic
anhydride 0.3 ml) (0.05 ml) was added. After mix-
ing, the contents of the screw-capped tubes were
allowed to react for I h at 95 ° C. After cooling, the
mixture was evaporated to dryness under vacuum at
60-65°C. The residue was resuspended in chloro-
form (0.25 ml) and applied to a diol cartridge
('Bond Elut'; Technicol, Stockport, UK) previously
conditioned with chloroform (2.0 ml). The cartridge
was washed with chloroform (3 x 0.25 ml) and the
combined eluate was evaporated to dryness under a
stream of nitrogen at 45 ° C. The residue was resus-
pended in methanol (0.1ml) and an aliquot
(0.02 ml) was injected into the chromatograph.
Chromatography
A Spectra-Physics SP8770 isocratic HPLC system
was used. The fluorescence detector was a Varian
Fluorochrom using an excitation wavelength of
364 nm and an emission wavelength of 470 nm. Iso-
cratic separation was achieved on a Partisil ODS 3
(10 ~tm particle size) reversed-phase column
(20 cm x 0.6 cm OD, HPLC Technology, Wilmslow,
G. Edwards et al.: Availability of Ivermectin
UK) using a mobile phase of acetonitrile :meth-
a n o l : w a t e r (100:15:1) flowing at 2.4ml.min -1.
The method was sensitive and selective without in-
terference from endogenous or exogenous substan-
ces and the minimum detectable concentration was
0.2 ng. m1-1. Inter- and intra-assay co-efficients of
variation were in agreement with those reported by
Chiou et al. (1987) and were~<10%.
Data Analysis
Peak plasma concentrations (Cmax) and the times at
which they were achieved (tma×) were obtained by
visual inspection of the plasma concentration vs
time profiles. The area under each of the plasma
concentration vs time curves, AUC, was obtained
by linear trapezoidal summation with extrapolation
of the log-linear portion (~24-72 h) to infinite time.
Since carry-over effects were shown to be absent,
the estimates of these variables were subjected to
analysis of variance for a three-period crossover de-
sign. The ratios of AUC (tablets) and AUC (cap-
sules) to AUC (solution) were calculated after con-
version of the individual AUC values to natural
logarithms, subtraction of the logarithms, and ex-
ponentiation. All tests of significance were two-
tailed, rejecting the null hypothesis if p>0.05.
Results
Safety
No clinical adverse effects were reported. Low
white cell counts (3.2-3.7 x 109.1-1) were reported
relative to the reference range (4-11 x t09.1-1) in
one subject (No.ll, Table 1) after two of the three
ivermectin treatments. No clinically important
changes between pre- and poststudy physical exam-
inations or ECG's were observed.
Pharmacokinetics
Mean plasma concentrations of ivermectin after
the administration of the different treatments are
shown together with two representative data sets in
Fig.1 and individual tmax, Cmax, and AUC values
are shown in Table 1. Both mean AUC and mean
Cma x w e r e significantly larger after the administra-
tion of ivermectin in an alcoholic solution than
after the administration of either capsules or ta-
blets (pairwise p values~<0.01). No significant dif-
ferences in mean AUC or mean Cmax was found
G. Edwards et al.: Availability of Ivermectin 683

Table 1. Estimates of pharmacokinetic variables for single dose administration of ivermectin (H2Bla) 12 nag formulated as (A) solution
in 40% v/v ethanol (0.6 rag- m l - 1), (B) 6 mg capsules (C) 6 mg tablets
trnax Craax AUC
(h) (ng.ml - I ) (ng-h-rnl i)
Subject A B C A B C A B C
1 4 4 3 92 62 63 2101 1394 989
2 3 3 4 89 52 21 1237 1268 417
3 1 4 3 106 54 55 1124 967 917
4 4 3 4 93 61 40 1154 750 448
5 4 4 4 86 59 40 1353 1357 671
6 4 3 4 108 45 52 2106 714 1232
7 2 3 4 80 64 97 1897 1248 1887
8 4 3 4 91 63 46 1411 868 718
9 4 4 4 46 23 22 1102 801 963
10 4 4 2 60 69 36 1339 1421 736
11 4 2 3 68 28 46 1500 590 864
12 6 4 4 48 23 38 1356 a 775
Mean 3.6 3.4 3.6 81 50 46 1473 1034 885
(SD) (1.2) (0.7) (0.7) (21) (17) (20) (362) (308) (389)
a not available

100-1

50

20

10

! I
6 10 2'0 Jo do sb 6'0 7b I, o 1o, 20, 30, so
., 6'0.........7b
Time (h)
Fig. 1. Plasma concentrations of ivermectin (H2Bla) in two representative subjects (2 and 5) covering the range of observed apparent
terminal half-lives after the administration of a single dose of ivermection (12 mg) formulated as a solution in 40% (v/v) ethanol
(0.6 rag- m l - 1) (O), 2 x 6 mg capsules (O), or 2 x 6 mg tablets (11). Inset: mean plasma concentrations of ivermectin (H2Bla) in twelve
volunteers each receiving ivermectin as a solution (O), capsule (O), or tablet (R)

after the administration of capsules and tablets of
ivermectin (pairwise p-values~>0.05). These results
are supported by an analysis based on confidence
intervals. The geometric means (95% confidence
limits) of the ratios of the AUC after the ivermec-
tin solution to the AUCs after tablets and capsules
of ivermectin were 1.75 (1.34-2.29) and 1.47
(1.08-2.01) respectively. The mean (95% con-
fidence limits) of the ratio of the AUC after cap-
sules of ivermectin to the AUC after tablets of
ivermectin was 1.22 (0.77-1.91).. No significant dif-
ferences were found among the mean tmax values
after the ivermectin solution, capsules, or tablets
(overall p-value>~0.05).
684
Discussion
Ivermectin is likely to b e c o m e the drug o f choice
against the microfilariae of Onchocerca votvulus.
Controlled clinical trials have shown its superiority
to diethylcarbamazine (Awadzi et al. 1985, G r e e n e
et al. 1986), single dose administration producing a
sustained microfilaricidal response without severe
adverse effects (White et al. 1987). However, the
clinical pharmacology of ivermectin is poorly
understood. There is no pharmacokinetic informa-
tion available from any o f the numerous studies o f
clinical efficacy in patients with onchocerciasis and
the animal data are limited (Wilkinson et al. 1985).
The initial h u m a n clinical studies to determine the
effect o f ivermectin against skin microfilariae o f
Onchocerca volvuIus were carried out using a cap-
sule formulation. We have c o m p a r e d the systemic
availability o f ivermectin in that capsule formula-
tion to that of a tablet and a hydroalcoholic solu-
tion, by comparing estimates o f the pharmacoki-
netics o f each o f the three formulations in a panel
o f 12 subjects. These data suggest that the rate of
absorption o f ivermectin is independent o f the for-
mulation administered and that the systemic avail-
ability o f ivermectin is similar in the capsule and ta-
blet formulations. The hydroalcoholic solution o f
ivermectin was approximately twice as available as
either of these solid formulations, suggesting that
the extent o f absorption o f ivermectin is limited in
part by its solubility. Further studies may therefore
be warranted in onchocerciasis patients in whom
differences in dietary intake m a y influence the sys-
temic availability of a less-soluble formulation.
Acknowledgements
We are grateful to Merck, Sharp, and D o h m e for
financial support. A D was the recipient of a Re-
G. Edwards et al. : Availability of Ivermectin
search Studentship awarded by the Mersey Re-
gional Health Authority. We thank Dr. P.Winstan-
ley for assistance with blood sampling and the ar-
rangement o f medical examinations. We also ac-
knowledge Dr. D.McDowell, Westman Medical
Laboratories Ltd., Bolton, U K for the biochemical
and haematological measurements.
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Received: May"4, 1988
accepted in revised form: July 20, 1988
Dr. G. Edwards
Department of Pharmacology and Therapeutics
The University of Liverpool
New Medicine Building
Ashton Street
P.O. Box 147
Liverpool L69 3BX, UK