Download Pharmacokinetics of Antimony in Children Treated for Leishmaniasis

MAJOR ARTICLE
Pharmacokinetics of Antimony in Children Treated
for Leishmaniasis with Meglumine Antimoniate
Adriana Cruz,1 Petrie M. Rainey,2 Barbara L. Herwaldt,3 Grazia Stagni,4 Ricardo Palacios,1,5 Rodolfo Trujillo,1
and Nancy G. Saravia1
1
Centro Internacional de Entrenamiento e Investigaciones Médicas, Cali, Colombia; 2Department of Laboratory Medicine, University
of Washington, Seattle; 3Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia; 4Arnold
& Marie Schwartz College of Pharmacy, Long Island University, Brooklyn, New York; 5Division of Infectious Diseases, Federal
University of São Paulo, São Paulo, Brazil
Background. In some settings, the response to pentavalent antimonial therapy for leishmaniasis may be lower
in children than in adults. We hypothesized that there are age-dependent pharmacokinetic differences of potential
clinical relevance.
Methods. We compared the pharmacokinetics of antimony (Sb) in adults and 2 groups of children 3–6 years
old who had cutaneous leishmaniasis treated with intramuscular meglumine antimoniate. Adults (n p 9 ) and the
first group of children (n p 9 ) received 20 mg Sb/kg/day for 20 days; the second group of children (n p 6)
received 20 mg Sb/kg for 19 days and 30 mg Sb/kg on day 20. Drug exposure was assessed by the area under the
24-h time-concentration curve (AUC0–24) in plasma.
Results. Children (vs. adults) who received 20 mg/kg had a 42% lower AUC0–24 (mean SE, 111 7 vs.
190 10 mg ⫻ h/L, compared with adults; P ! .001), a 16% lower peak concentration (32.7 0.9 vs. 38.8 2.1 mg/L; P p .04), and a 75% higher weight-adjusted clearance (0.185 0.013 vs. 0.106 0.006 L/h/kg; P !
.001). The 30 mg/kg dose in children increased the AUC0–24 to 164 10 mg ⫻ h/L and the peak concentration
to 43.8 2.3 mg/L.
Conclusions. Drug exposure is significantly lower in children than in adults treated with the same weightadjusted regimen of meglumine antimoniate, which primarily stems from a higher antimony clearance rate.
Leishmania species are protozoan pathogens transmitted by sand flies. They infect and persist indefinitely in
macrophages of human and other mammalian hosts.
Multiple species of Leishmania infect humans in different geographic regions worldwide. Pentavalent antimony (SbV) drugs have been considered to be the first-
Received 28 August 2006; accepted 28 September 2006; electronically published
11 January 2007.
Potential conflicts of interest: none reported.
Presented in part: Wellcome Trust–Burroughs Wellcome Fund Infectious
Diseases Initiative Meeting, Cape Town, South Africa, 7–9 November 2005;
Simposio Leishmaniasis, XII Congreso Colombiano de Parasitologı́a y Medicina
Tropical, Centro de Convenciones Gonzalo Jiménez de Quesada, Bogotá, Colombia,
3–6 November 2005.
Financial support: Wellcome Trust–Burroughs Wellcome Infectious Disease
Initiative (grant 059056/Z/99/Z); COLCIENCIAS (grant 2229-04-11722).
The findings and conclusions in this article do not necessarily reflect the views
of the Centers for Disease Control and Prevention.
Reprints or correspondence: Dr. Nancy Gore Saravia, Centro Internacional de
Entrenamiento e Investigaciones Médicas, Avenida 1 Norte No. 3-03, AA 5390,
Cali, Colombia ([email protected]).
The Journal of Infectious Diseases 2007; 195:602–8
2006 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2007/19504-0020$15.00
602 • JID 2007:195 (15 February) • Cruz et al.
line treatment for all clinical forms of leishmaniasis
(e.g., visceral, cutaneous, and mucosal) for 150 years.
However, understanding of the pharmacokinetics and
pharmacodynamics of Sb is limited in general and for
children in particular, which has hindered attempts to
tailor SbV dosage regimens for different age groups
and circumstances (e.g., particular geographic regions,
forms of leishmaniasis, and Leishmania species/strains).
The need to optimize treatment regimens for children
is particularly pressing in settings in which children
constitute a substantial proportion of the patient population and may have lower response rates to treatment
regimens that are effective in adults.
Broad generalizations can be dangerous, in part because of the diversity and specificity encompassed by
leishmaniasis and the paucity of direct comparisons
between data for children and adults. However, published and unpublished data, observations, and impressions for both the New and Old Worlds and both
cutaneous and visceral leishmaniasis suggest that young
children in some settings are at an increased epide-
miologic risk for infection, because of circumstances that have
promoted periurban and peri- and intradomiciliary transmission [1–6]; that they are at an increased biological risk for
disease, if infected, because of greater pathogenicity in children
[7–13]; and that, as a consequence, they bear a substantial
portion of the global disease burden of leishmaniasis. In addition, results of clinical trials of cutaneous leishmaniasis in
Colombia and of visceral leishmaniasis in East Africa (not designed or powered to compare response rates in different age
groups) have provided suggestive evidence that children may
have lower response rates to weight-adjusted daily doses of SbV
or to durations of therapy that are effective in adults [14–16].
In anthroponotic transmission cycles, suboptimal responses to
therapy may promote the development and dissemination of
drug resistance.
Although the response to SbV therapy is multifactorial, we
hypothesized that there could be age-specific differences in the
pharmacokinetics of antimony that are of potential clinical relevance in settings in which drug exposure could be an important contributory factor for therapeutic response. We assessed the pharmacokinetics of antimony in children (vs.
adults) who received the standard weight-adjusted regimen of
meglumine antimoniate (20 mg Sb/kg/day for 20 days) and in
children who received 20 mg Sb/kg/day for 19 days and a single
dose of 30 mg Sb/kg on day 20.
intramuscular (im) injection, once daily. The Ministry of Health
of Colombia provided the medication (Glucantime [81 mg Sb/
mL]; Sanofi-Aventis: adults and children in group A received
lot 108558, and children in group B received lot 704). The
adults and children in group A received the standard weightadjusted dose of 20 mg Sb/kg throughout the 20-day treatment
course, whereas children in group B received a dose of 20 mg
Sb/kg for 19 days and 30 mg Sb/kg on day 20. Comparing the
20 mg Sb/kg and 30 mg Sb/kg doses in the same children
increased the power to detect pharmacokinetic differences by
eliminating intersubject variability (see below); in general, the
number of patients per study group was selected to provide
adequate estimates of the population means for the pharmacokinetic parameters of interest.
The patients were hospitalized in Cali, Colombia, on days
when specimens were obtained for pharmacokinetic analysis:
day 20 for adults, days 1 and 20 for children in group A, and
days 19 and 20 for children in group B (table 2). EDTA-anticoagulated blood specimens were obtained before the dose
and at 0.5, 1.0, 1.5, 2, 3, 5, 8, 12, and 24 h after the dose (and
at 48 h after the 20th dose in adults and children in group B).
For children in group A, the collection times on day 20 were
0, 2, 8, and 24 h. For children in group B, timed urine specimens
also were obtained during portions of the dosing interval, and
the total volume of each specimen was measured. Plasma and
SUBJECTS, MATERIALS, AND METHODS
Study subjects and design. The investigations were designed
to determine and compare the pharmacokinetics of antimony
in children and adults who had parasitologically confirmed
cutaneous leishmaniasis treated with meglumine antimoniate.
The studies were not designed to compare the safety or efficacy
of different dosage regimens. Eligible subjects included otherwise healthy children 2–7 years old who weighed ⭓10 kg and
adults ⭓18 years old who weighed ⭓50 kg. Exclusionary criteria
included unavailability for specimen collection (see below), SbV
therapy during the preceding month, a relative or absolute
contraindication to SbV therapy, a concurrent condition requiring medication (e.g., malaria or anemia), mucosal leishmaniasis, pregnancy, and lactation.
Three groups of patients (table 1)—one group of adults
(n p 9), the first group of children (group A; n p 9 ), and the
second group of children (group B; n p 6)—were sequentially
enrolled and evaluated, such that the pharmacokinetic data
from each successive group could inform the study designs for
subsequent groups. The adults were subjects in a comprehensive
evaluation of the pharmacokinetics of antimony in different
target tissues (P.M.R., G.S., B.L.H., C. Rojas, R.P., and N.G.S.,
unpublished data) and were purposefully evaluated before the
children.
All patients were treated with meglumine antimoniate by
Table 1.
Patient characteristics, by study group.
Children
(n p 15)
Characteristic
Adults
(n p 9)
Group A
(n p 9)
Group B
(n p 6)
Age, median (range), years 26 (20–36)
4 (3–6)
4.5 (3–6)
Weight, median (range), kg 62 (56–120) 15 (13–18) 17.5 (13–21)
Sex
Male
Female
Race/ethnicity
Mestizo
Black
Indigenous
White
9
3
3
0
6
3
5
8
4
3
0
1
1
0
0
0
2
0
Region of Colombia
Pacific Coast
Magdalena Valley
Other
Leishmania species
L. (Viannia) panamensis
Not identified
6
4
3
0
3
5
0
3
0
4
5
6
3
3
3
NOTE. Data are no. of patients, unless otherwise indicated. None of the
patients needed to stop therapy because of drug-related toxicity. All but 1 of
the patients’ lesions had healed or substantially improved by the end of therapy.
Pharmacokinetics of Antimony in Children • JID 2007:195 (15 February) • 603
Table 2. Days and times for collection of plasma specimens to
compare the pharmacokinetics of antimony (Sb) in adults and
children administered intramuscular meglumine antimoniate.
Day 1
0
0.5
a
x
x
x
x
1
1.5
x
x
x
x
2
3
5
8
x
x
x
x
x
x
x
x
12
24
x
x
x
x
48c
x
Time, h
Group B
(n p 6)
Group A
(n p 9)
Adults,
(n p 9)
20 mg/kg,
day 20
20 mg/kg
20 mg/kg
30 mg/kg
Day 20
Day 19
Day 20
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
xb
x
x
x
b
x
x
NOTE. The adults and children in group A received 20 mg Sb/kg/day
throughout the 20-day treatment course, whereas children in group B received
30 mg Sb/kg on day 20. See Subjects, Materials, and Methods for details
about the collection of urine from children in group B.
a
Predose (trough) specimen.
The same specimen served as the 24-h specimen for day 19 and the time
0 specimen for day 20.
c
Collected on day 22, 2 days after the end of the 20-day course of therapy.
b
aliquots of urine were stored at ⫺20C until analysis for antimony content.
Monitoring for safety included symptom reports, testing of
blood specimens (for hemoglobin, alanine aminotransferase,
amylase, creatinine, and urea nitrogen levels), and electrocardiograms at periodic intervals. Informed consent was obtained
from adult patients and from the parents or guardians of children. The investigations were approved by the institutional
review boards of the Centro Internacional de Entrenamiento e
Investigaciones Médicas, the Centers for Disease Control and
Prevention, and the University of Washington.
Antimony analysis. Plasma and urine antimony concentrations were measured by electrothermal atomic absorption
spectroscopy. This method measures total antimony, without
regard to chemical form. Specimens were diluted, when possible, with 0.5% nitric acid to give a final concentration in the
optimal assay working range of 0.05–0.20 mg/L. Sample analysis
was performed with a GF90 Plus Thermo graphite furnace and
a Thermo Jarrel Ash Unicam Solaar 989QZ atomic absorption
spectrophotometer (both from Thermo Electron) at a wavelength of 217.6 nm and a bandwidth of 0.2 nm using an antimony hollow-cathode lamp and Zeeman background correction. An autosampler injected 15 mL of specimen and 2.5 mL
of 25 g/L nickelous nitrate hexahydrate in 10% nitric acid and
0.1% Triton X-100 into a graphite platform tube. The sample
was dried in 3 steps (20 s at 80C, 20 s at 100C, and 15 s at
604 • JID 2007:195 (15 February) • Cruz et al.
140C), ashed for 20 s, and atomized for 4 s, followed by
cleaning for 3 s. Ashing, atomization, and cleaning temperatures were reoptimized periodically. Ashing temperatures were
1250C–1300C, atomization temperatures were 2200C–2500C,
and cleaning temperatures were 2700C–2900C. Argon gas flow
was set at 0.2 L/min and was shut off during the atomization
phase.
Calibrators, controls, and patient specimens were analyzed
in duplicate, and mean values are reported. Calibrators were
prepared by diluting meglumine antimoniate (from the pertinent lot of drug for each study group) with 0.5% nitric acid
to give antimony concentrations of 0.00, 0.05, 0.10, and 0.20
mg/L. Calibrators were analyzed at the beginning and end of
each set of specimens, and the calibration curve was prepared
using the mean of the signals for the 2 sets of calibrators. Assay
precision, given as the coefficient of variation, was 11.1% at
0.02 mg/L, 5.5% at 0.11 mg/L, and 6.7% at 0.22 mg/L. The
detection limit was 0.01 mg/L.
Pharmacokinetic analysis. Plasma pharmacokinetic parameters were assessed by noncompartmental analysis using
WinNonLin Professional software (version 5.0; Pharsight). Values for half-life(b) and apparent volume of distribution [Vd/
F(b)] were calculated from the elimination rate constants associated with the log-linear portions of the time-concentration
curves. Renal clearance was calculated as ClR p [Sb]U ⫻ VU /
AUCa⫺b, where [Sb]U is the concentration of antimony in urine;
VU is the volume of urine in the specimen; and AUCa⫺b is the
area under the time-concentration curve for the urine collection
interval from time a to time b. To correct for expected variability
in pediatric urine collections, ClR was normalized to the creatinine clearance calculated for the same urine specimen, with
plasma creatinine measured on the 5-h specimens (ClR/ClCr).
The percentage of administered drug remaining in the body
at time t was calculated from the ratio of the AUC from time
t extrapolated to infinite time divided by the total AUC extrapolated to infinite time. Body surface area (BSA) was calculated as the square root of height (in centimeters) times
weight (in kilograms) divided by 3600 [17]. Values for pharmacokinetic parameters are reported as means SEs. The
significance of comparisons between 2 groups was assessed using the unpaired t test; comparisons within a group were evaluated with the paired t test.
RESULTS
Nine adults, 20–36 years old, and 15 children (9 in group A
and 6 in group B), 3–6 years old, participated in the investigations. Patient characteristics are summarized in table 1.
Pharmacokinetics of antimony in children. The graphs of
mean antimony concentration versus time in children given 20
mg Sb/kg demonstrate similar pharmacokinetics on day 1
(group A), day 19 (group B), and day 20 (group A) (figure 1).
the mean AUC0–24 in children increased to 86% of the adult
value and the mean peak level to 113% of the adult value. In
the third comparison, in which children in group B were treated
with 20 mg Sb/kg (day 19) and 30 mg Sb/kg (day 20), the 50%
higher dose resulted in a proportional (48%) increase in
AUC0–24. Cmax increased by only 34%, which possibly reflects
slower absorption of the larger dose. Although the C24 did not
substantially change, accumulation would require multiple
doses to become apparent. Cl/F, ClR/ClCr, half-life(b), and Vd/
F(b) values were essentially unchanged.
DISCUSSION
Figure 1. Mean antimony (Sb) concentration vs. time profiles in plasma
from children treated with intramuscular meglumine antimoniate (20 mg
Sb/kg/day). Group A, day 1 (white squares); group A, day 20 (white circles);
group B, day 19 (black circles). Error bars indicate SEs.
Although it is not apparent in the figure, a low-level accumulation of antimony was observed during treatment. Compared with the mean trough concentration (C24) on day 1
(0.025 0.006 mg/L), trough levels were higher on day 19
(0.113 0.015 mg/L; P p .002) and day 20 (0.089 0.042 mg/
L; P p .016).
The mean AUC values for the 24-h dosing interval (AUC0⫺24)
were different for group A, day 1, and group B, day 19 (89
16 vs. 111 7 mg ⫻ h/L; P p .027), reflecting differences
in mean weight-adjusted Cl/F (0.230 0.047 vs. 0.185 0.013 L/h/kg; P p .057), where Cl is total drug clearance and
F is bioavailability. For children in group A, the 4 data points
on day 20 (i.e., for times 0, 2, 8, and 24 h) were insufficient
for accurate calculations of AUC0–24 or Cl/F.
Comparative pharmacokinetics of antimony in children
and adults. Figure 2, which shows mean steady-state Sb concentrations versus time, and table 3, which summarizes the
associated pharmacokinetic parameters, facilitate 3 comparisons between age groups and drug doses. In the first comparison, in which both adults (day 20) and children in group B
(day 19) were treated with the same weight-adjusted dose (20
mg Sb/kg), plasma antimony concentrations in children were
lower than those in adults at all times after dosing (figure 2).
Overall drug exposure, as measured by the AUC0–24, was 58%
of adult exposure. Peak (Cmax) and trough (C24) levels averaged
84% and 57% of adult values, respectively (table 3). In the
second comparison, in which day 20 data are provided for
adults (20 mg Sb/kg) and children in group B (30 mg Sb/kg),
Improved understanding of the pharmacokinetics of antimony
in children in particular is important because children bear a
substantial portion of the global disease burden of leishmaniasis, and observations in some settings have suggested that
response rates to SbV therapy may be lower in children than
in adults. We hypothesized that there are age-dependent pharmacokinetic differences of potential clinical relevance and confirmed that children have lower systemic exposure to antimony,
as assessed by a ∼42% lower AUC0–24 when they were given the
standard weight-adjusted daily dose of 20 mg Sb/kg.
Under steady-state conditions, the AUC0–24 equals [(dose/F)/
Cl]. Under the assumption that bioavailability (F) is ∼100% in
otherwise healthy adults and children with im dosing, if the
same weight-adjusted dose is given, a lower drug exposure (as
Figure 2. Mean steady-state antimony (Sb) concentration vs. time profiles in plasma from adults and children treated with intramuscular meglumine antimoniate. Adults: day 20, 20 mg Sb/kg (black squares). Children
in group B: day 19, 20 mg Sb/kg (black circles); day 20, 30 mg Sb/kg
(white circles). Error bars indicate SEs.
Pharmacokinetics of Antimony in Children • JID 2007:195 (15 February) • 605
Table 3. Comparison of steady-state pharmacokinetic parameters of antimony (Sb) in adults (dose, 20 mg Sb/
kg) and children in group B (doses, 20 and 30 mg Sb/kg) treated with intramuscular meglumine antimoniate.
Parameter
AUC0–24, mg-h/L
Cl/F, L/h-kg
Adults,
20 mg/kg (1)
(n p 9)
Children,
20 mg/kg (2)
(n p 6)
Children,
30 mg/kg (3)
(n p 6)
190 10
0.106 0.006
111 7
0.185 0.013
164 10
0.186 0.012
38.8 2.1
32.7 0.9
43.8 2.3
Comparisons: ratio (P)
2 vs. 1
Cmax, mg/L
Tmax, h
1.0 (1.0–2.0)
0.875 (0.5–1.5)
1.0 (1.0–1.5)
C24, mg/L
C48, mg/L
0.198 0.023
0.089 0.007
0.113 0.015
NA
0.102 0.011
0.062 0.005
Half-life(b), h
Half-life24–48, h
1.99 0.08
b
20.6 1.8
1.48 0.02
NA
Vd/F(b), L/kg
ClR/ClCr
0.30 0.01
NA
0.58 (!.001)
1.75 (!.001)
0.84 (.04)
NS
a
3 vs. 1
3 vs. 2
0.86 (.08)
1.48 (.001)
1.75 (!.001)
1.13 (.15)
1.01 (.90)
1.34 (.003)
NS
NS
0.57 (.02)
NA
0.52 (.01)
0.70 (.01)
0.90 (.58)
NA
1.47 0.06
b
25.3 3.1
0.73 (!.001)
NA
0.72 (!.001)
1.33 (.19)
0.99 (.92)
NA
0.39 0.03
0.39 0.02
1.30 (.007)
1.30 (.004)
1.00 (.97)
0.95 0.09
0.90 0.05
NA
NA
0.95 (.70)
NOTE. Parameters are given as mean SE, except for Tmax, which is given as median (range). P values were determined using
the t test for comparisons between children and adults and the paired t test for comparisons between children in group B on days
19 (20 mg Sb/kg) and 20 (30 mg Sb/kg). AUC0–24, area under the time-concentration curve in plasma from 0 to 24 h after the dose;
Cmax, maximum plasma concentration; C24, trough concentration at the end of the usual 24-h dosing interval; C48, concentration 48 h
after the last dose (i.e., the dose on day 20); CL/F, drug clearance, adjusted for bioavailability (F); ClR/ClCr, renal clearance of antimony,
normalized to renal creatinine clearance; half-life(b), half-life during the b-elimination phase; half-life24–48, apparent half-life between 24
and 48 h (an approximation of the g-elimination half-life); Vd/F(b), apparent volume of distribution during the b-elimination phase; NA,
not applicable; NS, not significant; Tmax, time to reach maximum plasma concentration.
a
b
One implausible outlier was excluded before averaging.
Two implausible outliers were excluded before averaging.
reflected by the AUC0–24) is fully attributable to a higher total
weight-adjusted clearance (Cl).
The few previous studies of the pharmacokinetics of antimony in humans have largely been conducted using sodium
stibogluconate, a related drug, rather than meglumine antimoniate [18–21]; in one study [19], data for both drugs (used
to treat 2 and 3 patients, respectively) were compared and
combined. The results of all of these studies have been consistent with direct renal clearance being the predominant route
for the elimination of antimony. In our adult group, the total
weight-adjusted clearance was 0.086–0.144 L/h/kg (1.43–2.4
mL/min/kg), which is in the same range as the normal adult
glomerular filtration rate (GFR).
Difficulties in obtaining urine from young children precluded
the accurate direct measurement of renal antimony clearance.
However, we were able to estimate renal antimony clearance
in children in group B as being 90%–95% of the apparent
creatinine clearance measured using the same urine specimen
(table 3). Creatinine clearance approximates the GFR in children and adults with normal renal function. Weight-adjusted
GFR (in milliliters per minute per kilogram of weight) is higher in children than in adults [22], which is consistent with
the higher weight-adjusted total antimony clearance that we
observed.
In our studies, plasma antimony concentrations decreased
over time in a log-linear fashion between 2 and 8 h after the
dose in children and between 3 and 12 h in adults (the b-
606 • JID 2007:195 (15 February) • Cruz et al.
elimination phase). The corresponding half-lives were ∼1.5 and
2.0 h in children and adults, respectively (table 3). In adults,
the mean half-life of 1.99 0.08 h is comparable to previously
reported values of 2.02 0.11 h [19], 1.7 0.6 h [20], and
1.85 0.07 h [21]. Subsequent to the log-linear phase, the time
required for antimony concentrations to decrease by 50% became much longer. Although there was imprecision in measuring the low antimony concentrations present at later time
points, the apparent half-life between 24 and 48 h was ∼1 day
in both adults and children (table 3).
Most of the administered antimony appears to be removed
from the body during the b-elimination phase. After 12 h, 6.0%
of the administered antimony remained in children in group
B (day 20), and 8.0% remained in adults. After 24 h, the average
remaining antimony was 3.1% in children and 2.8% in adults.
There was evidence of some accumulation of antimony during
treatment, with the mean C24 value increasing from 0.025 0.003 to 0.089 0.016 mg/L between days 1 and 20 in children
in group A.
Our data for both children and adults are consistent with
the rapid equilibration of antimony into extracellular water
occurring simultaneously with absorption from the site of im
injection. Subsequently, most of the antimony is rapidly removed, primarily by glomerular filtration, with a portion distributing into a deeper compartment, possibly intracellular water. Slow release of antimony from the deeper compartment
may explain the longer apparent half-life noted between 24 and
48 h (table 3).
If pharmacokinetics are linear, the AUC0–24 value at steady
state is directly proportional to the dose and is inversely proportional to Cl/F. A consistent AUC0–24 value can be achieved
by using a dose that is proportional to the clearance. Increasing
the relative amount of antimony administered to children may
compensate for their higher weight-adjusted clearance. On day
20, we administered a 1-time dose of 30 mg Sb/kg to children
in group B, to assess the effect of this 50% dose increase on
AUC0–24 and other pharmacokinetic parameters and, thereby,
to confirm that the AUC0–24 in children is proportional to dose.
We conservatively decided to increase the dose by only 50%,
knowing that, if dose proportionality was maintained, an even
higher dose (per body weight) would be required for children
to achieve the AUC0–24 noted in adults treated with 20 mg Sb/
kg. The dose of 30 mg Sb/kg resulted in a mean increase in
AUC0–24 in the children that was proportional to the dose,
although the mean AUC0–24 with 30 mg Sb/kg was still only
86% of the mean adult AUC0–24 with 20 mg Sb/kg (figure 2;
table 3). The peak level (Cmax) was slightly greater than that
seen in the adult group but was not fully proportional to the
dose.
The GFR correlates better with BSA than with weight, and
GFR normalized to BSA is approximately constant from age 2
years through adulthood [22]. Normalizing drug doses to BSA
is a well-accepted alternative among pediatricians to weightadjusted dosing, especially for drugs for which exposure depends on renal clearance or cardiac output. The standard 20
mg Sb/kg dose is approximately equivalent to a dose of 800
mg/m2 in adults. In the children in group B, the 30 mg Sb/kg
dose was equivalent to 660–755 mg/m2. Under the assumption
that dose proportionality was maintained, if these children had
received 800 mg/m2, the expected mean AUC0–24 would have
been 182 10 mg ⫻ h/L (i.e., 96% of the mean adult AUC0–24
value).
A potential concern about using doses 120 mg Sb/kg in
children is that the doses could produce higher peak antimony
concentrations than are typically seen in adults, as we observed
with the single 30 mg Sb/kg dose. However, the peak levels per
se achieved with im dosing are unlikely to be a major concern,
in part because even higher peak levels are achieved with the
intravenous (iv) administration of SbVdrugs, the common route
used in many resource-rich countries. In addition, because the
iv and im routes of administration of SbVdrugs are considered
to be similar with respect to both efficacy and toxicity, peak
levels alone are unlikely to be predictive of drug effects. Nevertheless, the injection volume required for a 20 mg Sb/kg dose
in young children, let alone for higher doses, is relatively large
for small children. For the children in group B, who had a
mean weight of 16.8 kg and a mean BSA of 0.70 m2, the
amounts of meglumine antimoniate (concentration, 81 mg Sb/
mL) for doses of 20 mg Sb/kg and 800 mg/m2 are 336 mg (∼4
mL) and 560 mg (∼7 mL), respectively. (Although concentrations can vary among manufacturers and lots, the typical antimony concentrations for meglumine antimoniate and sodium
stibogluconate are ∼85 and ∼100 mg Sb/mL, respectively.) The
iv route of administration should produce the same 24-h total
AUC0–24 as im injection but is logistically and economically
impractical in many resource-poor countries. Dividing the daily
dose into 2 im injections, given several hours apart, would be
inconvenient but would provide the same total daily exposure
(with lower peak levels).
These examples of dosage regimens do not constitute recommendations. The objective of our investigations was to identify and define age-dependent differences in the pharmacokinetics of antimony, not to evaluate the need for larger doses,
which would be dependent on the setting, nor the efficacy,
safety, tolerability, or practicality of specific dosage regimens.
Our conclusions are based on the assumptions that total antimony concentrations in plasma (regardless of the chemical
form) correlate with the concentrations of active antimonial
compound(s) in the phagolysosomes of tissue macrophages
(where the parasite is found) and that the AUC0–24, in particular,
is a good measure of drug exposure in both adults and children.
Limitations of our investigations included the inability to
obtain complete urine collections from young children, the
inability to do all of the evaluations on plasma specimens from
the same group of children because of restrictions on the total
amount of blood that could be safely obtained from each child,
and the potential lack of generalizability of data from a relatively
small number of otherwise healthy children 3–6 years old with
cutaneous leishmaniasis to children of other ages and to children with visceral leishmaniasis (who commonly are malnourished and may have renal dysfunction).
To our knowledge, our investigations represent the first studies of the pharmacokinetics of antimony that have focused on
children. Our conclusions are robust: (1) lower drug exposure,
as assessed by the AUC0–24, occurs in young children (vs. adults)
treated for leishmaniasis with the same weight-adjusted regimen
of meglumine antimoniate; and (2) the lower exposure appears
to result primarily from higher weight-adjusted antimony
clearance.
Acknowledgments
We thank Dr. Maria Consuelo Miranda, Dr. Hernan Bermudez, Dr.
Claudia Posso, Dr. Jaime Restrepo, Dr. Hildegard Piñeros, Dr. Allisson
Sombredero, Dr. Harrison Barón, Dr. Boris Sanchez, Luz Mery Montero,
and Wilson Cortez for their assistance in the diagnosis, enrollment, and
clinical management of patients; Tracy Stream for determining the antimony concentrations in the specimens; and Liliana Valderrama for coor-
Pharmacokinetics of Antimony in Children • JID 2007:195 (15 February) • 607
dinating sample preparation, storage, and shipping and for assisting with
the preparation of the manuscript.
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