Safety, Tolerability, and Pharmacokinetics of Escalating High Doses of Ivermectin in Healthy Adult Subjects

Abstract

Safety and pharmacokinetics (PK) of the antiparasitic drug ivermectin, administered in higher and/or more frequent doses than currently approved for human use, were evaluated in a double-blind, placebo-controlled, dose escalation study. Subjects (n = 68) were assigned to one of four panels (3:1, ivermectin/placebo): 30 or 60 mg (three times a week) or 90 or 120 mg (single dose). The 30 mg panel (range: 34 7-594 microg/kg) also received a single dose with food after a 1-week washout. Safety assessments addressed both known ivermectin CNS effects and general toxicity. The primary safety endpoint was mydriasis, accurately quantitated by pupillometry. Ivermectin was generally well tolerated, with no indication of associated CNS toxicity for doses up to 10 times the highest FDA-approved dose of 200 microg/kg. All dose regimens had a mydriatic effect similar to placebo. Adverse experiences were similar between ivermectin and placebo and did not increase with dose. Following single doses of 30 to 120 mg, AUC and Cmax were generally dose proportional, with t(max) approximately 4 hours and t1/2 approximately 18 hours. The geometric mean AUC of 30 mg ivermectin was 2.6 times higher when administered with food. Geometric mean AUC ratios (day 7/day 1) were 1.24 and 1.40 for the 30 and 60 mg doses, respectively, indicating that the accumulation of ivermectin given every fourth day is minimal. This study demonstrated that ivermectin is generally well tolerated at these higher doses and more frequent regimens.

Full text

http://jcp.sagepub.com/
Pharmacology
The Journal of Clinical
http://jcp.sagepub.com/content/42/10/1122
The online version of this article can be found at:
2002 42: 1122J Clin Pharmacol
CA Guzzo, CI Furtek, AG Porras, C Chen, R Tipping, CM Clineschmidt, DG Sciberras, JY Hsieh and KC Lasseter
Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects
Published by:
http://www.sagepublications.com
On behalf of:
American College of Clinical Pharmacology
can be found at:The Journal of Clinical PharmacologyAdditional services and information for
http://jcp.sagepub.com/cgi/alertsEmail Alerts:
http://jcp.sagepub.com/subscriptionsSubscriptions:
http://www.sagepub.com/journalsReprints.navReprints:
http://www.sagepub.com/journalsPermissions.navPermissions:
at TEXAS A&M UNIV on September 19, 2011jcp.sagepub.comDownloaded from

GUZZOETALHIGHDOSESOF IVERMECTIN IN ADULTSPHARMACOKINETICSANDPHARMACODYNAMICS
Safety, Tolerability, and Pharmacokinetics
of Escalating High Doses of Ivermectin
in Healthy Adult Subjects
Cynthia A. Guzzo, MD, Christine I. Furtek, BS, Arturo G. Porras, PhD,
Cong Chen, PhD, Robert Tipping, MS, Coleen M. Clineschmidt, BA,
David G. Sciberras, PhD, John Y-K. Hsieh, PhD, and Kenneth C. Lasseter, MD
Ivermectin is a derivative of the avermectins, a family
of macrocyclic lactones produced by the filamen-
tous bacterium Streptomyces avermitilis. It is a highly
effective antihelmintic agent used in animals and hu-
mans. Ivermectin was first approved for human use in
1987 and is donated by Merck & Co., Inc., as Mectizan®
for the treatment of onchocerciasis and, more recently,
lymphatic filariasis in Africa and Latin America. More
than 200 million treatments have been distributed
through the program. It is also approved as Stromectol®
for the treatment of strongyloidiasis of the intestinal
tract and onchocerciasis. Recently, approved human in-
dications have been extended in France to include the
treatment of scabies. The approved treatment regimens
are as follows: 150 µg/kg once yearly for onchocerciasis,
200 µg/kg single dose for strongyloidiasis, and 150 to
200 µg/kg twice yearly or 300 to 400 µg/kg once yearly
in endemic areas for lymphatic filariasis. The greatest
experience with human use of ivermectin is in the dose
ranges of 150 to 200 µg/kg.
Early pharmacokinetic studies conducted to sup-
port registration of the drug as a therapeutic agent
against onchocerciasis demonstrated that plasma con-
centrations are approximately proportional to the dose,
following oral administration of 6, 12, or 15 mg of
ivermectin.1In two studies, after single 12 mg doses of
ivermectin (2 ×6 mg) in fasting healthy volunteers (rep-
resenting a mean dose of 165 µg/kg), the mean peak
1122 •J Clin Pharmacol 2002;42:1122-1133
Safety and pharmacokinetics (PK) of the antiparasitic drug
ivermectin, administered in higher and/or more frequent
doses than currently approved for human use, were evalu-
ated in a double-blind, placebo-controlled, dose escalation
study. Subjects (n=68) were assigned to one of four panels
(3:1, ivermectin/placebo): 30 or 60 mg (three times a week) or
90 or 120 mg (single dose). The 30 mg panel (range: 347-594
µg/kg) also received a single dose with food after a 1-week
washout. Safety assessments addressed both known
ivermectin CNS effects and general toxicity. The primary
safety endpoint was mydriasis, accurately quantitated by
pupillometry. Ivermectin was generally well tolerated, with
no indication of associated CNS toxicity for doses up to 10
times the highest FDA-approved dose of 200 µg/kg. All dose
regimens had a mydriatic effect similar to placebo. Adverse
experiences were similar between ivermectin and placebo
and did not increase with dose. Following single doses of 30
to 120 mg, AUC and Cmax were generally dose proportional,
with tmax ~4 hours and t1/2 ~18 hours. The geometric mean
AUC of 30 mg ivermectin was 2.6 times higher when adminis-
tered with food. Geometric mean AUC ratios (day 7/day 1)
were 1.24 and 1.40 for the 30 and 60 mg doses, respectively,
indicating that the accumulation of ivermectin given every
fourth day is minimal. This study demonstrated that
ivermectin is generally well tolerated at these higher doses
and more frequent regimens.
Journal of Clinical Pharmacology, 2002;42:1122-1133
©2002 the American College of Clinical Pharmacology
From Merck Research Laboratories, Blue Bell and West Point, Pennsylva-
nia, and Terlings Park, United Kingdom (Dr. Guzzo, Ms. Furtek, Dr. Porras,
Dr. Chen, Mr. Tipping, Ms. Clineschmidt, Dr. Sciberras, Dr. Hsieh) and
Clinical Pharmacology Associates, Miami, Florida (Dr. Lasseter). This study
was sponsored by a grant from Merck Research Laboratories, a division of
Merck & Co., Inc. Dr. Lasseter has no financial interest in Merck & Co. Dr.
Sciberras was employed by Merck & Co., Inc., at the time of the study. All
other authors are currently employed by Merck & Co., Inc. Submitted for
publication March 5, 2002; revised version accepted June 30, 2002. Ad-
dress for reprints: Ms. Christine Furtek, Merck & Co., Inc., BLX-29, P.O. Box
4, West Point, PA 19486.
DOI: 10.1177/009127002237994
at TEXAS A&M UNIV on September 19, 2011jcp.sagepub.comDownloaded from

plasma concentrations of the major component (H2B1a)
were 46.6 ±21.9 (range: 16.4-101.1) ng/ml and 30.6 ±15.6
(range: 13.9-68.4) ng/ml, respectively, at approximately
4 hours after dosing.2Ivermectin is metabolized in the
liver, and ivermectin and/or its metabolites are ex-
creted almost exclusively in the feces over an estimated
12 days, with < 1% of the administered dose excreted
in the urine. Estimates of plasma half-life have varied
from about 12 to 56 hours.3-7
Oral ivermectin has been considered as a possible
treatment for head lice. In recent years, this condition
has become a significant problem in developed coun-
tries, resulting in school absenteeism, social distress,
and stigmatization. The economic loss to parents can
also be substantial; informal estimates from the Centers
for Disease Control and Prevention show that the cost
of lost work time due to head lice infestations exceeds
$1 billion annually.8Initial exploratory studies evalu-
ated ivermectin doses of 100 to 200 µg/kg.9-11 However,
none of these early studies demonstrated eradication of
head lice, suggesting that higher or more frequent doses
may be necessary for this use.
Since the majority of safety and pharmacokinetic
data on oral ivermectin are with single doses of 150 to
200 µg/kg, the primary objective of this study was to ob-
tain additional information at higher and multiple
doses. Doses up to 10 times the 200 µg/kg dose were
evaluated to provide a substantial safety margin over
the anticipated dosage range for head lice treatment.
Specifically, for assessment of safety, signs observed in
animal toxicity studies, as well as in documented hu-
man overdose cases, were chosen as safety end-
points. In particular, mydriasis was evaluated as the
primary safety endpoint because it could be accurately
measured with a previously validated method,
pupillometry. The pharmacokinetic objectives were to
evaluate the pharmacokinetics of ivermectin with
higher doses, the extent of any ivermectin accumulated
with multiple doses, and the effect of food and gender.
METHODS
Subjects
Both male and female subjects were considered eligible
to participate if they were between 18 and 45 years of
age and in good health on the basis of history, physical
examination, and routine laboratory data. Female sub-
jects of childbearing potential agreed to use an effective
double-barrier birth control method from at least 1
month prior to the start of the study until 1 month after
the completion of the study. Weight requirement for
subjects varied with treatment panel: 50 to 90 kg for
panels 1 and 2 and 60 to 90 kg for panels 3 and 4. All
subjects must have been nonsmokers for ≥6 months.
Subjects were ineligible for enrollment if they had
any ocular abnormality that might interfere with
pupillometry assessment, including corrected visual
acuity worse than 20/30 in both eyes (contact lenses ac-
ceptable), a current eye disorder requiring the attention
of an ophthalmologist, or a history of intraocular sur-
gery. Pregnant or breast-feeding women were ex-
cluded. Subjects with a history of neurologic or CNS
disease; treated or untreated hypertension, asthma, or
other pulmonary disease; major gastrointestinal abnor-
malities/peptic ulceration; cardiovascular, hepatic, or
renal disease; drug allergy; drug or alcohol abuse; or
any illness that, in the opinion of the investigator,
might have confounded the results of the study or
posed additional risk in administering ivermectin to
the subject could not participate. Other exclusion crite-
ria included donation of a unit of blood or participation
in another clinical trial with an investigational agent
within 4 weeks prior to commencement of the study,
regular use of any illicit drugs, intake of excessive
amounts of caffeinated coffee or beverages (> 8
cups/day), or use of prescription or nonprescription
medicine that could not be discontinued 2 weeks be-
fore the start of the study. Subjects with a known hyper-
sensitivity to any component of the ivermectin product
or who had any condition that the investigator felt
might interfere with participation were not eligible.
This study was conducted at Clinical Pharmacology
Associates (Miami, FL) in conformance with applica-
ble country or local requirements regarding ethical
committee review, informed consent, and other stat-
utes or regulations regarding the protection of the rights
and welfare of human subjects participating in biomed
-
ical research. The study protocol and subject consent
form were approved by a private, nonaffiliated institu-
tional review committee (Southern Institutional Re-
view Board, Inc., Miami, FL), which was properly con-
stituted according to the applicable regulations.
Written informed consent was obtained from each
subject.
Study Design
This was a double-blind, placebo-controlled, multiple
rising dose study in healthy adult men and women.
Subjects were sequentially assigned to one of four treat-
ment panels and were randomized to receive iver-
mectin or placebo within each panel (12 active, 4 pla-
cebo per panel) using a computer-generated allocation
schedule. Subjects were also stratified by gender
within each panel to ensure that equal numbers of sub-
PHARMACOKINETICS AND PHARMACODYNAMICS 1123
HIGH DOSES OF IVERMECTIN IN ADULTS
at TEXAS A&M UNIV on September 19, 2011jcp.sagepub.comDownloaded from

jects of each gender were assigned to each treatment
regimen.
Ivermectin was administered as a fixed dose extend
-
ing from 30 mg in panel 1 to 120 mg in panel 4. Doses
consisted of ten to forty 3 mg tablets of ivermectin as
necessary to achieve the stipulated dose. When consid
-
ering the weight limitations of the protocol, this corre-
sponded to the potential delivery of 333 µg/kg to 2000
µg/kg. Actual dose range delivered (µg/kg) in enrolled
subjects in each dose group is indicated in the follow-
ing descriptions of the dosing regimens. Panel 1 sub-
jects received treatment A: ivermectin 30 mg (347-594
µg/kg) or placebo, three times a week (days 1, 4, 7), in
the fasted state during study week 1. After a washout
period of at least 1 week, they then received treatment
E: ivermectin 30 mg (347-541 µg/kg) or placebo, single
dose, in the fed state during study week 3. Panel 2 re-
ceived treatment B: ivermectin 60 mg (713-1091 µg/kg)
or placebo, three times a week (days 1, 4, 7), in the
fasted state during study week 5. Panel 3 received treat-
ment C: ivermectin 90 mg (1031-1466 µg/kg) or pla-
cebo, single dose, in the fasted state during study week
9. Panel 4 received treatment D: ivermectin 120 mg
(1404-2000 µg/kg) or placebo, single dose, in the fasted
state during study week 11.
The treatment regimens were selected based on the
possibility that doses higher than 200 µg/kg would be
needed to eradicate head lice. The 30 and 60 mg doses
were administered to evaluate safety in potential thera-
peutic dose ranges for head lice treatment, spanning
347 to 1091 µg/kg for the participants in this study. The
regimen for these dose levels was the maximum fre-
quency anticipated for head lice treatment (three doses
in 7 days) and allowed for assessment of possible accu-
mulation. The 90 and 120 mg doses were evaluated
only to assess toxicity and provide an additional mar-
gin of safety; therefore, these treatments were adminis-
tered as single doses.
Confirmation of quantifiable pupillometry was not
initially an entrance criterion for the study. However,
after completion of the original 16 subjects in panel 1, it
was observed that pupillometry measurements for 5
subjects were difficult to quantify due to the unex-
pected extreme pigmentation of the iris in this particu-
lar study population. For one of these subjects, accurate
pupil measurements could not be obtained. Therefore,
the protocol was amended to add an entry criterion
specifying that subjects must have a quantifiable pupil
measurement at the prestudy visit (1-2 weeks prior to
study start). Pupillometry was added to the prestudy
visit procedures to accommodate this requirement. In
addition, since testing of the primary hypothesis for
this study was dependent on the pupillometry mea-
surements from this subject panel, the protocol
amendment also enrolled 4 additional subjects to panel
1 to compensate for the missing data. These 4 subjects
received treatment A only (30 mg or placebo, days 1, 4,
7, fasted) and were dosed concurrently with panel 2.
They were not administered treatment E (30 mg or pla-
cebo, single dose, fed) because the primary hypothesis
related to treatment A only. A group of 4 subjects was
considered appropriate because a blocking factor of 4
was used for the allocation schedule (3 active: 1 pla-
cebo). In addition, at the time of the amendment, it was
unknown if more than 1 subject would have missing
data.
All treatment doses were administered in the Clini-
cal Research Unit (CRU) under medical supervision.
Before each treatment period, subjects reported to the
CRU at a predetermined time the evening prior to dos-
ing on day 1. Subjects were required to fast from all
food and liquid, except water, from midnight before all
treatment days. Study drug was provided as ivermectin
3 mg tablets and matching placebo tablets and was ad-
ministered with a total of 16 ounces of water to accom-
modate the large numbers of tablets administered at the
higher doses. For consistency, the same amount of wa-
ter was administered for all dose levels. For treatment
E, subjects consumed a standard high-fat breakfast
(31.3 g protein, 57.16 g carbohydrates, 48.6 g fat, 784
kcal) beginning 20 minutes before dosing. The dose
was administered within 5 minutes after completion of
the meal. For all other treatments, fasting (except for
water) continued on all treatment days until the 4-hour
plasma sample was collected, after which subjects con-
sumed a meal of approximately 500 calories. Subjects
resumed regular meals after the 8-hour plasma sample
had been collected. Standardized meals were provided
in the CRU at scheduled times.
Safety monitoring included careful clinical observa-
tion for adverse experiences as well as physical exami-
nations (1-2 weeks prestudy [PS] and 5-7 days
posttreatment [PT]), neurological examinations (PS;
–1, 4, and 12 h; and PT), pupillometry (PS; –1, 4, 6, and
24 h; and PT), vital signs (PS; –1, 0, 1, 2, 4, 8, and 24 h;
and PT), electrocardiograms (PS, –1 and 4 h, and PT),
and clinical laboratory tests consisting of a CBC, blood
chemistry, and urinalysis (PS, –1 h, and PT). In the neu-
rological exam, tests to detect signs of ivermectin toxic-
ity were emphasized and accurately quantitated when
possible (e.g., heel-toe to evaluate ataxia). Details of
pupillometry are described in the next section. All ad-
verse events were recorded. The investigator paid par-
1124 •J Clin Pharmacol 2002;42:1122-1133
GUZZO ET AL
at TEXAS A&M UNIV on September 19, 2011jcp.sagepub.comDownloaded from

ticular attention to any evidence of CNS toxicity, such
as vomiting, mydriasis, or gait disturbance.
Treatment panels were dosed sequentially so that
safety was established at a lower dose level (given in
the fasted state) before proceeding to the next higher
dose level. Safety parameters were chosen based on ex-
perience with human overdose and animal toxicity.
For an individual subject, the investigator was in-
structed to discontinue a subject’s test drug if any of the
following signs or symptoms were observed postdose:
one or more episodes of drug-related vomiting (exclud-
ing episodes occurring within1hofdosing), mydriasis
(defined as absence of change in pupil size upon transi-
tion from low-light to high-light conditions during
pupillometry), or gait disturbance (defined as a con-
firmed abnormal result from heel-toe test as compared
with baseline prestudy assessment). For a dosage
panel, the investigator was instructed to discontinue
advancement to the next dose level if any of the follow-
ing situations occurred: mydriasis or gait disturbance
(as defined above for an individual subject) was ob-
served in 1 or more subjects, a ≥2 mm increase in pupil
diameter over baseline (predose) was observed in 2 or
more subjects, or drug-related vomiting (excluding epi-
sodes occurring within 1 h of dosing) was observed in 3
or more subjects in a panel. In addition, the incidence
of one or more drug-related serious adverse experi-
ences or two or more drug-related severe adverse expe-
riences in a panel would have warranted consideration
of discontinuing dose-level advancement.
For pharmacokinetic analysis, plasma samples were
collected at predefined intervals on days 1, 4, and 7 for
treatments A and B and on day 1 only for treatments C,
D, and E and analyzed for ivermectin concentration.
The predefined intervals were predose (0 h) and at 0.5,
1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, and 60 hours
postdose on days 1 and 7 and predose only on day 4.
For treatments A and B, subjects remained in the
CRU until the final day 7 blood sample was obtained
(60 h after the day 7 dose). For treatments C, D, and E,
subjects remained in the CRU until the final day 1
blood sample was obtained (60 h after the day 1 dose).
Subjects returned for a posttreatment assessment 5 to 7
days following the last dose of study drug in a treat-
ment period.
Pupillometry
To monitor for any evidence of mydriasis, this study
used a method of pupillometry that had been validated
internally and successfully used in a previous study of
a mydriatic agent. The method accurately and
reproducibly measures pupil diameter by photograph
under standard lighting conditions. Photographic
equipment consisted of a single-lens reflex camera
(Nikon F70 camera body and Nikon 105 micro lens)
with flash unit (Nikon SB23 with remote link),
mounted on a support device in front of and facing the
subject with the camera lens projecting through a re-
flective lighting screen. The subject’s head was posi-
tioned on a head rest (similar to those found in a slit
lamp unit). To reduce the influence of accommodation
movement on the pupil, subjects focused through a
hole in the reflective screen on an object 3 m beyond
the camera.
All pupil measurements were made in a room
equipped with black-out shades. Standard lighting
conditions were created using two banks of four low-
voltage tungsten lamps, projected from behind the sub-
ject onto a white screen located approximately 0.5 m in
front of the subject. Dimmer switches attached to each
bank of lights enabled the lamp units to be adjusted to
either low-light (10-foot candles) or high-light (200-foot
candles) conditions. A calibrated light meter (Gossen)
placed at the temple of the subject’s head, adjacent to
the eye, was used to confirm that the proper light levels
reached the subject’s corneal plane. The left eye was
photographed under both standard lighting condi-
tions, in duplicate, at each time point prescribed by the
protocol. In cases where a subject’s corrected visual
acuity was worse than 20/30 in the left eye, the right
eye was photographed. Measurements of the maximal
horizontal diameter of the pupillary area were obtained
via image analysis of the developed transparencies
(MCID M1 image analysis system, Imaging Research
Inc., Ontario) and recorded in millimeters for statistical
analysis. Photographs taken of a measuring scale
(graph paper), placed at the same eye-to-camera dis-
tance used for pupil measurement, were used for
calibration.
Prior to enrolling subjects into this study, pupil mea-
surement standards and reproducibility were estab-
lished at the study site. The method was tested under
the same lighting conditions and in the same examina-
tion room subsequently used in performing the pupil
measurements for the clinical study. Prestudy testing of
the photographic measurement methodology was con-
ducted by the same study personnel who performed
pupil measurements during the study.
In addition, visual accommodation was measured
predose for all subjects to obtain a baseline value (be-
fore the first dose of study drug only). Subsequently, if
mydriasis was observed in a subject at any time during
the study, accommodation was to be measured (as soon
as possible after observation of mydriasis) to determine
if there was accompanying cycloplegia.
PHARMACOKINETICS AND PHARMACODYNAMICS 1125
HIGH DOSES OF IVERMECTIN IN ADULTS
at TEXAS A&M UNIV on September 19, 2011jcp.sagepub.comDownloaded from

Ivermectin Assay
Plasma was separated by centrifugation from blood
samples collected from the original 48 subjects on ac-
tive treatment, at the time points specified above, and
analyzed for ivermectin H2B1a. The additional 4 sub-
jects added per protocol amendment were for safety as-
sessment only, and samples from these subjects were to
be assayed only in the event of a drug-related or serious
adverse experience. Assay of plasma samples for
ivermectin H2B1a concentration was performed by the
Drug Metabolism Department, Merck Research Labora-
tories (West Point, PA), using a high-performance liq-
uid chromatography (HPLC) method with fluorescence
detection. The protein was removed from plasma sam-
ples by precipitation with acetonitrile. Ivermectin and
the internal standard were then recovered from the ma-
trix by liquid/solid-phase extraction on ChemElut car-
tridges. Reconstituted extracts were online derivatized
and separated by reverse-phase HPLC and quantitated
by fluorescence detection.
A standard curve of 0.5, 1, 2.5, 5, 10, 20, and 40
ng/ml ivermectin spiked into human control plasma
was analyzed daily along with clinical samples. Accu-
racy ranged from 98.6% to 102% of nominal concentra-
tions; precision ranged from 2.2% to 5.9% through the
entire curve. Plasma quality control samples at low
(1.25 ng/ml), medium (7.5 ng/ml), and high (25 ng/ml)
concentrations were prepared prior to the start of the
study and subjected to replicate within-day analyses
(n= 5). Two high, two medium, and two low quality
control samples were analyzed daily along with clini-
cal samples to assess interday variability. Accuracy av-
eraged 99.9%, 104.7%, and 102.6% for the low, me-
dium, and high quality control samples, respectively.
The corresponding values for precision were 7.9%,
6.1%, and 4.7%, respectively. The limit of reliable
quantification for ivermectin H2B1a was 0.5 ng/ml.
Pharmacokinetic
Calculations
The following pharmacokinetic parameters were eval-
uated: area under the plasma concentration-time curve
from time 0 to infinity (AUC0-∞), maximum plasma con-
centration (Cmax), time of occurrence for maximum
(peak) plasma concentration (tmax), and half-life (t½).
AUC0-∞was estimated by the trapezoidal method to the
60-hour point and extrapolated to infinity by the half-
life estimated for that curve. Cmax and tmax values were
estimated by inspection of the plasma concentration-
time curve. Half-life was estimated by the method of
Kwan et al.12 Accumulation ratios were approximated
from ratios of AUC0-60 h since these were the closest val-
ues available to the ratio of AUCτ(τ= 72 h) for this
study. Computed values of AUC and half-life were
calculated in EXCEL (Microsoft Corporation,
Redmond, WA).
Statistical Analysis
Safety
The primary parameter for the safety assessment of
ivermectin was change in pupil size under high-light
conditions between baseline (day 1 predose) and the
approximate time of maximum drug concentration
(Cmax) on day 7 (maximum of the 4- and 6-h time
points). The primary hypothesis was that oral adminis-
tration of ivermectin in the fasted state, at a regimen of
30 mg for three doses over 1 week (days 1, 4, 7), does not
affect the maximum pupil diameter change from base-
line at high-light conditions on day 7 as compared to
placebo; a mean difference of 1 mm between the 30 mg
ivermectin and placebo groups was considered signifi-
cant. The difference in maximum (of the 4- and 6-h
time points) pupil diameter change from baseline (day
1 predose) at high-light conditions on day 7 between
the groups receiving 30 mg ivermectin (in the fasted
state) and placebo (pooled from treatments A and B)
was assessed using an analysis of variance (ANOVA)
model with gender, treatment, and gender-by-treatment
interaction as factors. A 90% confidence interval for
the mean difference (30 mg ivermectin [in the fasted
state] vs. placebo) in maximum (of the 4- and 6-h
postdose time points) pupil diameter change from
baseline (day 1 predose) at high-light conditions on day
7 was calculated using the MSE from the ANOVA refer-
encing a t-distribution. Whether or not to combine the
results from males and females within each treatment
was determined by assessing the gender-by-treatment
interaction. The assumption of normality was tested
using the Shapiro-Wilk statistic.
Given a parallel study with 12 subjects in one group
(30 mg fasted) and 8 in the other (placebo) and similar
between-subject variation (mean square error = 0.0361)
as estimated from historical data, there is a > 99% prob-
ability that the observed 90% confidence interval for
the mean difference in maximum pupil diameter
change from baseline (day 1 predose) between the 30 mg
ivermectin (in the fasted state) group and the placebo
group would fall within the equivalence interval of
(–1.0, 1.0), if the true difference was 0. Probabilities were
calculated using SAS 6.12 (SAS Institute, Cary, NC).
1126 •J Clin Pharmacol 2002;42:1122-1133
GUZZO ET AL
at TEXAS A&M UNIV on September 19, 2011jcp.sagepub.comDownloaded from

Although not specified in the primary hypothesis,
an analysis of the pupil diameter changes for the other
30 mg time points (days 1 and 4, high light; days 1, 4,
and 7, low light) and for the other dose groups was done
using the same criteria as for the primary analysis.
General safety and tolerability were assessed by ex-
amining adverse experiences and laboratory data. Ad-
verse experiences were tabulated and summarized.
Pharmacokinetics
Estimation of the pharmacokinetic parameters of
ivermectin in this four-panel, escalating dose study
was accomplished by using an ANOVA model with
gender, dose, and gender-by-dose interaction as factors.
The analysis of the day 1 data included data from treat-
ments A, B, C, and D. The day 7 analysis included data
from only treatments A and B. Whether or not to com-
bine the results from males and females within each
treatment was determined by assessing the gender-
by-dose interaction. The assumption of normality was
tested using the Shapiro-Wilk statistic.
The effect of food on the pharmacokinetics of
ivermectin on day 1 was estimated by comparing the
natural log-transformed AUC0-∞values for the 30 mg
dose of ivermectin in the fed and fasted states (treat-
ment E vs. treatment A). An ANOVA model, including
treatments A and E with subject and treatment as fac-
tors, was used. A 95% confidence interval for the AUC
geometric mean ratio (30 mg ivermectin fed [treatment
E]/30 mg ivermectin fasted [treatment A]) was calcu-
lated using the MSE from the ANOVA referencing a
t-distribution.
Ivermectin accumulation was assessed in the fol-
lowing manner: an ANOVA model including treat-
ments A and B with dose, day, and dose-by-day interac-
tion as factors was used to analyze the natural
log-transformed AUC0-60 h values. Ninety-five percent
confidence intervals for the AUC geometric mean ratio
(day 7, last dose/day 1, first dose) were calculated using
the MSE from the ANOVA referencing a t-distribution
for the 30 mg ivermectin fasted (treatment A) and 60 mg
ivermectin (treatment B) treatment groups.
RESULTS
Subjects
Sixty-eight subjects (51 ivermectin, 17 placebo) en-
tered the study and were sequentially assigned to one
of four treatment panels. The subjects’ ages ranged
from 21 to 45 years, with a median of 34.5 years.
Thirty-five subjects (51.5%) were male and 33 subjects
(48.5%) were female. Subjects were 89.7% Hispanic,
4.4% Caucasian, 4.4% Black, and 1.5% Asian. The dis-
tribution of age, gender, and racial origin appeared to be
similar across the treatment groups. Overall, the study
population was generally healthy with few medical
problems. Secondary diagnoses were similar across the
treatment groups, consisting primarily of a history of
cesarean section or tubal ligation.
Safety
Pupillometry
Table I summarizes pupil diameter changes from base-
line (day 1 predose) in all study groups postdose (days
1, 4, and 7, when measured) at both low-light and
high-light conditions. The mean pupil diameter in the
ivermectin 30 mg (fasted) treatment regimen decreased
slightly from baseline for both males (–0.119 mm) and
females (–0.107 mm). The mean pupil diameter in the
placebo regimen remained virtually unchanged from
baseline for both males (–0.002 mm) and females
(0.035 mm). Gender effect was not significant at the
95% confidence level from an analysis of variance
(ANOVA) model with gender, treatment, and gender-
by-treatment interaction as factors.
The difference in pupil diameter change from base-
line (day 1 predose) at high-light conditions on day 7
between the groups receiving 30 mg ivermectin in the
fasted state and placebo (pooled from treatments A and
B) was –0.013. The 90% confidence interval (–0.239,
–0.021) for the difference falls within the equivalence
interval (–1.0, 1.0), indicating that the ivermectin 30
mg regimen in the fasted state had an equivalent
mydriatic effect as compared with placebo, according
to prespecified criteria. Exploratory examination of pu-
pil size of all other groups on days 1, 4, and 7 at both
high-light and low-light conditions confirmed that
there was no evidence of a mydriatic effect.
Adverse Events
Clinical adverse experiences reported during the study
are presented in Table II. Of the 51 subjects who re-
ceived ivermectin, 12 subjects (24%) reported at least
one clinical adverse experience. This rate was similar
to that observed in the placebo group (6 subjects, 35%).
In addition, there was no consistent trend in the inci-
dence of adverse experiences indicative of a dose re-
sponse. All clinical adverse experiences were transient
and mild, and no adverse experience recurred with re-
peated dosing. The most commonly reported adverse
experiences were headache, nausea, dizziness, and
rash, occurring in both ivermectin- and placebo-treated
PHARMACOKINETICS AND PHARMACODYNAMICS 1127
HIGH DOSES OF IVERMECTIN IN ADULTS
at TEXAS A&M UNIV on September 19, 2011jcp.sagepub.comDownloaded from

subjects. Seven ivermectin-treated subjects (14%) and
3 placebo-treated subjects (18%) had drug-related clin-
ical adverse experiences. None of the subjects discon-
tinued due to clinical adverse experiences. None of the
clinical adverse experiences was serious.
Two subjects experienced laboratory adverse experi-
ences, both in the 30 mg ivermectin group. A
37-year-old female developed increased alanine
transaminase (ALT) to approximately 2.5 times normal
on day 14 and elevated gamma-glutamyl transferase
(GGT) to approximately 4 times normal on day 18. ALT
returned to normal on day 23, but GGT remained
mildly elevated (no baseline values obtained). Further
hepatic evaluation revealed cholelithiasis (a gallblad
-
der filled with stones). The investigator rated both labo-
ratory adverse experiences as possibly related to study
drug. The second subject, a 25-year-old male, devel-
oped hematuria that resolved after passing a kidney
stone, and the event was evaluated as definitely not re-
lated to study drug.
Two subjects developed elevated liver function tests
(LFTs) at least two times the upper limit of normal. The
first subject was in the 30 mg ivermectin group and de-
veloped increased ALT and GGT levels, which were re-
ported as laboratory adverse experiences (described
above). The second subject, a 38-year-old male on pla-
cebo treatment, developed increased aspartate
transaminase (AST) and ALT levels to approximately
two times normal on day 7. The investigator consid-
ered these elevations to be not clinically significant.
Two subjects discontinued the study. One subject in
the 30 mg ivermectin group discontinued due to a labo-
ratory adverse experience (37-year-old female de-
scribed above). One subject in the placebo group was
lost to follow-up.
Pharmacokinetics
General
Pharmacokinetic results (AUC0-∞,C
max,t
max, and
half-life) are shown in Table III. In addition, box plots of
AUC0-∞by ivermectin dose (day 1, fasted only) are dis-
played in Figure 1. For single doses of 30 to 120 mg ad
-
ministered in the fasted state, the AUC and Cmax of
ivermectin increase with increasing dose and appear
generally dose proportional in this range. A high vari-
ability in absorption is apparent from examination of
1128 •J Clin Pharmacol 2002;42:1122-1133
GUZZO ET AL
Table I Mean (SD) of Pupil Diameter Changes (mm)
from Baseline by Treatment Regimen and Light Conditions
Ivermectin 30 mg Ivermectin 60 mg Ivermectin 90 mg Ivermectin 120 mg Ivermectin 30 mg
Placeboa(fasted) (n= 15) (fasted) (n= 12) (fasted) (n= 12) (fasted) (n= 12) (fed) (n=11
b)
At high-light
conditions
Day 1 0.064 –0.103 0.050 0.088 0.020 0.013
(0.167) (0.165) (0.132) (0.104) (0.129) (0.089)
Day 4 0.001 –0.021 –0.097 NA NA NA
(0.146) (0.263) (0.136)
Day 7 0.016 –0.114 –0.036 NA NA NA
(0.155) (0.140) (0.294)
(–0.239, –0.021)c
At low-light
conditions
Day 1 0.139 0.050 0.151 0.273 0.237 –0.009
(0.471) (0.382) (0.363) (0.417) (0.207) (0.283)
Day 4 0.113 –0.016 –0.028 NA NA NA
(0.469) (0.486) (0.339)
Day 7 0.199 –0.081 0.095 NA NA NA
(0.903) (0.458) (0.570)
a. Excluding 1 subject from panel 1 whose pupillometry measurements were not quantifiable. For day 1, pooled from treatments A, B, C, and D, n= 16; for days 4
and 7, pooled from treatments A and B, n=8.
b. One subject discontinued prior to receiving fed treatment and did not contribute to the corresponding analysis.
c. The 90% confidence interval (CI) for the primary endpoint (difference in mean change between ivermectin 30 mg, fasted and placebo at high-light conditions
on day 7). The 90% CI falls within the predetermined equivalence interval of (–1.0, 1.0) mm.
at TEXAS A&M UNIV on September 19, 2011jcp.sagepub.comDownloaded from

standard deviations and from the overall trends in AUC
and Cmax with increasing dose. Specifically, AUC and
Cmax do not appear to increase between the doses of 60
and 90 mg. However, a nearly proportional increase is
seen with the 120 mg dose, indicating that absorption is
not saturated in this range. tmax and half-life were gener-
ally invariant across the dose range, as would be ex-
pected from linear kinetics. There was no significant
trend indicative of a gender effect.
Accumulation
The mean plasma concentration profiles on days 1 and
7 following multiple doses of 30 and 60 mg ivermectin
given in the fasted state are shown in Figure 2. The geo-
metric mean ratio (GMR) of the AUC0-60 h of ivermectin
on day 7 to the AUC0-60 h on day 1 was calculated for as-
sessing accumulation. GMRs (day 7/day 1) were 1.24
and 1.40 for the ivermectin 30 and 60 mg doses, respec-
tively. This result suggests minimal accumulation of
drug with day 1, 4, and 7 dosing, consistent with a short
half-life relative to the dosing interval (72 h). The 95%
confidence interval was (0.80, 1.92) and (0.91, 2.18) for
the 30 mg (in the fasted state) level and the 60 mg level,
respectively.
Food Effect
The effect of food on the pharmacokinetics of
ivermectin was estimated by comparing the mean nat-
ural log-transformed AUC0-∞values for the 30 mg dose
of ivermectin in the fed and fasted states (treatment E
vs. A). The mean plasma concentration profiles in the
fed and fasted states are presented in Figure 3. The geo-
PHARMACOKINETICS AND PHARMACODYNAMICS 1129
HIGH DOSES OF IVERMECTIN IN ADULTS
Table II Clinical Adverse Experiences by Body System
Placebo Ivermectin Ivermectin Ivermectin Ivermectin
(n= 17) 30 mg (n= 15) 60 mg (n= 12) 90 mg (n= 12) 120 mg (n= 12)
Number % Number % Number % Number % Number %
Subjects with one or more
adverse experiences 6 35.3 5 33.3 5 41.7 2 16.7 0 0.0
Subjects with no
adverse experience 11 64.7 10 66.7 7 58.3 10 83.3 12 100
Body as a whole/site
unspecified 0 0.0 2 13.3 1 8.3 0 0.0 0 0.0
Fever 0 0.0 1 6.7 0 0.0 0 0.0 0 0.0
Flu-like illness 0 0.0 0 0.0 1 8.3 0 0.0 0 0.0
Pain, abdominal 0 0.0 1 6.7 0 0.0 0 0.0 0 0.0
Digestive system 1 5.9 1 6.7 1 8.3 1 8.3 0 0.0
Dry mouth 0 0.0 0 0.0 0 0.0 1 8.3 0 0.0
Fecal abnormality 0 0.0 1 6.7 0 0.0 0 0.0 0 0.0
Nausea 1 5.9 0 0.0 1 8.3 0 0.0 0 0.0
Vomiting 0 0.0 0 0.0 1 8.3 0 0.0 0 0.0
Musculoskeletal system 1 5.9 2 13.3 0 0.0 0 0.0 0 0.0
Pain, back 0 0.0 1 6.7 0 0.0 0 0.0 0 0.0
Pain, leg 1 5.9 0 0.0 0 0.0 0 0.0 0 0.0
Stiffness 0 0.0 1 6.7 0 0.0 0 0.0 0 0.0
Nervous system and
psychiatric disorder 3 17.6 1 6.7 4 33.3 1 8.3 0 0.0
Anxiety 0 0.0 0 0.0 1 8.3 0 0.0 0 0.0
Dizziness 1 5.9 0 0.0 1 8.3 0 0.0 0 0.0
Headache 2 11.8 1 6.7 3 25.0 1 8.3 0 0.0
Skin and skin appendage 1 5.9 0 0.0 1 8.3 0 0.0 0 0.0
Rash 1 5.9 0 0.0 1 8.3 0 0.0 0 0.0
Urogenital system 0 0.0 1 6.7 0 0.0 0 0.0 0 0.0
Urolithiasis 0 0.0 1 6.7 0 0.0 0 0.0 0 0.0
Although a subject may have had two or more adverse experiences, the subject is counted only once within a category. The same subject may appear in different
categories. All body systems are listed in which at least 1 subject had an adverse experience.
at TEXAS A&M UNIV on September 19, 2011jcp.sagepub.comDownloaded from

metric mean ratio of AUC0-∞values (fed/fasted) was
2.57. The 95% confidence interval was (2.16, 3.05).
DISCUSSION
This study was designed primarily to evaluate the
safety and tolerability of oral ivermectin to support its
1130 •J Clin Pharmacol 2002;42:1122-1133
GUZZO ET AL
Table III Mean (SD) of Pharmacokinetic Parameters by Treatment Regimen
Ivermectin Ivermectin
30 mg (fasted) (n= 12)a60 mg (n= 12)
Ivermectin 30 mg Ivermectin Ivermectin
Parameter (fed) (n=11
b) Day 1 Day 7 Day 1 Day 7 90 mg (n= 12) 120 mg (n= 12)
AUC0-∞(ng•h/ml)c4564.6 1724.3 2819.4 2984.0 6061.7 2910.2 4547.7
(1892.5) (830.5) (1691.2) (1530.1) (4243.7) (1801.9) (2402.9)
AUC0-60 (ng•h/ml)dNA 1166.3 1444.3 2099.3 2947.2 NA NA
AUC0-∞(ng•h/ml)d3951.9 1538.4 NA NA NA NA NA
Cmax (ng/ml)c260.5 84.8 87.0 165.2 186.2 158.1 247.8
(172.1) (42.7) (43.2) (98.6) (130.8) (87.6) (158.9)
t1/2 (h)e15.0 20.1 17.7 19.6 17.5 18.8 19.1
tmax (h)c4.6 4.3 4.2 3.6 4.0 4.9 4.2
(0.9) (1.0) (0.9) (0.9) (1.1) (1.8) (0.9)
a. As prespecified in the protocol amendment, the plasma samples from the 3 additional subjects receiving 30 mg ivermectin treatment were not analyzed and
did not contribute to the pharmacokinetic analyses.
b. One subject discontinued prior to receiving fed treatment and did not contribute to the corresponding analysis.
c. Arithmetic mean (standard deviation).
d. Geometric mean.
e. Harmonic mean.
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
AUC, ng hr/mL
30 60 90 120
Ivermectin Dose (mg)
Figure 1. Box plots of AUC by ivermectin dose (day 1, fasted only).
The box represents the middle half of the data with the bottom and
top of the box representing the 25th and 75th percentiles. The me-
dian is portrayed by a horizontal line segment within the box, and the
mean is represented by an asterisk. The height of the box is multi-
plied by 1.5 to determine the height of the “step.” The upper vertical
line extends up to the highest data value within the step, and the
lower vertical line extends down to the lowest data value within the
step. Circles represent data values that exceed the 25th and 75th per-
centiles by more than the height of the step. Mean AUC does not ap-
pear to increase between the doses of 60 and 90 mg, largely due to the
influence of the two outliers in the 60 mg dose group. A nearly pro-
portional increase is seen with the 120 mg dose, indicating that ab-
sorption is not saturated in this range.
Time, hr
0 1224364860
Day 1 Day 7
Time, hr
0 1224364860
Concentration, ng/mL
0
50
100
150
200
30 mg
60 mg
Figure 2. Mean plasma concentration (ng/ml) profiles of
ivermectin on days 1 and 7 following multiple oral doses of 30 and 60
mg given fasted on days 1, 4, and 7.
at TEXAS A&M UNIV on September 19, 2011jcp.sagepub.comDownloaded from

use for the treatment of head lice infestation. Head lice
predominantly affect school-age children. However,
for both ethical and practical reasons, it was felt appro-
priate to conduct this study in healthy adult subjects.
Extensive safety data are available for ivermectin, pri-
marily at dose levels of 150 to 200 µg/kg. There also are
published studies conducted at doses higher than 200
µg/kg for the treatment of internal parasites.13-21 The
present study expanded the safety data available for
ivermectin at higher doses in subjects without internal
parasitic infestations. The safety and tolerability of
ivermectin were evaluated from two perspectives in
this study: (1) assessment of CNS effect, the sole target
of previously documented ivermectin toxicity, and (2)
assessment of the general toxicity of ivermectin. No
CNS toxicity was detected in the study, and ivermectin
was generally well tolerated. Therefore, this study
demonstrates that ivermectin is well tolerated in
healthy subjects and provides additional evidence that
the more severe reactions observed in the treatment of
onchocerciasis and lymphatic filariasis are most likely
due to the death of the organisms.22
A second purpose of the study was to collect addi-
tional pharmacokinetic data on ivermectin. Spe-
cifically, the study was designed to extend the kinetic
understanding of this drug beyond the doses (up to 15
mg) examined previously, to document its behavior
when administered in repeated doses in the manner
contemplated for use against head lice, and to examine
the effect of a high-fat meal on absorption.
Safety and Tolerability
Specific signs or symptoms of CNS toxicity were based
on those determined in previous high-dose animal
studies and observations of human overdose and in-
cluded emesis, mydriasis, and ataxia. Mydriasis was
chosen as the endpoint for the primary hypothesis
since it can be accurately quantitated through
pupillometry. Pupillometry is a simple, accurate, and
reproducible method to measure pupil diameter quan-
titatively, which was validated internally prior to use
in this study. It was observed in the first treatment
panel that measurement of pupil diameter was difficult
in persons with extremely dark iris color. However,
with the addition of a screening evaluation at the
prestudy visit, this difficulty was resolved.
No indication of CNS toxicity associated with oral
ivermectin was observed for any of the doses admin-
istered in this study. This was most strongly sup-
ported by the absence of a mydriatic effect using
quantitative pupillometry. The primary analysis of the
pupillometry data was in the 30 mg ivermectin treat-
ment group since this fixed dose spanned the range (in
µg/kg) most likely to be employed in head lice therapy.
Comparison of pupil size to baseline was made after the
third dose, when maximum drug concentration was
likely to be present if any accumulation occurred. Con-
sidering this criterion, the change in pupil size follow-
ing 30 mg ivermectin administration was not different
from that observed with placebo. Escalation to a single
dose of up to 2 mg/kg, 10 times the approved dose, was
also unassociated with any mydriatic effect. This sup-
ports the safety of ivermectin in the anticipated dosage
range for head lice and provides a significant margin of
safety.
Ivermectin was generally well tolerated. There were
no serious clinical or laboratory adverse experiences.
Clinical adverse experiences were similar between the
ivermectin and placebo groups.
Specific adverse experiences to consider are those
within the gastrointestinal and nervous systems since
emesis, ataxia, and mydriasis are cardinal signs of
ivermectin toxicity. Three of 51 subjects in the
ivermectin-treated groups (1 fecal abnormality, 1 nau-
sea, 1 vomiting) and 1 of 17 subjects in the placebo
groups (1 nausea) experienced gastrointestinal adverse
experiences. The adverse experience of vomiting oc-
curred in a subject administered 60 mg of ivermectin
on day 4. The event was evaluated as not related to
ivermectin and did not occur after the day 1 dose, nor
PHARMACOKINETICS AND PHARMACODYNAMICS 1131
HIGH DOSES OF IVERMECTIN IN ADULTS
Time, hr
0 102030405060
Concentration, ng/mL
0
50
100
150
200
250
Fasted
Fed
Figure 3. Mean plasma concentration (ng/ml) profiles of
ivermectin following single oral doses of 30 mg (fed and fasted
administration).
at TEXAS A&M UNIV on September 19, 2011jcp.sagepub.comDownloaded from

did it recur with the day 7 dose. Six of the 51 subjects in
the ivermectin-treated groups (4 headache, 1 anxiety, 1
dizziness) and 3 of the 17 subjects in the placebo
groups (2 headache, 1 dizziness and headache) experi-
enced nervous system adverse experiences. No in-
crease in any adverse experiences was noted with dose
escalation, and no adverse experience recurred with re-
peated dosing. Of note, no adverse experiences were re-
ported in the subjects who received 120 mg of
ivermectin.
Two subjects developed increases in LFTs during
the study, 1 on ivermectin 30 mg and 1 on placebo. The
subject on active drug was subsequently identified as
having cholelithiasis, which was unlikely to be related
to acute treatment with ivermectin. No other clinically
significant LFT abnormalities occurred despite dose
escalation to 120 mg. These data, together with exten-
sive animal and human exposure, suggest that routine
monitoring of laboratory values is unnecessary at the
dose levels anticipated for head lice treatment.
Pharmacokinetics
Pharmacokinetic parameters of ivermectin following
single doses were consistent with previous observations1
and with linear behavior up to single doses of 120 mg.
Substantial variability in absorption was apparent
across doses, but this phenomenon was attributable to
absorption rates of < 50% in the fasted state and to the
parallel panel design of the study.
Absorption of ivermectin was significantly higher
when administered following a high-fat meal, approxi-
mately 2.5 times that in the fasted state. Although the
effect of food on absorption of ivermectin had not been
previously studied, this result was not unexpected.
When the drug was administered in a hydroalcoholic
solution,1a similar increase in bioavailability was ob-
served (compared to administration as a tablet). The ex-
tent of agreement between these results suggests that
the poor solubility in water of the lipophilic ivermectin
molecule limits absorption, but agents that help to
solubilize the molecule (such as alcohol or bile) in-
crease absorption of the drug. However, the standard
high-fat meal is not representative of typical food inges-
tion. Furthermore, it is reassuring that despite a sub-
stantial increase in the AUC of ivermectin with admin-
istration of a high-fat meal, no toxicity was noted.
The apparent half-life for ivermectin identified in
the product label is 16 hours or longer. The overall esti-
mate from this study (approximately 18 h) is slightly
longer. Half-life estimates varied somewhat with dose
and means of administration from approximately 15
hours in fed subjects given 30 mg ivermectin doses to
approximately 20 hours in the same group following
administration of 30 mg ivermectin in the fasted state.
Since the bioavailability is substantially higher when
the drug is administered in the fed state, and a shorter
half-life was observed in this state, it is possible that the
half-life observed following oral administration is in-
fluenced by slow absorption of the drug, rather than be-
ing a true estimate of elimination half-life.
The accumulation observed following administra-
tion of drug every fourth day was rather modest and
consistent with a moderate elimination half-life. The
apparent change observed between the 30 and 60 mg
dose regimens is likely attributable to the significant
variability in absorption and the small number of sub-
jects studied. In fact, accumulation ratios for both doses
were statistically indistinguishable from 1. No signifi-
cant pharmacokinetic differences were observed be-
tween men and women. No information has been gath-
ered on the pharmacokinetics of ivermectin in
children, but given the generally consistent kinetic be-
havior among many different species of widely distrib-
uted body sizes, it is expected that the pharma-
cokinetics in children will be consistent with those in
adults.
In summary, the safety profile generated in this
study supports the use of oral ivermectin at the ap-
proved dose levels and at dose levels being considered
for the treatment of head lice. Furthermore, a signifi-
cant safety margin is demonstrated. However, studies
in the pediatric population are necessary to confirm
safety in children at higher dose levels. The
pharmacokinetic parameters are consistent with those
previously established, with the exception of a slightly
longer half-life. A significant food interaction was
demonstrated.
We would like to acknowledge the following individuals for their
considerable contributions to this study: Mr. Manuel Pinto and the
staff of Clinical Pharmacology Associates for their invaluable help
with study conduct and patient recruitment, Ms. Geraldine Bolden of
Merck Research Laboratories for her excellent work in conducting
the image analysis of the pupillometry transparencies, Ms. Mitra
Asgary of Merck Research Laboratories for her contribution in ana-
lyzing the pharmacokinetic samples, and Dr. Stephanie Larouche,
formerly of Merck Research Laboratories, for her encouragement and
scientific guidance.
REFERENCES
1. Fink DW, Porras AG: Pharmacokinetics of ivermectin in animals
and humans, in: Campbell WC (ed.), Ivermectin and Abamectin.
New York: Springer-Verlag, 1989;113-130.
2. U.S. Package Circular: STROMECTOL®(ivermectin). Whitehouse
Station, NJ: Merck & Co., Inc., 1998.
1132 •J Clin Pharmacol 2002;42:1122-1133
GUZZO ET AL
at TEXAS A&M UNIV on September 19, 2011jcp.sagepub.comDownloaded from

3. Njoo FL, Beek WM, Keukens HJ, Van Wilgenburg H, Oosting J,
Stilma JS, Kijlstra A: Ivermectin detection in serum of onchocerciasis
patients: relationship to adverse reactions. Am J Trop Med Hyg
1995;52(1):94-97.
4. Krishna DR, Klotz U: Determination of ivermectin in human plasma
by high-performance liquid chromatography. Arzneimittelforschung
1993;43(5):609-611.
5. Okonkwo PO, Ogbuokori JE, Ofoegbu E, Klotz U: Protein binding
and ivermectin estimations in patients with onchocerciasis. Clin
Pharmacol Ther 1993;53(4):426-430.
6. Ette EI, Thomas WO, Achumba JI: Ivermectin: a long-acting
microfilaricidal agent. DICP 1990;24(4):426-433.
7. Baraka OZ, Mahmoud BM, Marschke CK, Geary TG, Homeida
MMA, Williams JF: Ivermectin distribution in the plasma and tissues
of patients infected with Onchocerca volvulus.Eur J Clin Pharmacol
1996;50(5):407-410.
8. Hansen RC, Brogdon WG, Dillenberg J, Gittes J, Pollack RJ,
Poundstone J, et al: Guidelines for the treatment of resistant pedicu-
losis. Contemporary Pediatrics 2000;7(suppl):1-10.
9. Dunne CL, Malone CJ, Whitworth JAG: A field study of the effects
of ivermectin on ectoparasites of man. Trans R Soc Trop Med Hyg
1991;85:550-551.
10. Glaziou P, Nyguyen LN, Moulia-Pelat JP, Cartel JL, Martin PMV:
Efficacy of ivermectin for the treatment of head lice (Pediculosis
capitis). Trop Med Parasitol 1994;45(3):253-254.
11. Bell TA:Treatment of Pediculus humanus var. capitis infestation in
Cowlitz county, Washington, with ivermectin and the Licemeister®
Comb. Pediatr Infect Dis J 1998;17(10):923-924.
12. Kwan KC, Bohidar NR, Hwang SS: Estimation of an effective
half-life, in: Benet LZ, Levy G, Ferraiolo BL (eds.), Pharmacokinetics:
A Modern View. New York: Plenum, 1984;147-162.
13. Cooper PJ, Awadzi K, Ottensen EA, Remick D, Nutman TB:
Eosinophil sequestration and activation are associated with the onset
and severity of systemic adverse reactions following the treatment of
onchocerciasis with ivermectin. J Infect Dis 1999;48:738-742.
14. Addiss DG, Beach MJ, Streit TG, Lutwick S, LeConte FH,
Lafontant JG, et al: Randomized placebo-controlled comparison of
ivermectin and albendazole alone and in combination for
Wuchereria bancrofti microfilaremia in Haitian children. Lancet
1997;350(9046):480-484.
15. Ismail MM, Weil GJ, Jayasinghe KSA, Premaratne UN,
Abeyewickrem W, Rajaratnam HN, et al: Prolonged clearance of
microfilaraemia in patients with bancroftian filariasis after multiple
high doses of ivermectin or diethylcarbamazine. Trans R Soc Trop
Med Hyg 1996;90(6):684-688.
16. Nguyen NL, Moulia-Pelat JP, Martin PMV, Cartel JL: Advantages
of ivermectin at a single dose of 400 mcg/kg compared with 100
mcg/kg for community treatment of lymphatic filariasis in Polynesia.
Trans R Soc Trop Med Hyg 1994;88:461-464.
17. Awadzi K, Hero M, Opoku NU, Buttner DW, Coventry PA, Prime
MA, et al: The chemotherapy of onchocerciasis: XVII. A clinical eval-
uation of albendazole in patients with onchocerciasis: effects of food
and pretreatment with ivermectin on drug response and
pharmacokinetics. Trop Med Parasitol 1994;45(3):203-208.
18. Van den Enden E, Gompel AV, Van der Stuyft P, Vervoort T, Van
Den Ende J: Treatment failure of a single high dose of ivermectin for
Mansonela perstans filariasis. Trans R Soc Trop Med Hyg 1993;
87(1):90.
19. Martin-Prevel Y, Cosnefroy JY, Tshipamba P, Ngari P,
Chodakewitz JA, Pinder M: Tolerance and efficacy of single high-
dose ivermectin for the treatment of loiasis. Am J TropMed Hyg 1993;
48(2):186-192.
20. Addiss DG, Eberhard ML, Lammie PJ, Hitch WL, Spencer HC:
Tolerance of single high-dose ivermectin for treatment of lymphatic
filariasis. Trans R Soc Trop Med Hyg 1991;85(2):265-266.
21. Richards FO, Eberhard ML, Bryan RT, McNeeley DF, Lammie PJ,
McNeeley MB, et al: Comparison of high dose ivermectin and
diethylcarbamazine for activity against bancroftian filariasis in Haiti.
Am J Trop Med Hyg 1991;44(1):3-10.
22. Cartel JL, Nguyen NL, Moulia-Pelat JP, Plichart R, Martin PMV,
Spiegel A: Mass chemoprophylaxis of lymphatic filariasis with a sin-
gle dose of ivermectin in a Polynesian community with a high
Wuchereria bancrofti infection rate. Trans R Soc Trop Med Hyg 1992;
86(5):537-540.
PHARMACOKINETICS AND PHARMACODYNAMICS 1133
HIGH DOSES OF IVERMECTIN IN ADULTS
at TEXAS A&M UNIV on September 19, 2011jcp.sagepub.comDownloaded from