Download Efficacy and Safety of Dihydroartemisinin

MAJOR ARTICLE
Efficacy and Safety of DihydroartemisininPiperaquine (Artekin) in Cambodian Children
and Adults with Uncomplicated
Falciparum Malaria
Mey Bouth Denis,1,2 Timothy M. E. Davis,4 Sean Hewitt,1 Sandra Incardona,3 Khim Nimol,3 Thierry Fandeur,3
Yi Poravuth,2 Chiv Lim,2 and Doung Socheat2
1
European Commission, Cambodia Malaria Control Programme, 2National Malaria Centre, and 3Institut Pasteur du Cambodge, Phnom Penh,
Cambodia; and 4University of Western Australia, Department of Medicine, Fremantle Hospital, Fremantle, Western Australia, Australia
The safety and efficacy of a novel combination of dihydroartemisinin (DHA) and piperaquine, Artekin (Holleykin Pharmaceuticals), were assessed in 106 patients (76 children and 30 adults) with uncomplicated falciparum malaria from 2 remote areas in Cambodia. Age-based doses were given at 0, 8, 24, and 32 h. Mean
total DHA and piperaquine doses were 9.1 and 73.9 mg/kg, respectively, for children and 6.6 and 52.9 mg/kg
for adults. All patients became aparasitemic within 72 h. Excluding the results for 1 child who died on day
4, there was a 96.9% 28-day cure rate (98.6% in children and 92.3% in adults). Patients who had recrudescent
infection received low doses of Artekin. Side effects were reported by 22 patients (21%) but did not necessitate
premature cessation of therapy. Although Artekin is a promising and inexpensive option for antimalarial
therapy, further efficacy and pharmacokinetic studies are needed, especially for its use in children.
Artemisinin derivatives are rapidly effective antimalarial
drugs [1]. Their main drawback is that conventional
courses (3–5 days) are associated with a high rate of
recrudescence, typically 125% [1, 2]. In addition, there
is the risk that parasite resistance will develop when
antimalarial drugs are used alone [3]. Because artemisinin derivatives are now the first-line treatment for
multidrug-resistant falciparum malaria in many tropical countries, the appearance of artemisinin-resistant
Plasmodium falciparum would have serious implications. The development of suitable combinations of an
Received 16 May 2002; accepted 15 August 2002; electronically published 2
December 2002.
Financial support: European Commission; Cambodia Malaria Control Programme;
Institut Pasteur du Cambodge.
Reprints or correspondence: Dr. T. M. E. Davis, University of Western Australia,
Dept. of Medicine, Fremantle Hospital, PO Box 480, Fremantle, Western Australia
6959, Australia ([email protected]).
Clinical Infectious Diseases 2002; 35:1469–76
2002 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2002/3512-0003$15.00
artemisinin compound with a second drug is therefore
a priority [4].
Recent data on the use of sequential artesunate and
mefloquine treatment suggest that this approach cures
the individual and safeguards against resistance [5]. The
choice of a suitable partner for the artemisinins has,
however, proved problematic. Mefloquine can have unpleasant adverse effects, especially neurological effects
[6], and is expensive. Atovaquone-proguanil is more
costly than mefloquine. Pyrimethamine-sulfadoxine and
chloroquine can be unsuitable in patients infected with
parasites with high-grade antimalarial resistance. Other
candidates are being developed, including piperaquine,
pyronaridine, and naphthoquinone [4, 7].
Piperaquine (1,3-bis[1-(7-chloro-4quinolyl)-4-piperazinyl]-propane) is a member of the 4-aminoquinoline group that includes chloroquine. The first human studies of piperaquine were carried out in the
1970s and involved its prophylactic use in several
thousand adults and children [8]. Piperaquine proved
to be effective and well tolerated, and no cross-resisEfficacy of Dihydroartemisinin-Piperaquine • CID 2002:35 (15 December) • 1469
tance with chloroquine was observed [8]. More recently, piperaquine has been used as part of short-course artemisininbased combination oral therapies designed to have a high cure
rate, to have few side effects, and to reduce malaria transmission. The first such combination was China-Vietnam 8 (CV8;
Tonghe Pharmaceutical), which included dihydroartemisinin
(DHA), piperaquine, primaquine, and trimethoprim. Although
CV8 seems to be effective [4, 9], the role of trimethoprim is
questionable because of its weak antimalarial activity. In addition, the high prevalence of glucose-6-phosphate dehydrogenase deficiency among Asians means that primaquine-induced
RBC hemolysis is of concern. The total DHA dose in a course
of CV8 given under the manufacturer’s recommendations (80
mg over the course of 2 days) was lower than that given in the
form of DHA monotherapy for acute malaria (480 mg over
the course of 7 days) [10]. The piperaquine-based formulation
most recently made available, Artekin (Holleykin Pharmaceuticals), contains neither trimethoprim nor primaquine, and its
DHA content is higher than that of CV8. Although Artekin is
the simplest and least expensive drug of the CV8 group, there
are no published safety and efficacy data for its use in humans.
We therefore carried out safety and efficacy studies of the use
of Artekin to treat Cambodian children and adults with uncomplicated falciparum malaria.
PATIENTS AND METHODS
Study sites. Patients were recruited from the Anlong Veng
district, Oddor Meanchey Province, in northwestern Cambodia
and from the Snoul district, Kratie Province, in eastern Cambodia between October 2001 and February 2002. Both areas
are covered in secondary mixed deciduous mosaic forest, and
Anopheles dirus mosquitoes are thought to be the primary malaria vector. Transmission is seasonal, peaking in October at the
end of the rains. In Anlong Veng, most patients were recruited
from roadside settlements newly established by economic migrants from areas of central Cambodia in which malaria is not
endemic. There is limited immunity to malaria in these communities. In Snoul, patients were from long-established forestfringe communities in which the level of transmission is greater
(between meso- and hyperendemic) and in which the rate of
adult immunity is relatively high. Both districts are now served
by health centers, but access is difficult, and reliance on the
private health sector is high. Under these circumstances, patients often receive inappropriate or incomplete antimalarial
therapy. Most patients recruited in Anlong Veng were detected
through routine outreach, and most patients in Snoul were
recruited through arranged village visits.
Eligibility and recruitment of subjects. Patients with a
recent history of fever were screened for falciparum malaria by
use of Paracheck-Pf (Orchid Biomedical Systems). All patients
with positive results who had no clinical evidence of complications were transferred to the health center within 3 h for
further assessment, including blood film microscopic examination. Transferred patients were eligible to participate in the
study if they were 1–60 years old and had uncomplicated falciparum malaria with a parasite density 11000 parasites/mL of
whole blood. Informed consent was obtained from each patient
or, in the case of those !18 years old, from a parent or guardian.
Exclusion criteria included mixed malarial infection, concomitant illness, pregnancy, and previous antimalarial therapy (receipt of quinine or an artemisinin drug within 7 days of study
entry, of a 4-aminoquinoline within 14 days, or of pyrimethamine, sulfonamide, or both within 28 days). The study protocol was approved by and the research was performed in accordance with the ethical standards of the Ministry of Health,
Phnom Penh, Cambodia, and in accordance with the human
experimentation guidelines of the authors’ institutions.
Clinical procedures. Clinical procedures and follow-up
were selected on the basis of the World Health Organization’s
28-day test [11]. All recruits were admitted to the health care
center. A clinical assessment was performed, and blood was
drawn to assess hematocrit levels, leukocyte counts, and plasma
glucose concentrations. A blood spot was taken on Whatman
Table 1. Recommended Artekin (dihydroartemisinin [DHA]-piperaquine) dosing schedule, by
patient age, for treatment of malaria.
Dose
Patient age,
years
Formulation
No. of
granules
or tabletsa
b
Total, mg
DHA
Piperaquine
Based on body weight,
b
mean mg/kg SD
DHA
Piperaquine
2–3
Granules (sachet)
1
60
480
8.1 2.2
64.8 17.3
4–6
Granules (sachet)
1.5
90
720
7.9 3.5
63.2 28.0
7–10
Tablet
1
160
1280
10.1 1.9
81.2 15.6
11–15
Tablet
1.5
240
1920
10.1 1.8
80.6 14.3
⭓16
Tablet
2
320
2560
6.6 1.1
52.9 8.5
a
b
For each of 4 administrations.
Total of 4 administrations.
1470 • CID 2002:35 (15 December) • Denis et al.
Table 2. Characteristics of Cambodian patients included in a study of the use of Artekin (dihydroartemisinin-piperaquine)
to treat malaria, at the time of admission to the study, classified by study site and age group.
Anlong Veng
Snoul
Characteristic
No. of patients
Children
Adults
Children
Adults
55
6
21
24
Age, mean years SD
6.0 2.3
36.8 13.2
7.5 3.3
32.0 12.7
Male sex, % of subjects
62
33
52
79
Body weight, mean kg SD
13.8 4.4
45.0 5.2
16.1 6.0
50.1 8.8
Oral temperature,
mean C SD
38.4 0.8
37.9 0.7
38.6 0.7
38.5 0.8
Venous hematocrit,
mean % SD
27.4 4.6a
36.8 4.5
22.9 6.2
Parasitemia, geometric mean
parasites/mL (range)
Plasma glucose level,
mean mM SD
a
a
32.6 8.0
9820 (1010–137,930)
5080 (1000–105,260)
13,350 (1000–150,000)
18,400 (1920–150,000)
4.7 1.0a
5.8 0.8
5.6 1.2
6.0 1.3
P ! .001, vs. all other groups.
filter paper for molecular studies. Each patient received DHApiperaquine at 0, 6, 24, and 32 h in the dose recommended by
the manufacturer (table 1). All treatments were supervised, and
patients were observed for 11 h after the first dose. Patients
who vomited during this period required a second course of
treatment, with artesunate and mefloquine (as recommended
under Cambodian national treatment guidelines), and were excluded from the study.
The temperature of each patient was measured orally every
6 h, and pulse, blood pressure, and blood smear results were
recorded daily for the first 3 days. At each daily assessment,
symptoms were recorded on standard forms and graded (mild,
moderate, or severe). Patients were hospitalized for 13 days if
it was clinically indicated or if blood smear slides continued
to indicate the presence of parasites. Additional blood films
were taken daily until parasite clearance was confirmed by 2
consecutive negative results. If gametocytes were present, their
density was quantified.
All patients were asked to return on days 7, 14, 21, 28, 35,
42, 49, and 56 or if they became symptomatic. To maximize
the completeness and accuracy of follow-up data, outreach
teams visited the patients in their villages if the patients could
not come to the health center. In addition, photographic identification, which included issuing a unique code each week, was
used at every follow-up assessment. A blood smear was obtained, and a clinical assessment was performed. A second
blood spot was obtained from patients whose slides were positive for P. falciparum, and those patients were re-treated with
artesunate and mefloquine. Patients infected with Plasmodium
vivax received chloroquine.
Parasite resistance was categorized as RI (prompt and sustained asexual parasite clearance through day 7 but reappearance before day 28), RII (175% decrease in asexual parasitemia
by 48 h, but not clearance, and persistent parasitemia on day
7), or RIII (!25% decrease in asexual parasitemia by 48 h and
persistent parasitemia on day 7); in all other cases, a sensitive
response was recorded [11]. Clinical and parasitological data
were used to categorize therapeutic response as “early treatment
failure” (within the first 3 days), “late treatment failure” (between 4 and 14 days), or “adequate clinical response” [12].
Laboratory methods. Giemsa-stained thick blood smears
were examined by a skilled microscopist. At least 100 fields
were examined at ⫻1000 magnification before a slide was considered to be negative. For positive slides, parasite density was
calculated from the number of asexual forms per 1000 leukocytes and from the whole-blood leukocyte count. Venous
hematocrit levels were measured via microcentrifuge, and
plasma glucose concentrations were measured at the bedside
(Exactech; Medisense).
To differentiate between recrudescence and reinfection, parasite DNA extracted from blood spots obtained during both
primary and recrudescent infections was analyzed by PCR amplification of the highly polymorphic genes MSA1, MSA2,
GLURP, and TRAP and the multigene family pf60.1. Because
of the high sensitivity of PCR, the genetic diversity of parasite
strains, and the wide range of markers used, it was assumed
that genetically different parasite strains could be accurately
differentiated [13–17]. DNA was extracted from blood spots
with the QIAamp DNA Mini Kit (Qiagen) [18] and amplified
under standard reaction conditions with specific amplification
primers and programs selected depending on the gene of interest. MSA1 block 2, MSA2, and TRAP were amplified as described elsewhere [14]. The MSA1 PCR products were subtyped
by separate nested PCRs, using primers specific to the allelic
families Mad20, K1, and Ro33. Nested PCR was performed as
described elsewhere [15]. The R2 repeat region of GLURP was
Efficacy of Dihydroartemisinin-Piperaquine • CID 2002:35 (15 December) • 1471
Table 3. Outcome variables of interest among Cambodian patients included in a
study of the use of Artekin (dihydroartemisinin-piperaquine) to treat malaria, classified by study site and age group.
Snoul
Outcome variable
Parasite clearance time,
median days (range)
Fever clearance time,
median h (range)
Children
Anlong Veng
Adults
Children
Adults
2 (1–3)
2 (1–3)
2 (1–2)
2 (1–3)
24 (0–72)
18 (6–32)
24 (12–54)
21 (12–48)
Recrudescence within 28
days, n/N (%)
1/53 (1.9)
0/5 (0)
0/18 (0)
2/21 (9.5)a
Reinfection within 28 days,
n/N (%)
0/53 (0)
0/5 (0)
1/18 (5.5)b
0/21 (0)
Recrudescence between 28
and 56 days, n/N (%)
1/50 (2.0)
0/5 (0)
0/17 (0)
0/17 (0)
Reinfection between 28
and 56 days, n/N (%)
5/50 (10.0)c
0/5 (0)
0/17 (0)
0/17 (0)
a
b
c
Plasmodium malariae was also identified in 1 of these 2 cases.
Plasmodium vivax was also identified.
Excludes 10 patients (20%) who re-presented with P. vivax.
amplified with the primers GLURP-E and GLURP-F [15]. PCR
amplification of pf60.1 was also performed as described elsewhere [16]. Restriction fragment–length polymorphism (RFLP)
methods were used to further analyze MSA1 and MSA2 PCR
products [17] and the TRAP gene [14]. Size polymorphisms
were analyzed by agarose gel electrophoresis.
Statistical analysis. Statistical analysis was performed using SPSS for Windows. Two-sample comparisons were made
using Student’s t test. Multiple comparisons were made using
analysis of variance and the Scheffé post hoc test. All tests were
2-tailed.
RESULTS
Patient characteristics. We recruited 76 children aged 1–14
years and 30 adults (table 2). Children had significantly lower
hematocrit levels than did adults at each study site. Plasma
glucose concentrations were significantly lower among children
from Snoul than in the other 3 groups.
Clinical course. All patients achieved initial parasite clearance within 72 h after the first dose, and fever clearance times
were short (table 3). Only 1 patient remained hospitalized for
13 days. This patient, an 8-year-old boy from Anlong Veng,
died on the fourth day. At admission, the patient’s body weight
was 16 kg; pulse, 120 beats/min; blood pressure, 100/60 mm
Hg; oral temperature, 39.5C; hematocrit level, 27.0%; WBC
count, 7400 ⫻ 10 9 cells/L; and plasma glucose concentration,
7.8 mM. All of these values were within the ranges for the other
children of his age from Anlong Veng who were included in
the study. The patient’s level of parasitemia was 7200 parasites/
mL, and young ring forms were the predominant developmental
1472 • CID 2002:35 (15 December) • Denis et al.
stage. He received a full course of Artekin without incident,
and the results of examination of a blood slide were negative
on the second day. Although the patient remained aparasitemic
and was eating, drinking, and urinating, he had persistent fever.
On the fourth day, he became hypotensive, his consciousness
level deteriorated, and he died, despite attempts at resuscitation.
Because of the limited facilities available, no bacteriological
investigations were possible. A postmortem examination was
not performed.
A 28-day follow-up period was completed for 39 (89%) of
44 assessable patients from Anlong Veng and 58 (95%) of 61
patients from Snoul (92% of the entire subject group). Complete outcome data at 56 days after study entry, excluding data
from the patient who died and including patients who experienced recrudescence and reinfection, were available for 37
(84%) of 44 patients from Anlong Veng and 56 (92%) of 61
patients from Snoul (89% of the entire subject group). The
results of follow-up assessments are summarized in table 3.
Although there were no early or late treatment failures in the
first 14 days, fever and parasitemia returned in 4 subjects at
14–28 days and in 6 more subjects at 28–56 days.
For 2 adults from Anlong Veng, PCR products and RFLP
profiles found before treatment were identical to those found
after treatment (table 4) and were therefore considered to indicate treatment failure resulting from infection with parasites
with RI resistance. One child from Snoul also had treatment
failure resulting from infection with parasites with RI resistance.
Another child from Snoul experienced recrudescence between
day 28 and day 56. In all other patients in whom P. falciparum
parasitemia reappeared, analysis of at least 1 gene confirmed
differences in PCR or nested PCR products or in RFLP profiles,
Table 4. PCR analysis of paired blood spots obtained during primary and recrudescent infection from Cambodian patients included
in a study of the use of Artekin (dihydroartemisinin-piperaquine) to treat malaria.
Size of restriction fragments
for indicated gene and enzyme, bp
Size of PCR products
for indicated gene, bp
Location, patient,
study day
GLURP
MSA1
(subtype)
MSA2
pf60.1
TRAP
MSA1/RsaI
MSA2/RsaI
TRAP/TaqI
Interpretation
a
380/360
—
—
300/280
—
—
a
380/360
—
—
300/280
—
Recrudescence
a
—
—
—
300/280
—
a
380/360
—
—
300/280
—
a
350/330
—
—
300/230
—
—
a
350/330
—
—
300/230
—
Recrudescence
b
—
690
80/50/40
360/250/120/70/50 305/205/180
b
—
690
80/50/40
360/250/120/60
a
—
—
—
—
—
a
—
—
—
—
—
a
—
—
130/120/110/40 280/140/80
—
a
—
—
200/115/100/40 300/280
—
Anlong Veng
1
0
1250
180 (Mad20)
620
21
1250
180 (Mad20)
620
0
1180
180 (Mad20)
700
27
1180
150 (K1)
700
0
1180
150 (K1)
700
28
1180
150 (K1)
700
2
—
Reinfection
3
Snoul
c
1
0
1350
170 (K1)
900
28
1350
170 (K1)
900
0
1400
—
520
35
1300
—
540
305/205/180
—
Recrudescence
2
—
Reinfection
3
0
1300
400
615
49
1300
440/410
620
0
1300
—
—
Reinfection
4
a
705/620/520
—
—
—
—
—
—
—
—
—
—
630/520
—
700
—
350/240/140
305/250/225/215/205/180
a
—
700
—
350
305/215/180
a
—
—
—
—
—
a
—
—
—
—
—
a
—
—
—
—
—
a
—
—
—
—
—
a
49
1300
—
580
0
1300
—
—
Reinfection
d
5
a
56
1300
—
520
0
1300
—
620
—
500
—
Recrudescence
6
56
—
Reinfection
7
a
b
c
d
0
1400
—
620
56
1300
—
590
—
Reinfection
Primers MSA2-1 and MSA2-4 were used [12].
Primers MSA2-2 and MSA2-3 were used [12].
Minor differences in MSA2/RsaI were attributable to incomplete digestion; all other genetic markers were identical.
One of 2 strains present on day 0 recrudesced on day 56.
indicating that reinfection had occurred (table 4). Overall, there
was a 96.9% cure rate at day 28. The cure rate among children
!14 years old was 98.6%, and the rate among adults was 92.3%.
At the end of the 56-day follow-up period, the cure rate for
the entire group was 95.5%; the rate was 97.0% among children
and 90.9% among adults.
One of the 2 adults who was infected with parasites with RI
resistance had received the lowest dose of Artekin (4.2 mg/kg
DHA and 33.7 mg/kg piperaquine), and the other had received
the fourteenth-lowest dose (5.9 mg/kg DHA and 47.4 mg/kg
piperaquine) among all 106 patients (table 1). The 2 children
who experienced recrudescence within 56 days also received
relatively low doses (4.5 mg/kg DHA and 36.0 mg/kg piperaquine and 4.7 mg/kg DHA and 37.9 mg/kg piperaquine), compared with the means for their age groups (7.9 mg/kg DHA
and 63.2 mg/kg piperaquine; table 1). As a group, the doses of
DHA and piperaquine administered to these 4 patients were
significantly lower than those of subjects who did not experience recrudescence (P ! .001).
P. vivax was found by microscopic examination in 10 children from Snoul between day 28 and day 56 and was part of
a mixed infection with a new strain of P. falciparum found on
Efficacy of Dihydroartemisinin-Piperaquine • CID 2002:35 (15 December) • 1473
Figure 1. Percentages of patients for whom gametocytes were present on blood smears at each sampling time point (top) and median gametocyte
densities (ranges are indicated by vertical lines) among the patients in whom gametocytes were present at any time during follow-up (bottom).
day 28 in an adult from Anlong Veng. Two other children from
Snoul presented a second time with vivax malaria after the final
study visit, in both cases on day 62. There were no malaria
infections in any of the assessable patients from Anlong Veng
during the second month of the study (table 3). Gametocytes
were present in 15.1% of patients (16 patients) at the time of
presentation. This percentage peaked at 17.0% (18 patients) on
day 1 and then decreased progressively (figure 1). Among patients in whom gametocytes were found at any time during
follow-up, parasite densities were !70 parasites/mL of whole
blood, and all patients had negative results of testing for gametocytes by day 28 (figure 1).
Side effects. Twenty-two patients (8 adults and 14 children;
20.8%) reported side effects after therapy was initiated (table
5). Three subjects reported 2 side effects. All side effects were
transient, and none necessitated premature cessation of treatment. Gastrointestinal complaints were most frequently encountered, but no patient vomited after taking Artekin.
DISCUSSION
The combination of DHA and piperaquine in the form of
Artekin was developed as an alternative to established combinations, such as artesunate-mefloquine, primarily to reduce
treatment costs and toxicity. Our data show that Artekin was
effective and well tolerated by Cambodian children and adults
with uncomplicated falciparum malaria from 2 geographically
distinct areas. We recruited 106 patients, mostly children, and
were able to obtain validated 28-day follow-up data for 97
1474 • CID 2002:35 (15 December) • Denis et al.
patients (91.5%). Recrudescence occurred within 28 days in 2
adults and 1 child, all of whom received relatively low doses
(based on body weight) of Artekin. One child with features of
sepsis died despite prompt parasite clearance, but adverse events
were usually mild and short lived in the rest of the patients
and were difficult to distinguish from symptoms of malaria.
These data suggest that Artekin could prove to be suitable for
use as combination antimalarial therapy but that pharmacokinetic studies and further efficacy evaluation with close monitoring of clinical outcomes should be carried out.
Despite concerns regarding animal neurotoxicity [19], artemisinin derivatives such as DHA have been used safely in
large numbers of patients with uncomplicated or severe malaria
Table 5. Side effects reported after initiation of Artekin (dihydroartemisinin-piperaquine) therapy in Cambodian patients with malaria.
No. of patients with
side effect of indicated degree
Side effect
Mild
Moderate
Severe
a
0
Anorexia
0
4
Nausea/vomiting
0
5
0
Abdominal pain
0
5
0
Diarrhea
5b
0
0
Dizziness/vertigo
4
1
0
Itch
0
1
0
a
a,b
Two patients experienced moderate anorexia and nausea.
One patient experienced mild diarrhea and moderate
vomiting.
b
[1, 20]. Piperaquine has been used much less widely. Data from
in vitro and animal studies suggest that it is as potent as chloroquine but less toxic [21–25]. In the first human studies of
piperaquine, the main side effects were mild headache, listlessness, nausea, and dizziness, and no patients died [8]. Although no preclinical studies of the combination of DHA and
piperaquine have been published, early human trials of Artekin
carried out in the past 2 years in several hundred Vietnamese
and Cambodian adults with uncomplicated malaria have shown
high cure rates and minimal side effects (L. G. Qiao and J.
Farrar, personal communication). With the exception of the
single child who died, the side-effect profile of the patients in
the present study was consistent with that seen in previous
studies of piperaquine, regardless of whether it was given alone
or in combination with DHA.
The patient who died had no clinical or laboratory indicators
of complications of malaria or serious concomitant illness at
entry, and he initially responded to treatment. The subsequent
rapid deterioration, with fever, hypotension, and altered consciousness, could have been due to sepsis. Secondary bacterial
infection complicates approximately one-third of cases of severe
falciparum malaria [26]. Gram-negative septicemia is one such
infection and could have occurred in our patient. An alternative
explanation is that he experienced a severe idiosyncratic reaction to DHA, piperaquine, or both or to a metabolite. This
seems less likely, because the half-life of DHA after oral administration is ∼60 min [27], and, if piperaquine exhibits similar pharmacokinetics to those of the chemically related drug
chloroquine [28], the patient’s deterioration occurred 124 h
after peak serum concentrations were reached. Hydroxypiperaquine is the major active metabolite of piperaquine [29, 30],
but, to our knowledge, there have been no toxicologic or pharmacokinetic studies of this compound.
Recommended Artekin dose regimens have been developed
empirically, because the pharmacokinetic properties of piperaquine are unknown. The pattern of increasing periods between
doses reflects those used for artesunate [2]. Divided doses may
also allow adequate amounts of piperaquine to be provided
without risking the toxicity associated with a single large dose;
this is similar to the way in which chloroquine regimens were
developed [28]. However, it is interesting that the 4 recrudescent infections we observed occurred in adults and children
who received relatively low doses. This suggests that, rather
than a dosing profile based on age groups, Artekin should be
administered on a body-weight basis, as are chloroquine and
quinine. Nevertheless, the mean doses (based on body weight)
administered to children were greater than those administered
to adults. It may be that the doses recommended, in milligrams
per kilogram, for children should be larger. There is an urgent
need for pharmacokinetic studies to guide rational dosing
regimens.
The 56-day follow-up period, which is longer than that recommended by the World Health Organization, confirmed that
the endemicity of malaria in the Snoul area is greater than that
in Anlong Veng; 10% of the children from Snoul experienced
new P. falciparum infections. Vivax malaria was also commonly
encountered during follow-up at Snoul, as was reported elsewhere for Thai patients treated successfully for falciparum malaria [31]. Whether these patients also had submicroscopic P.
vivax parasitemia at first presentation is unknown. Further investigation of this by molecular methods was beyond the scope
of the present study. Gametocyte carriage was detected in a
minority of patients and at low densities, which was consistent
with the known gametocidal activity of the artemisinin derivatives [32, 33].
Artekin is composed of 2 drugs developed independently by
Chinese researchers. Artemisinins such as DHA were brought
into widespread clinical use without the stages of pharmaceutical development required by regulatory authorities such as
the US Food and Drug Administration [1]. Piperaquine has
followed this course. Furthermore, the present study represents
a phase 2 or 3 evaluation of a combination therapy that itself
has not yet been through full preclinical evaluation. Nevertheless, in countries in which malaria is endemic and that have
limited health care resources, there is a need for safe, effective,
easily administered, and inexpensive therapies. It is, therefore,
not surprising that artemisinin drugs and their combinations
have been made available for use before they have been fully
evaluated, especially in Southeast Asian areas where multidrugresistant P. falciparum are present. At a cost of ∼US$1–2 for
each 2-day treatment course, Artekin is an attractive option,
but our data argue that further pharmacokinetic and efficacy
evaluation should be conducted before its widespread use can
be supported.
Acknowledgments
We thank Thai Khieng Heng and Va Such of the National
Malaria Center and to Chim Peaktra of the Institut Pasteur du
Cambodge for technical and logistic assistance. We also thank
the staff at the Anlong Veng and Snoul health centers for dedicated assistance in the field.
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