ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Nov. 2010, p. 4780–4788
0066-4804/10/$12.00 doi:10.1128/AAC.00252-10
Copyright © 2010, American Society for Microbiology. All Rights Reserved.
Vol. 54, No. 11
Population Pharmacokinetics and Pharmacodynamics of Artemether
and Lumefantrine during Combination Treatment in Children with
Uncomplicated Falciparum Malaria in Tanzania䌤
Sofia Friberg Hietala,1* Andreas Mårtensson,2,3 Billy Ngasala,4 Sabina Dahlström,2
Niklas Lindegårdh,5,6 Anna Annerberg,5 Zul Premji,4 Anna Färnert,2 Pedro Gil,2,7
Anders Björkman,2 and Michael Ashton1
Received 20 February 2010/Returned for modification 6 April 2010/Accepted 7 August 2010
The combination of artemether (ARM) and lumefantrine is currently the first-line treatment of uncomplicated falciparum malaria in mainland Tanzania. While the exposure to lumefantrine has been associated with
the probability of adequate clinical and parasitological cure, increasing exposure to artemether and the active
metabolite dihydroartemisinin (DHA) has been shown to decrease the parasite clearance time. The aim of this
analysis was to describe the pharmacokinetics and pharmacodynamics of artemether, dihydroartemisinin, and
lumefantrine in African children with uncomplicated malaria. In addition to drug concentrations and parasitemias from 50 Tanzanian children with falciparum malaria, peripheral parasite densities from 11 asymptomatic children were included in the model of the parasite dynamics. The population pharmacokinetics and
pharmacodynamics of artemether, dihydroartemisinin, and lumefantrine were modeled in NONMEM. The
distribution of artemether was described by a two-compartment model with a rapid absorption and elimination
through metabolism to dihydroartemisinin. Dihydroartemisinin concentrations were adequately illustrated by
a one-compartment model. The pharmacokinetics of artemether was time dependent, with typical oral clearance increasing from 2.6 liters/h/kg on day 1 to 10 liters/h/kg on day 3. The pharmacokinetics of lumefantrine
was sufficiently described by a one-compartment model with an absorption lag time. The typical value of oral
clearance was estimated to 77 ml/h/kg. The proposed semimechanistic model of parasite dynamics, while a
rough approximation of the complex interplay between malaria parasite and the human host, adequately
described the early effect of ARM and DHA concentrations on the parasite density in malaria patients.
However, the poor precision in some parameters illustrates the need for further data to support and refine this
model.
Artemisinin-based combination therapy is generally accepted
as treatment of choice for acute uncomplicated Plasmodium
falciparum malaria (31). A fixed-dose combination containing
artemether (ARM) and lumefantrine (LUM) is currently the
first-line treatment of uncomplicated falciparum malaria in
mainland Tanzania. The rationale behind combining ARM
with LUM is to make use of the disparate pharmacokinetic
profiles of the two drugs and thereby improve treatment efficacy and delay development of drug resistance. While ARM
and its primary active metabolite dihydroartemisinin (DHA)
are rapidly eliminated, LUM is slowly cleared from the body.
ARM is the lipid-soluble methyl-ether derivative of DHA. It
is rapidly absorbed from the gastrointestinal tract, reaching
maximum concentrations (Cmax) within 2 h of administration
(6, 20, 24). ARM is metabolized to DHA with a reported
half-life of 0.8 to 4 h (6, 20, 24). DHA is formed through
cytochrome P450-mediated demethylation (25). The metabolite reaches Cmax in plasma at approximately the same time as
ARM, within 2 h of ARM administration (6, 20, 24). The
reported elimination half-life of DHA ranges from 0.4 to 12.5 h
(6, 24).
LUM is a fluorene derivative that was discovered at the
Academy of Military Medical Sciences in China. LUM is slowly
absorbed, with an estimated absorption half-life of 5.3 h. Cmax
is reached in approximately 10 h (6). The exposure to LUM
has been shown to increase up to 16-fold due to concomitant
administration of food or a fatty drink (2, 6a). The elimination
of LUM is slow, and the terminal half-life is 3 to 4 days in adult
malaria patients (6).
There is a dose dependency in the efficacy of the ARMLUM combination. The 28-day cure rate of the combination
has been associated with the body-weight-normalized dose (4).
* Corresponding author. Mailing address: Department of Pharmacology, University of Gothenburg, Box 431, SE-405 30 Gothenburg, Sweden. Phone: 46 31 786 34 12. Fax: 46 31 786 32 84. E-mail:
sofiafriberghietala@gmail.com.
䌤
Published ahead of print on 16 August 2010.
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Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, Sahlgrenska Academy at the University of Gothenburg,
Gothenburg, Sweden1; Infectious Diseases Unit, Department of Medicine, Karolinska University Hospital/Karolinska Institutet,
Solna, Sweden2; Division of Global Health, Department of Public Health Sciences, Karolinska Institutet, Solna, Sweden3;
Department of Parasitology, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania4;
Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand5; Nuffield Department of
Clinical Medicine, Centre for Tropical Medicine, University of Oxford, Oxford, United Kingdom6;
and Centre of Molecular and Structural Biomedicine, Institute of Biotechnology and
Bioengineering, University of Algarve, Faro, Portugal7
VOL. 54, 2010
ARTEMETHER-LUMEFANTRINE PHARMACOKINETICS IN CHILDREN
MATERIALS AND METHODS
Subjects and study design. The patient study was conducted at Fukayosi
Primary Health Care Centre, Bagamoyo District, Tanzania, as reported elsewhere (A. Mårtensson, A. M. Carlsson, B. Ngasala, S. Dahlström, C. Membi,
M. A. Musih, S. Omary, S. M. Montgomery, L. Rombo, S. Abdullah, Z. Premji,
J. P. Gil, et al., submitted for publication). Briefly, a total of 50 patients with the
following characteristics were included: ages 1 to 10 years, with microscopically
confirmed acute uncomplicated P. falciparum malaria with an asexual parasite
density of 2,000 to 200,000/l and fever (axillary temperature of ⱖ37.5°C) or a
history of fever within 24 h, and whose parent/legal guardian gave their written
informed consent. Exclusion criteria included a hemoglobin level of ⬍70 g/liter,
severe malnutrition, signs of severe malaria, or any other danger signs.
All patients were hospitalized. Follow-up duration was 72 h. A clinical assessment was performed at 0, 2, 4, 8, 16, 24, 36, 48, 60, and 72 h. This included a
physical examination and questions related to malaria-associated symptoms/
potential side effects of the study drug as well symptoms and/or signs of severe
malaria.
Weight-based doses of Coartem (20 mg artemether plus 120 mg lumefantrine),
manufactured by Novartis Pharma, Ltd., Switzerland, were administered at 0, 8,
24, 36, 48, and 60 h. Patients weighing 5 to 14 kg received one tablet/dose,
patients weighing 15 to 24 kg received two tablets/dose, and patients weighing 25
to 34 kg received three tablets/dose. Patients were randomly allocated either to
ingest each drug dose with a glass of full-fat (3.4%) cow’s milk (200 ml) (n ⫽ 25)
or to take the medicine with water (n ⫽ 25). Patients received oral iron supplementation at the day of discharge from the study.
Venous blood samples for drug concentration analyses and for determination
of parasitemia were obtained at 0, 2, 4, 8, 16, 24, 36, 48, 60, and 72 h following
treatment initiation. Whole blood (700 l) was collected in BD Microtainer
plasma tubes with lithium heparin and gel. The tubes were centrifuged according
to the manufacturer’s recommendations within 1 h and kept on ice for up to 24 h
after sampling.
An additional capillary blood sample for the assessment of parasitemia was
obtained 2 h prior to treatment initiation. Giemsa-stained thick blood films were
prepared and examined at the study site by experienced microscopists. The
number of parasites was calculated as the number of parasites seen against 500
leukocytes in the thick blood film, and parasite density was reported as asexual
parasites/l blood. Plasma for drug concentration analyses was stored at ⫺20°C
until transport on dry ice to Sweden and Thailand. Only patients whose parent/
guardian gave their written consent were included in the study.
Parasite density data from two previously published studies in asymptomatic
children in a similar coastal setting in Tanzania were included in the parasite
growth model (8, 8a). In one study, capillary samples were obtained every 6 h for
5 days (n ⫽ 1), and in the other study, daily samples were obtained for 14
consecutive days (n ⫽ 10). Parasite densities were determined in Giemsa-stained
thin films in 200 fields and read in random order. The included children remained asymptomatic throughout the studies.
The studies were approved by the National Institute for Medical Research,
Dar es Salaam, Tanzania, and by the Regional Ethics Committee, Stockholm,
Sweden.
Bioanalysis. Concentrations of ARM and DHA in plasma were measured by
high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/
MS) (10). In brief, plasma samples were purified by solid-phase extraction (Oasis
HLB elution plate; Waters, Milford, MA) and quantified by LC-MS/MS. Stable-isotope-labeled ARM and DHA were used as internal standards. ARM and
DHA were quantified using an API 5000 triple-quadrupole mass spectrometer
(Applied Biosystems/MDS SCIEX, Foster City, CA), with a TurboV ionization
source (TIS) interface operated in the positive-ion mode. Quantification was
performed using selected reaction monitoring (SRM) for the transitions m/z 316
to 163 and 320 to 163 for ARM and stable-isotope-labeled ARM, respectively,
and 302 to 163 and 307 to 166 for DHA and stable-isotope-labeled DHA,
respectively. The performance data for the assay during analysis of all samples,
expressed as the coefficients of variation (CV) (relative standard deviation
[RSD%]), for quality control samples were below 6% throughout the calibration
range. The lower limits of quantification (LLOQ) for the assay were 4.8 nM and
5.0 nM for ARM and DHA, respectively.
LUM concentrations were determined using a solid-phase extraction (SPE)
liquid chromatographic (LC) assay with UV detection as described by Annerberg
et al. (1a). Briefly, plasma was precipitated with acidic acetonitrile (containing, as
the internal standard, a hexyl analogue of desbutyl-lumefantrine; Novartis no.
TA 213/435/16). The precipitated plasma samples were buffered and purified
using a 3 M Empore C8-SD deep-well SPE 96-well plate (Presearch, Ltd.,
Hampshire, United Kingdom). The dried SPE eluates were reconstituted in 200
l, and 50 l was injected into a LaChrom Elite LC system (SB-CN column;
Zorbax, Inc.) with a mobile phase containing 0.01 M sodium perchlorate and
acetonitrile-phosphate buffer (pH 2; 0.1 M at 57:43 [vol/vol]). The CVs (RSD%)
during the analysis were below 5% for all QC concentrations. The lower limit of
quantification for the assay was 47 nM. The drug analyses were performed at the
Clinical Pharmacology Laboratory in the Faculty of Tropical Medicine, Bangkok,
Thailand.
PK-PD modeling. The population PK and PD of ARM, DHA, and LUM
were modeled using the nonlinear mixed effects approach as implemented in
NONMEM, version VI, level 1.1 (Icon Development Solutions, MD). The firstorder (FO) conditional estimation method with interaction (FOCE-I) was used
throughout the PK model-building process, while the FO method was used for
the PD model.
The individual post hoc parameter estimates from the PK models were introduced as fixed parameters in the PD model. The PD of ARM, DHA, and LUM
were described using a semimechanistic model of parasite development, incorporating features of previously presented models such as the spleen compartment for damaged but not yet cleared parasites, separate compartments for
visible and invisible parasites, and a sine function describing the oscillations in
visible parasitemia (9, 22, 23).
The drug effects were modeled sequentially, beginning with ARM and DHA,
as they have been shown to contribute most significantly to the immediate
decline in parasitemia (30). Compounds with highly similar PK profiles need to
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While the efficacy of the six-dose regimen currently used in
Tanzania is high, with PCR-corrected 28- or 42-day cure rates
of 92 to 98% in pediatric patients in Africa (7, 15, 18, 19, 21),
an earlier four-dose regimen resulted in reported 14-day cure
rates of 86% (10a). In a study of the correlation between
pharmacokinetics (PK) and pharmacodynamics (PD) of ARM
plus LUM in adult patients, increasing exposure to LUM was
associated with a greater chance of adequate clinical and parasitological cure but did not explain variability in parasite
clearance time (PCT) (6). In contrast, increasing areas under
the concentration-time curve (AUCs) of ARM and DHA both
caused a decrease in PCT but did not significantly influence the
cure rate.
A challenge when modeling the effect of antimalarials is to
adequately describe the dynamics of the parasite population in
the absence of drugs. A number of semimechanistic pharmacodynamic models based on the erythrocytic life cycle of P.
falciparum have been presented (9, 9a, 23). Common features
of these models are the description of the age stages of P.
falciparum and the division of the parasite population into
circulating and sequestered parasites. This approach allows for
the description of potentially stage-specific drug action as well
as renders estimates of the total, rather than visible, parasite
load.
To date, models of the dynamics of untreated parasitemia
are derived primarily from adult patients inoculated with P.
falciparum to treat neurosyphilis (12, 22). In this analysis, we
include multiple daily observations of parasitemias from
asymptomatic children from the same region as the symptomatic patients to obtain parameter estimates regarding the behavior of the parasite population.
The aim of this study was to present population pharmacokinetic models describing the kinetics of ARM, DHA, and
LUM in children treated for uncomplicated malaria and to
model the effect of ARM (DHA) and LUM concentrations on
parasite density in malaria patients. A secondary aim was to
evaluate the effect of concomitant milk intake on the modelestimated PK parameters of LUM in this pediatric population.
The patient study (no. NCT00336375) is registered at www
.Clinical.Trials.gov.
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ANTIMICROB. AGENTS CHEMOTHER.
be administered separately in order to determine the relative contribution of
each substance to the effect. The parallel concentration profiles for ARM and
DHA precluded the estimation of separate effect parameters for the two compounds. In vitro studies have suggested similar potencies of the two substances,
making the assumption of an equal effect slope relevant (1).
Homoscedastic and heteroscedastic error models were tested to describe residual error in concentration and in parasitemias. Variability was estimated as
interindividual variability (IIV) and as interoccasion variability (IOV). Possible
effects of covariates milk intake, group allocation, dose number, age, weight,
gender, parasitemia, fever, and concomitant administration of paracetamol (n ⫽
23) on fixed effects of the PK and PD models were identified using the general
additive method (GAM) as implemented in Xpose, version 4.0 (14).
The likelihood ratio test (LRT)—i.e., the difference in the value of the objective function (OFV)—was used to discriminate between nested models. The
OFV is essentially equal to ⫺2 ⫻ log likelihood of the data, and the difference
in OFV is approximately 2 distributed (3). Parameters producing a decrease in
the OFV exceeding 3.8, indicating a better fit at the 0.05 level of significance,
were retained in the full model. Backward deletion of a covariate from the full
model was based on the difference in OFV being less than 6.6 (at the 0.01 level
of significance) as well as failure of the covariate to explain interindividual
variability.
The uncertainty in PK parameter estimates, expressed as the 95% confidence
interval (95% CI), was evaluated from 1,000 nonparametric bootstrap samples.
Bootstrap analyses were performed in PsN (17). The predictive performances of
the final models were assessed with visual predictive checks as described by
Holford (11).
RESULTS
Demographics and safety. A total of 50 children (19 male
and 31 female) were enrolled. Mean age and weight were 4
years (range, 1 to 10 years) and 14 kg (range, 8 to 30 kg),
respectively. No death or serious adverse event occurred.
Forty-nine children completed the study. All had adequate clinical and parasitological response at 72 h. The remaining patient
was withdrawn after 48 h due to the parents’ request. All data
collected from this child were included in the analysis until exit
of the trial. Patients allocated to receive milk with each dose
completed the 200 ml on 43% of occasions. During the 72 h
follow-up, two patients received antibiotics. One child was
treated with cloxacillin from 48 h due to a skin/soft tissue
infection related to the intravenous (i.v.) cannula. The other
child received amoxicillin from 60 h after having developed
high fever of unknown origin. The latter child cleared parasitemia by 36 h.
Totals of 397 ARM, 400 DHA, and 423 LUM plasma concentrations obtained from the 50 patients were included in the
analysis (Fig. 1 and 2). Nine ARM, 21 DHA, and 19 LUM
concentrations below the limit of detection (LOD) were excluded. Twelve ARM and 47 DHA concentrations below the
LLOQ were set to 1⁄2 LLOQ (2 and 3 nM for ARM and DHA,
respectively).
A total of 356 peripheral parasite counts from the 50 patients (Fig. 3) and 104 from 11 asymptomatic subjects were
included in the PD model. Undetectable parasitemias were
excluded.
Pharmacokinetics of artemether, dihydroartemisinin, and
lumefantrine. There was no a priori information on the absolute bioavailability of ARM or the fraction eliminated through
metabolism to DHA, and it was assumed that all ARM is
eliminated via this pathway. Fixing the bioavailability of DHA
to 1 also rendered the metabolite model identifiable.
The distribution of ARM was best described by a two-compartment model with first-order absorption. The parameter
estimates for the ARM/DHA PK model are presented in Table
1. There was very little information on the rate of absorption in
the data, and the absorption rate constant was fixed to 1/h in
the final model. Altering the rate of absorption between 0.2
and 2/h did not significantly influence the remaining parameter
estimates.
There was a trend toward a reduction in the trough concentrations of ARM and DHA, as illustrated in Fig. 4. This time
dependency was described by a model including occasion (occ)
as a covariate on clearance (CL)/FARM: CL/FARM ⫽ 1 ⫻ [1 ⫹
2 (occ ⫺ 1)] ⫻ exp, where 1 is the typical value of CL/FARM
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FIG. 1. Artemether (solid lines) and dihydroartemisinin (dashed lines) concentrations over time during treatment with weight-based doses of
artemether and lumefantrine (Coartem) administered at 0, 8, 24, 36, 48, and 60 h. Lines are interpolated between observations.
VOL. 54, 2010
ARTEMETHER-LUMEFANTRINE PHARMACOKINETICS IN CHILDREN
4783
for the first dose and 2 is the fractional change in CL/FARM
with each occasion (occ). The inclusion of occasion as a covariate on CL/FARM resulted in ⌬OFV ⫽ ⫺167. The performance of the PK model is illustrated in Fig. 5.
The DHA concentrations were best illustrated by a covariate-free one-compartment distribution model.
The PK of LUM was best described by a one-compartment
model with a combined proportional and additive residual
error. The introduction of an absorption lag time significantly
improved the model (⌬OFV ⫽ ⫺96).
The inclusion of milk intake as a covariate on the PK parameters of LUM did not explain the variability in LUM pharmacokinetics and did not result in an improvement of the
model. The population pharmacokinetic parameters for LUM
are presented in Table 2.
Pharmacodynamic model. The PD model, illustrated in Fig.
6, is initiated by the introduction of a certain parasitemia (Pinit)
into the compartment denoted by tiny rings, PTR, representing
parasites in the earliest ring stage. The intraerythrocytic stage
of the infection was assumed to have started 10 cycles prior to
FIG. 3. Observed parasitemia (solid lines) and body temperature (dashed lines) over time in pediatric patients during treatment with
weight-based doses of artemether and lumefantrine administered at 0, 8, 24, 36, 48, and 60 h. Lines are interpolated between observations.
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FIG. 2. Observed lumefantrine concentrations over time during treatment with weight-based doses of artemether and lumefantrine (Coartem)
administered at 0, 8, 24, 36, 48, and 60 h. Lines are interpolated between observations.
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TABLE 1. Population pharmacokinetic parameters for artemether and dihydroartemisinin in pediatric patients with uncomplicated
falciparum malaria during a 3-day treatment with six weight-based doses of artemether and lumefantrine (Coartem)
Estimate (95% CI)a
IIV, % CV
(95% CI)a
ka (per h)
CL/FARM (liters/h/kg)
1
2
Vc/FARM (liters/kg)
QARM (liters/kg)
Vp/FARM (liters/kg)
CL/FDHA (liters/h/kg)
V/FDHA (liters/kg)
prop ARM (%)
add ARM (nM)
prop DHA (%)
add DHA (nM)
1 (fixed)
1 ⫻ 关1 ⫹ 2 ⫻ (occ ⫺ 1)兴
2.6 (1.5–2.6)
0.57 (0.39–0.75)
5.2 (3.5–7.1)
1.4 (1.1–1.8)
41.4 (29.0–58.1)
6.8 (5.8–8.0)
3.7 (2.3–8.7)
61 (54–67)
2 (fixed)
82 (73–90)
3 (fixed)
NEb
41 (37–50)
NE
NE
NE
NE
NE
47 (35–57)
NE
a
b
Parameter description
Absorption rate
Oral clearance
Typical value of CL/FARM
Fractional change in CL/FARM with dose
Oral volume of distribution of the central compartment
Intercompartment clearance
Oral volume of distribution of the peripheral compartment
Oral metabolite clearance
Oral metabolite volume of distribution
Proportional residual error
Additive residual error
Proportional residual error
Additive residual error
95% CI from 1,000 nonparametric bootstrap data sets.
NE, not estimated.
the first sample in asymptomatic individuals, corresponding to
a time when the model infection is at steady state. The number
of cycles passed since model initiation was fixed to 4 in patients. The parameter estimates are reported in Table 3.
The parasites mature through the erythrocytic stages: tiny
rings (PTR), small rings (PSR), large rings (PLR), and mature
trophozoites/schizonts (PMT). Parasites that are killed or injured due to drug action were assumed to remain in the blood
until removed by the spleen or macrophages. These parasites
are represented by the compartment denoted Pspleen. The inclusion of the spleen compartment produced a significant drop
in the OFV (⫺61). The elimination rate from the spleen compartment, ks, was fixed to that described by Gordi et al. (9).
Growth was modeled as a multiplication rate (REPL) from
schizonts to tiny rings. Only the parasites in the ring stages and
those injured by drugs were assumed to be visible through
microscopy. The mean time to complete an intraerythrocytic
cycle (MTT) was estimated to be 48.5 h, and the mean rate of
transfer between visible compartments, kVPT, was modeled
as 3/VPT, where VPT was estimated to 15.5 h. The mean
time for transfer from the sequestered state, kIPT, was fixed
to 1/(MTT ⫺ VPT).
To account for fluctuations in the parasite population over
time, a sine function was applied to the input to the PTR
compartment. The amplitude, A, of the sine function varies
with the synchronicity in the parasite population. The sine
function produced a significant drop in the OFV (⫺42) in
asymptomatic individuals but was not supported by the sparse
data in symptomatic patients. The wavelength of the sine function was fixed to the MTT.
The growth rates of the parasite population differ between
patients and asymptomatic individuals. In asymptomatic children, the parasitemia was approximated by a steady state and
the REPLa was fixed to 1. Patients experience a net growth of
parasitemia prior to treatment, and the REPLp was estimated
to 4.
The effects of ARM and DHA plasma concentrations were
modeled on all developmental stages as kARM ⫽ SARM/DHA ⫻
log [ARM] and kDHA ⫽ SARM/DHA ⫻ log [DHA], where
SARM/DHA is the slope of both the artemether and DHA concentration-effect correlations.
The introduction of an effect of LUM did not significantly
improve the model fit, and the parameter estimates for LUM
effect could not be estimated.
The rate of change of parasitemia in the different compartments was described by equations 1 to 5. The fit of the model
is illustrated in a visual predictive check in Fig. 7:
FIG. 4. Trough concentrations of artemether and dihydroartemisinin (12 h postdose) during treatment with weight-based doses of artemether
and lumefantrine (Coartem) administered at 0, 8, 24, 36, 48, and 60 h. The right panel shows the dihydroartemisinin/artemether ratio over time.
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Parameter
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ARTEMETHER-LUMEFANTRINE PHARMACOKINETICS IN CHILDREN
4785
FIG. 5. Visual predictive checks of the pharmacokinetic models. The open circles are the observed concentrations. The shaded area represents
the 95% prediction interval, calculated from simulated observations from 1,000 studies.
⫻ SIN
冉
2兿
⫻t
MTT
冊冊
⫺ PTR 共kVPT ⫹ kARM ⫹ kDHA兲
(1)
dPSR
⫽ kVPT ⫻ PTR ⫺ PSR 共kVPT ⫹ kARM ⫹ kDHA兲
dt
(2)
dPLR
⫽ kVPT ⫻ PSR ⫺ PLR 共kVPT ⫹ kARM ⫹ kDHA兲
dt
(3)
冉
冉
dPMT
⫽ kVPT ⫻ PLR ⫺ PMT kIPT ⫻ 1 ⫹ A
dt
⫻ SIN
冉
2兿
⫻t
MTT
冊冊
⫹ kARM ⫹ kDHA
冊
(4)
dPspleen
⫽ kARM 共PTR ⫹ PSR ⫹ PLR ⫹ PMT兲 ⫹ kDHA 共PTR ⫹ PSR
dt
while a rough approximation of the complex interplay between
malaria parasite and the human host, adequately described the
early effect of ARM and DHA concentrations on the parasite
density in malaria patients (Fig. 7). To gain a better understanding of the parasite dynamics, stage-specific parasite
counts should be obtained both prior to and during drug treatment.
The PK of ARM and DHA following oral administration of
ARM were described by a three-compartment model, consisting of two distribution compartments for the parent compound
and one for DHA. Model-estimated CL/FARM increased more
than 3-fold from dose 1 to dose 6. Previous studies have indicated a time dependency in the ARM kinetics (6, 26, 27). In a
study of the kinetics of ARM in Chinese adults, the Cmax
following the last dose in a 2-day twice-a-day (BID) treatment
was one-third of the Cmax after dose 1 (26). The decreased
Cmax and/or AUC of ARM with consecutive doses have been
attributed to enzyme induction (26, 27).
The introduction of IOV in the bioavailability of ARM resulted in a significant reduction of the OFV; however the data
(5)
⫹ PLR ⫹ PMT兲 ⫺ kspleen ⫻ Pspleen
DISCUSSION
Data describing the parasitemia in pediatric patients as well
as in untreated, asymptomatic children from a nearby geographic region in Tanzania were analyzed in order to describe
the within-host parasite dynamics in the presence and absence
of antimalarial drugs. The proposed semimechanistic model,
TABLE 2. Population pharmacokinetic parameters for lumefantrine
in pediatric patients with uncomplicated falciparum malaria during
a 3-day treatment with six weight-based doses of artemether
and lumefantrine (Coartem)
Parameter
Estimate
(95% CI)a
IIV, % CV
(95% CI)a
Lag
1.92 (1.86–1.96)
NEb
ka (per h)
0.82 (0.45–1.61) 156 (126–190)
CL/F (ml/h/kg) 77 (52–105)
NE
V/F (liters/kg)
8.9 (6.8–11.7)
82 (66–102)
prop (%)
46 (41–52)
add (nM)
43 (19–66)
a
Parameter description
Absorption lag time
Absorption rate
Oral clearance
Oral volume of distribution
Proportional residual error
Additive residual error
95% CI from 1,000 nonparametric bootstrap data sets.
b
NE, not estimated.
FIG. 6. Pharmacodynamic model based on the blood stages of P.
falciparum. Compartments within the dashed rectangle represent parasites visible in peripheral blood.
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冉
dPTR
⫽ Pinit ⫹ kIPT ⫻ PMT ⫻ REPL ⫻ 1 ⫹ A
dt
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TABLE 3. Parameter estimates for the pharmacodynamic model of the effects of artemether and dihydroartemisinin
in pediatric patients with uncomplicated malaria
Parameter
Estimate (95% CI)a
IIV, % CV (95% CI)a
Parameter description
119.2 (98–161)
VPT (h)
15.5 (9.7–21.5)
NEb
Mean visible parasite transit time
MTT (h)
48.5 (48.0–49.1)
NE
Mean parasite transit time
Patients
REPLp
Ap
kspleen
4 (3.6–4.4)
0 (fixed)
0.26 (fixed)c
NE
NE
NE
Replication factor
Amplitude of oscillations
Rate of elimination of dead or injured parasites
Asymptomatic children
REPLa
Aa
1 (fixed)
1.01 (0.71–1.37)
NE
NE
Replication factor
Amplitude of oscillations
0.073 (0.049–0.423)
138 (125–258)
NE
Slope of the ARM and DHA effect
Residual error
Drug effects
SARM/DHA
(%)
Initial parasitemia
a
95% CI from 1,000 nonparametric bootstrap data sets.
NE, not estimated.
c
The estimate was fixed to a literature value from Gordi et al. (9).
b
did not allow the determination of this parameter with adequate precision. A similarly variable absorption was described
by Ezzet and colleagues, who found a significantly elevated
bioavailability of both ARM and DHA with dose 3 compared
to doses 1, 2, and 4 (6).
The pharmacokinetics of LUM during the first 3 days of
treatment were adequately described by a one-compartment
distribution model with first-order absorption. The predicted
median LUM concentration on day 3, calculated from 1,000
realizations of the pharmacokinetic model under the study
conditions, came to 9.3 M and was similar to the median of
11.3 M reported by Checci and colleagues from pediatric
patients in Uganda (4). The typical value of CL/F was estimated to 77 ml/h/kg, which is within the range of 40 to 200
ml/h/kg reported in adults (6, 16).
Earlier pharmacokinetic models of LUM have used a twocompartment distribution model with a slow terminal elimina-
FIG. 7. Visual predictive check of the pharmacodynamic model.
The open circles are the observed log-transformed parasitemias. The
shaded area represents the 95% prediction interval, calculated from
simulated observations from 1,000 studies, and the solid lines represent the simulated median parasitemia.
tion half-life of 3 to 4 days. The model estimated elimination
half-life in our study was approximately 2 days. The trend
toward underestimation of the LUM concentrations on day 3
indicates that a two-compartment model with a slower terminal phase may have provided a better description of the elimination. A two-compartment model was investigated during the
model-building process but did not result in improved model
performance. The shorter half-life in the present study may be
an effect of the relatively short duration of sampling.
There was no significant impact of milk intake on the pharmacokinetics of LUM. A possible explanation for the discrepancy in the results compared to the previous report by Ashley
and colleagues (2) is the fact that the investigated patients
were unable to comply with the milk intake in almost 50% of
administrations. The resulting number of doses actually administered with an adequate amount of milk may have been too
small to allow the detection of a difference.
The within-host P. falciparum dynamics are complex and
include stages of variable drug sensitivity as well as sequestering stages not detectable in peripheral blood (8, 8a, 28, 29).
Models describing the in vivo dynamics of untreated P. falciparum infection have primarily been developed from data from
adult, nonimmune, patients inoculated with malaria to treat
neurosyphilis (12, 22). The proposed PD model is based on
data from both symptomatic and asymptomatic children in
rural settings in Tanzania. The number of compartments describing the visible parasite stages was chosen based on the
feasible resolution in parasite data using microscopy: tiny
rings, small rings, and immature trophozoites (8). The influence of polyclonal infections, semi-immunity, fever, and
other clinical symptoms of malaria on parasite population
dynamics in vivo need to be investigated in further studies. In
the proposed model, we assumed that the mean transit times
were equal in asymptomatic and symptomatic patients and that
the rates of development through the parasite stages were the
same across patients and asymptomatic carriers.
Downloaded from http://aac.asm.org/ on July 22, 2019 by guest
1 (fixed)
Pinit (parasites/l)
VOL. 54, 2010
ARTEMETHER-LUMEFANTRINE PHARMACOKINETICS IN CHILDREN
ACKNOWLEDGMENTS
Financial support was received from Sida (grant SWE-2005 017).
Niklas Lindegårdh and Anna Annerberg are funded by the Wellcome
Trust-Mahidol University-Oxford Tropical Medicine Research Programme (077166/Z/05/Z), supported by the Wellcome Trust of Great
Britain.
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The model allows for variation in the degree of synchronicity
in the infecting parasite population as studies have suggested a
difference between the dynamics of parasites in symptomatic
and asymptomatic patients. Parasite populations in asymptomatic individuals appear relatively synchronized, resulting in a
distinct cyclical pattern in peripheral parasitemia (8, 8a, 13a).
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late failures and thus to accurately model the LUM effect.
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kinetics described in adults was evident also in this population.
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