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JAC Advance Access published online on September 19, 2007
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkm355
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Pharmacokinetics of two paediatric artesunate–mefloquine drug formulations in the treatment of uncomplicated falciparum malaria in Gabon

Michael Ramharter1,2,3,*, Florian M. Kurth1, Sabine Bélard1, Marielle K. Bouyou-Akotet4, Modeste Mabika Mamfoumbi4, Selidji T. Agnandji1,2, Michel A. Missinou1,2, Ayola A. Adegnika1,2, Saadou Issifou1,2, Nathalie Cambon5, János L. Heidecker5, Maryvonne Kombila4 and Peter G. Kremsner1,2

1 Medical Research Unit, Albert Schweitzer Hospital, Lambaréné, Gabon 2 Institute for Tropical Medicine, Department for Parasitology, University of Tübingen, Tübingen, Germany 3 Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria 4 Département de Parasitologie-Mycologie et Médecine Tropicale, Faculté de Médecine, Université des Sciences de la Santé, Libreville, Gabon 5 Pharmaceutical Research Development and Manufacture, Mepha Ltd, Aesch, Switzerland

* Corresponding author. Tel: +43-1-40400-4440; Fax: +43-1-40400-4418; E-mail: michael.ramharter{at}meduniwien.ac.at

Received 3 June 2007; returned 28 July 2007; revised 5 August 2007; accepted 20 August 2007


   Abstract
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Objectives: Paediatric drug formulations of artemisinin combination therapies and pharmacokinetic data supporting their use in African children are urgently needed for the effective treatment of young children suffering from falciparum malaria in sub-Saharan Africa.

Patients and methods: In this study, the pharmacokinetic characteristics of a novel paediatric granule formulation of artesunate–mefloquine therapy were evaluated in comparison to the standard tablet formulation in the treatment of uncomplicated malaria in paediatric patients. Twenty-four patients were assigned to treatment according to body weight with either a fixed-dose paediatric granule co-formulation (10–20 kg body weight) or a free-dose co-blister tablet formulation of artesunate–mefloquine (>20–40 kg body weight).

Results: Median values for Cmax (861 and 930 ng/mL), Tmax (1.5 and 1.5 h) and AUC0–t (2050 and 2470 ng·h/mL) were comparable for dihydroartemisinin in the two groups. Exploratory analysis of mefloquine plasma levels revealed a trend towards higher concentrations in the younger age group during the absorption phase (2550 and 1815 ng/mL, 54 h after initiation of treatment, respectively). Median mefloquine concentrations at day 28 were 197 and 343 ng/mL, respectively.

Conclusions: The pharmacokinetic characteristics of the two paediatric dosage forms, i.e. the novel fixed-dose co-formulation and the standard co-blister of artesunate–mefloquine show comparable results in the two treatment groups. The novel fixed-dose paediatric formulation is an interesting option for outpatient treatment of uncomplicated malaria in African children.

Key Words: malaria , Plasmodium falciparum , PK , Africa


   Introduction
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African children suffer the highest morbidity and mortality attributed to malaria worldwide. Current WHO guidelines for the treatment of uncomplicated falciparum malaria recommend the use of artemisinin-containing combination regimens.1 Artesunate–mefloquine was historically the first representative of novel artemisinin combinations and for more than one decade, it has remained a highly successful therapeutic regimen in regions harbouring the most resistant isolates worldwide.2,3 The use of artesunate–mefloquine as antimalarial therapy for African children was first precluded because of sparse data on safety and tolerability in this target population and the lack of paediatric drug formulations.1,4 Furthermore, no data on the pharmacokinetics of artesunate–mefloquine combination therapy supporting their use in African children were available.

Recently, an innovative galenic co-formulation of artesunate–mefloquine was developed for the treatment of paediatric patients. The drug combination is formulated as granules, which may be administered directly into the mouth of the patient. Taste-masking of active ingredients with mango flavour and a slippery consistency of the drug formulation are further characteristics for improved acceptability by paediatric patients. This novel drug formulation is a line extension of mefloquine–artesunate co-blister tablet formulations developed by Mepha Ltd, with varying strengths of mefloquine.5–7 Following a recent change in recommendations of WHO for areas of high malaria transmission, the total mefloquine dosage in the co-blister tablet formulation and the novel paediatric formulation was increased to 25 mg/kg body weight.1

In this study, we evaluated two paediatric drug formulations—the co-blister artesunate–mefloquine tablet formulation (Artequin 300/750) and the novel fixed-dose paediatric co-formulation (Artequin Paediatric)—in the treatment of uncomplicated falciparum malaria in African children. It was the first use in humans and the first clinical evaluation of the fixed-dose paediatric drug formulation. Here, we report on the pharmacokinetic characteristics of artesunate–mefloquine therapy in a subgroup of 24 patients participating in the extended pharmacokinetics protocol.


   Materials and methods
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The study was conducted at the Medical Research Unit of the Albert Schweitzer Hospital, Lambaréné and the Department of Paediatrics at the Centre Hospitalier de Libreville, from October 2005 to February 2006. Gabon is characterized by high-perennial malaria transmission and local strains of Plasmodium falciparum are highly resistant to chloroquine in vitro and in vivo.8–10 Mefloquine is still active against P. falciparum isolates in vitro and in vivo despite the rare occurrence of borderline resistant isolates.9,11–14

The study was designed as an open label, stratified clinical trial assessing the efficacy, tolerability, safety and pharmacokinetics of two paediatric formulations of artesunate–mefloquine. Treatment allocation of patients was based on body weight (group A 10–20 kg and group B >20–40 kg). Antimalarial treatment in group A was the novel fixed-dose paediatric formulation of artesunate–mefloquine, whereas patients in group B received the paediatric dose of standard co-blister tablets. The first 12 patients of each cohort who were eligible for pharmacokinetic analysis were included in the pharmacokinetic protocol at the Medical Research Unit of the Albert Schweitzer Hospital. The study was approved by the Ethics Committee of the International Foundation for the Albert Schweitzer Hospital in Lambaréné and written informed consent was obtained from all study participants’ legal representatives. The study protocol was registered prior to recruitment at clinicaltrials.gov (NLM identifier NCT00243737 [ClinicalTrials.gov] ).

Patients presenting with symptomatic P. falciparum infection were eligible for this study if the following inclusion criteria were met: peripheral asexual P. falciparum parasitaemia between 1000 and 250 000 per µL of blood, fever (≥37.5°C) or history of fever in the last 48 h, haemoglobin ≥7 g/100 mL blood. Exclusion criteria were the presence of any of the following criteria: signs or symptoms of severe malaria; known hypersensitivity or allergy to artemisinin derivatives, mefloquine, or related compounds; adequate antimalarial treatment within 1 week prior to inclusion; administration of quinine or artemisinin derivatives at any dose within 12 h prior to inclusion; known history of psychiatric disorders, cardiac diseases, arrhythmia, sickle cell disease; clinical signs or laboratory evidence of any other severe underlying disease; pregnancy or lactation.

Study flow

Demographic characteristics, physical examination and medical history were obtained at admission. Investigations comprised electrocardiography, measurement of oral temperature, biochemistry, haematology, vital signs and thick blood smear. Follow-up assessments of parasitaemia and temperature were performed every 12 h until resolution. Weekly follow-up visits were scheduled until day 28.

Study drugs

Artesunate–mefloquine was administered orally once daily for 3 days at the nearest approximation of a daily dose of 4 and 8 mg/kg body weight for each group, respectively. The novel fixed-dose paediatric formulation (Artequin Paediatric®, Mepha Ltd, Aesch, Switzerland) was used for group A (body weight from 10 to 20 kg). Each stickpack contains 50 mg of artesunate and 125 mg of mefloquine for one dose once daily for 3 days. The active ingredients are formulated as taste masked granules (mango flavour). Granules were administered directly into the mouth immediately forming a slippery, sweet substance with the saliva. Artequin 300/750® (Mepha Ltd, Aesch, Switzerland) co-blister tablets were used for group B (body weight from >20 to 40 kg). Each co-blister package consists of one tablet artesunate and one tablet mefloquine, containing 100 and 250 mg of active substance, respectively. Patients in group B were treated with one co-blister package once daily for 3 days. Study drugs were administered with a glass of water under the supervision of a study physician.

Blood sampling and pharmacokinetic analysis

The aim of the analysis was to evaluate standard pharmacokinetic parameters for dihydroartemisinin, the major metabolite of artesunate, and to evaluate the concentration of mefloquine at four predefined time points. These included the absorption phase in which time mefloquine supports artesunate in eliminating the parasites as well as the plasma concentration at the end of the follow-up period, bridging the period of prophylactic efficacy. For each sample, 4 mL of blood was drawn from the cubital vein in lithium-heparinized tubes. Owing to the young age of our study participants, the quantity and frequency of blood draws for pharmacokinetic analysis were reduced to the minimal acceptable amount. Blood sampling for dihydroartemisinin was scheduled for the following time points on the first day of treatment: before and 30, 60, 90, 120, 240 and 360 min after drug administration. Blood samples for mefloquine analysis were obtained prior to study drug administration and 6 h, 54 h and 28 days after drug intake. Plasma was stored at –80°C immediately after centrifugation of blood samples.

Reverse-phase HPLC was used for analysis of plasma samples. Dihydroartemisinin was extracted prior to analysis by solid-phase extraction (Inertsil OSD 10 µm extract column; Knauer, Mainz, Germany). Plasma concentrations were obtained by HPLC and tandem mass spectroscopy (API 2000; Applied Biosystems/MDS Sciex, Foster City, CA, USA). Artemisinin was used as internal standard. Mefloquine was extracted from plasma samples (Perisorb RP-2 extraction column; Merck, Darmstadt, Germany) before measurement by HPLC with UV detection (UV-2075, Jasco; 222 nm). The lowest concentration quantified by the system was 10 ng/mL plasma for dihydroartemisinin and mefloquine (inter-assay repeatability coefficient 4.7% to 6.2% and 1.1% to 4.2%, respectively).

Assessment of classic pharmacokinetic parameters was sought for dihydroartemisinin. These were the observed maximum plasma concentration (Cmax), time to Cmax (Tmax), elimination constant {lambda}z, which was estimated for each individual from at least three concentration–time points, terminal elimination half-life (t1/2) calculated as ln 2/{lambda}z, the area under the plasma concentration–time curve to the last sample with quantifiable drug concentration (AUC0–t) and AUC extrapolated to infinity (AUCt–{infty}). The elimination constant {lambda}z was computed by log-linear regression employing the method of least squares. Mefloquine analysis was restricted to the assessment of plasma levels at respective time points due to the limited number of scheduled blood draws. Pharmacokinetic analysis of plasma samples was computed with standard non-compartmental methods.

Data management and statistical analysis

Data were captured on paper case record forms. Double data entry and additional manual review were performed prior to closure of the database. Descriptive statistics and linear regression analysis of mefloquine drug concentrations were performed. Comparisons of groups were performed using non-parametric tests (Wilcoxon Rank Sums Test; JMP 5.0, SAS Institute Inc., NC, USA). The association of potential confounding variables on peak plasma concentrations was evaluated by multivariate regression analysis. Correlation analysis of dihydroartemisinin and mefloquine plasma concentrations was analysed by non-parametric correlation analysis (Spearman’s rho).


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Study flow

Seventy-one patients were enrolled in this clinical trial: 41 in group A and 30 in group B, respectively. Twelve patients of each group participated in the pharmacokinetics protocol. One patient in group A was withdrawn from the study and treated with rescue medication due to repeated vomiting on the first day of treatment. He was excluded from pharmacokinetic analysis and replaced by an additional patient.

Baseline characteristics of the study population were similar in both treatment groups (Table 1) and not different from the total study population (data not shown). Patients in treatment group A were of younger age, less weight and therefore lower body mass index and body surface area following inclusion criteria. Biochemical markers for renal and hepatic function were within the expected range for paediatric patients suffering from uncomplicated P. falciparum malaria. The effective mean total dose of artesunate was 10.1 (±2.2; range: 7.9–13.4) and 11.0 (±2.2; range: 8.1–14.3) mg/kg body weight in treatment groups A and B, respectively. Mefloquine was administered at a mean total dose of 25.1 (±3.9; range: 19.7–33.5) and 27.6 (±5.4; range: 20.3–35.7) mg/kg body weight over a 3 day period. There was no clinical or parasitological treatment failure in this study population up to day 28.


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  		Table 1. Admission characteristics of patients participating in the pharmacokinetic protocol

 
Pharmacokinetic analysis

Dihydroartemisinin. Median peak plasma concentrations for dihydroartemisinin were 861 and 930 ng/mL in treatment groups A and B, respectively (Table 2 and Figure 1). A higher variation of Cmax was observed in the lower body-weight group A compared with group B (range: 130–3390 and 286–2190 ng/mL, respectively). Median Tmax values were very similar for both drug formulations (1.5 and 1.5 h, respectively). Median AUC0–t of dihydroartemisinin was 2050 and 2470 ng·h/mL, respectively.


Figure 1
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  		Figure 1. Mean plasma concentration–time profile of dihydroartemisinin for treatment groups A (paediatric formulation) and B (co-blister tablets). Time points for plasma sampling are depicted on x-axis. Log transformed mean plasma concentrations (and standard error of the mean) are depicted on y-axis.

 


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  		Table 2. Pharmacokinetic characteristics of artesunate–mefloquine in the fixed-dose drug formulation and as co-blister tablets (n = 12 per group)

 
Four patients showed a delayed pattern of peak plasma concentrations reaching maximum—but still considerably lower—drug concentrations only at the last sampling time point for dihydroartemisinin (6 h: 158, 420, 130 ng/mL in group A and 286 ng/mL in group B, respectively). Observed peak plasma concentrations were considerably lower in these participants and cumulative results for Cmax, Tmax and AUC0–t were therefore distorted. Similarly, elimination constant {lambda}z, t1/2 and AUC0–{infty} could not be computed in these patients. For the remaining participants, AUC0–{infty} was comparable in treatment groups A (3024 ng·h/mL) and B (2815 ng·h/mL). The terminal half-life of dihydroartemisinin was 0.9 and 1.0 h for the two drug formulations, respectively.

The influence of potentially confounding co-variables (treatment group, age, gender, weight, body mass index, packed cell volume, parasitaemia and temperature) on pharmacokinetic parameters (Cmax, Tmax and AUC0–t) was assessed in post hoc analysis by multivariate regression analysis using stepwise forward selection. Among those, gender showed a considerable effect on peak plasma concentrations of dihydroartemisinin. Male participants had median peak plasma concentrations of 737 ng/mL (10% and 90% quantiles: 130–1700 ng/mL) in group A and 543 ng/mL (10% and 90% quantiles: 286–1710 ng/mL) in group B. Median Cmax levels of females were higher in group A (922 ng/mL; 10% and 90% quantiles: 420–3390 ng/mL; P = 0.12) and group B (1730 ng/mL; 10% and 90% quantiles: 927–2190 ng/mL; P = 0.04), respectively. Plasma concentrations of dihydroartemisinin were positively correlated with mefloquine concentrations 6 h after drug administration but not later on (r = 0.53, P = 0.007). These findings might be explained by varying rates of drug absorption or biotransformation in a subgroup of patients.

Mefloquine. Mefloquine plasma samples were obtained 6 h, 54 h and 28 days after initiation of antimalarial treatment. All drug concentrations were comparable in the two treatment groups, although mefloquine concentrations in the younger age group receiving the fixed-dose paediatric drug formulation showed a statistically non-significant trend towards higher concentrations 54 h after initiation of treatment (n = 24; P = 0.10) and lower plasma levels on day 28 (n = 24; P = 0.06). Median mefloquine plasma levels for treatment groups A and B were 724 and 588 ng/mL, 2550 and 1815 ng/mL and 197 and 343 ng/mL for the respective time points (Table 2 and Figure 2). The limited number of sample time points precluded the computation of classical pharmacokinetic parameters.


Figure 2
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  		Figure 2. Mean plasma concentration–time profile curve of mefloquine for treatment groups A (paediatric formulation) and B (co-blister tablets). Time points for plasma sampling are depicted on x-axis. Log transformed mean plasma concentrations (and standard error of the mean) are depicted on y-axis.

 

   Discussion
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African children are the main target population for artemisinin combination therapy. Therefore, there is an urgent need for adequate paediatric drug formulations for most current artemisinin combinations. Data on pharmacokinetics of current artemisinin combination therapies are limited for paediatric patients in Africa.

Artesunate–mefloquine is one therapeutic option recommended by WHO for the treatment of uncomplicated malaria.1 Recently, an innovative paediatric granule formulation of artesunate and mefloquine has become available for use in young children. In this study, we assessed the pharmacokinetics of this novel drug formulation in comparison with a standard co-blister tablet when administered to paediatric patients of two body-weight groups (10–20 and >20–40 kg body weight, respectively).

Dihydroartemisinin—the major active metabolite of artesunate—is responsible for most of the antimalarial activity of artesunate and was used for pharmacokinetic analysis in this study. Median Cmax for dihydroartemisinin was similar in both groups but marked inter-participant variations were observed. Three patients in group A did not reach maximum plasma levels within the 6 h sampling schedule. This variation was similarly reflected by a wide variation of AUC0–t. Despite these marked inter-participant variations of dihydroartemisinin plasma levels, efficacy of the study treatment was 100% at 14 and 28 days in both study groups (manuscript in preparation).

Our data on dihydroartemisinin pharmacokinetics are comparable to a previous report on Vietnamese children suffering from moderately severe malaria.15 In that study, dose normalized Cmax and AUC0–t levels—analysed by using a radioisotopic bioassay—were similar (885 ng/mL and 1714 h·ng/mL if extrapolated to 4 mg/kg body-weight dosing of artesunate) and distinct inter-personal differences were described. Bioavailability of artemisinin derivatives showed similar high variation after intramuscular or rectal route of administration.15–18 A considerable difference of dihydroartemisinin peak plasma concentrations was observed between male and female participants confirming findings of a recent report on pharmacokinetic characteristics of artesunate suppositories.18

To date the clinical importance of reduced plasma levels of dihydroartemisinin is not understood. In general, 99% in vitro growth inhibition by an antimalarial is considered as threshold for MICs in non-immune patients. Even the lowest observed Cmax level in our study population (130 ng/mL) was more than 13 times higher than previous results for the MIC in various in vitro drug sensitivity studies in Gabon (34 nmol/L equivalent to 9.7 ng/mL).19 Despite advances in the understanding of the mechanism of action of artemisinin derivatives, there is a lack of appropriate pharmacokinetic–pharmacodynamic models for this class of antimalarials.20

Mefloquine plasma concentrations were predictive for treatment outcome in previous studies.21 In our trial, pharmacokinetic analysis of mefloquine was essentially restricted to descriptive statistics of plasma levels at the respective sampling time points. Mefloquine concentrations at 6 and 54 h after initiation of treatment were used for evaluation of absorption. True Cmax—and therefore also Tmax—were most likely missed due to the restricted sampling schedule. The mean mefloquine plasma concentrations 6 h after the administration of the first dose of each formulation are similar in the two groups. The mean observed plasma concentration 6 h after dosing on day 3 appears lower in group B. However, maximum observed plasma levels of mefloquine were within the range of previous reports.22,23 Values at the end of the observation period, on the other hand, are slightly higher in treatment group B as compared with group A.

Median mefloquine plasma concentrations at the end of the study were 197 and 343 ng/mL, respectively. This finding may be interpreted as a trend towards a higher rate of mefloquine elimination in smaller children although the difference between groups was not statistically significant in our study population. In previous studies, 500 ng/mL has been determined as threshold level for therapeutic and prophylactic efficacy.21,23 This would translate into a median effective prophylactic period of 21.6 and 22.2 days post-treatment for groups A and B, respectively. The advantage of such a prolonged period of protection against new P. falciparum infections has to be weighed against the suspected increase in the risk for the selection of drug-resistant isolates in areas of high malaria transmission. More recently however, the benefit of reduced rates of re-infection and relapse due to long acting antimalarial drugs has been emphasized.24,25 The debate on this risk/benefit analysis is still ongoing and needs further epidemiological evidence for areas of both low and high malaria endemicity.4,26,27

In summary, we report on the pharmacokinetic characteristics of two paediatric artesunate–mefloquine combinations for the treatment of uncomplicated falciparum malaria in paediatric patients. In our study, plasma concentrations of dihydroartemisinin and mefloquine were satisfying and in concordance with previous reports from differing patient populations and drug formulations, there was no treatment failure observed in this study protocol. The development of adequate paediatric drug formulations is of high importance for the effective treatment of paediatric patients on an outpatient basis.27 By this means, paediatric formulations also contribute to an improved allocation of resources in health services of malaria endemic regions. Further careful monitoring of safety, tolerability and efficacy of this new fixed-dose, artesunate–mefloquine combination is needed for continuous confirmation of its qualification for wide scale use also in African children.


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The conduct of this study was supported financially by Mepha Ltd.


   Transparency declarations
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N. C. and J. L. H. are employees of Mepha Ltd. The sponsor had no influence on study conduct, data analysis and interpretation of data. All other co-authors report no conflict of interest.


   Acknowledgements
 
We gratefully acknowledge the participation of the children and their parents in this clinical study protocol. We further thank the technical staff of the Medical Research Unit for the continued excellent support in this work.


   References
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1 . World Health Organization. WHO guidelines for the treatment of malaria. (2006) Geneva, Switzerland.

2 . Looareesuwan S, Viravan C, Vanijanonta S, et al. Randomised trial of artesunate and mefloquine alone and in sequence for acute uncomplicated falciparum malaria. Lancet (1992) 339:821–4.[CrossRef][Web of Science][Medline]

3 . Nosten F, van Vugt M, Price R, et al. Effects of artesunate-mefloquine combination on incidence of Plasmodium falciparum malaria and mefloquine resistance in western Thailand: a prospective study. Lancet (2000) 356:297–302.[CrossRef][Web of Science][Medline]

4 . Kremsner PG, Krishna S. Antimalarial combinations. Lancet (2004) 364:285–94.[CrossRef][Web of Science][Medline]

5 . Bhatt KM, Samia BM, Bhatt SM, et al. Efficacy and safety of an artesunate/mefloquine combination (Artequin) in the treatment of uncomplicated P. falciparum malaria in Kenya. East Afr Med J (2006) 83:236–42.[Medline]

6 . Massougbodji A, Agbo K, Faye O, et al. Efficacy and safety of a combination of artesunate/mefloquine, ArtequinTM in African children and adults with uncomplicated P. falciparum malaria. (2005) 4th MIM Pan-African Malaria Conference: Yaounde.

7 . Massougbodji A, Kone M, Kinde-Gazard D, et al. Randomised double blind study on the efficacy and safety of a practical 3 day regimen with artesunate and mefloquin for the treatment of uncomplicated malaria in Africa. Trans R Soc Trop Med Hyg (2002) 96:655–9.[CrossRef][Web of Science][Medline]

8 . Borrmann S, Binder RK, Adegnika AA, et al. Reassessment of the resistance of Plasmodium falciparum to chloroquine in Gabon: implications for the validity of tests in vitro vs. in vivo. Trans R Soc Trop Med Hyg (2002) 96:660–3.[CrossRef][Web of Science][Medline]

9 . Ramharter M, Wernsdorfer WH, Kremsner PG. In vitro activity of quinolines against Plasmodium falciparum in Gabon. Acta Trop (2004) 90:55–60.[CrossRef][Web of Science][Medline]

10 . Wildling E, Winkler S, Kremsner PG, et al. Malaria epidemiology in the province of Moyen Ogoov, Gabon. Trop Med Parasitol (1995) 46:77–82.[Web of Science][Medline]

11 . Kreidenweiss A, Mordmuller B, Krishna S, et al. Antimalarial activity of a synthetic endoperoxide (RBx-11160/OZ277) against Plasmodium falciparum isolates from Gabon. Antimicrob Agents Chemother (2006) 50:1535–7.[Abstract/Free Full Text]

12 . Pradines B, Fusai T, Daries W, et al. Ferrocene-chloroquine analogues as antimalarial agents: in vitro activity of ferrochloroquine against 103 Gabonese isolates of Plasmodium falciparum. J Antimicrob Chemother (2001) 48:179–84.[Abstract/Free Full Text]

13 . Radloff PD, Philipps J, Nkeyi M, et al. Arteflene compared with mefloquine for treating Plasmodium falciparum malaria in children. Am J Trop Med Hyg (1996) 55:259–62.[Abstract/Free Full Text]

14 . Uhlemann AC, Ramharter M, Lell B, et al. Amplification of Plasmodium falciparum multidrug resistance gene 1 in isolates from Gabon. J Infect Dis (2005) 192:1830–5.[CrossRef][Web of Science][Medline]

15 . Bethell DB, Teja-Isavadharm P, Cao XT, et al. Pharmacokinetics of oral artesunate in children with moderately severe Plasmodium falciparum malaria. Trans R Soc Trop Med Hyg (1997) 91:195–8.[CrossRef][Web of Science][Medline]

16 . Halpaap B, Ndjave M, Paris M, et al. Plasma levels of artesunate and dihydroartemisinin in children with Plasmodium falciparum malaria in Gabon after administration of 50-milligram artesunate suppositories. Am J Trop Med Hyg (1998) 58:365–8.[Abstract]

17 . Nealon C, Dzeing A, Muller-Roemer U, et al. Intramuscular bioavailability and clinical efficacy of artesunate in Gabonese children with severe malaria. Antimicrob Agents Chemother (2002) 46:3933–9.[Abstract/Free Full Text]

18 . Simpson JA, Agbenyega T, Barnes KI, et al. Population pharmacokinetics of artesunate and dihydroartemisinin following intra-rectal dosing of artesunate in malaria patients. PLoS Med (2006) 3:2113–23.

19 . Ramharter M, Noedl H, Winkler H, et al. In vitro activity and interaction of clindamycin combined with dihydroartemisinin against Plasmodium falciparum. Antimicrob Agents Chemother (2003) 47:3494–9.[Abstract/Free Full Text]

20 . Eckstein-Ludwig U, Webb RJ, Van Goethem ID, et al. Artemisinins target the SERCA of Plasmodium falciparum. Nature (2003) 424:957–61.[CrossRef][Medline]

21 . Slutsker LM, Khoromana CO, Payne D, et al. Mefloquine therapy for Plasmodium falciparum malaria in children under 5 years of age in Malawi: in vivo/in vitro efficacy and correlation of drug concentration with parasitological outcome. Bull World Health Organ (1990) 68:53–9.[Web of Science][Medline]

22 . Karbwang J, Na Bangchang K, Thanavibul A, et al. Pharmacokinetics of mefloquine alone or in combination with artesunate. Bull World Health Organ (1994) 72:83–7.[Web of Science][Medline]

23 . Price R, Simpson JA, Teja-Isavatharm P, et al. Pharmacokinetics of mefloquine combined with artesunate in children with acute falciparum malaria. Antimicrob Agents Chemother (1999) 43:341–6.[Abstract/Free Full Text]

24 . Shanks GD. Treatment of falciparum malaria in the age of drug resistance. J Postgrad Med (2006) 52:277–80.[Web of Science][Medline]

25 . Van Vught M, Phaipun L, Hutatalung R, et al. Longer acting anti-malarials reduce significantly the rate of re-infection with P. falciparum and relapse of P. vivax following treatment for P. falciparum in Western Thailand. Medicine and Health in the Tropics, September 2005: Marseille—France.

26 . Ramharter M, Oyakhirome S, Klouwenberg PK, et al. Artesunate-clindamycin versus quinine-clindamycin in the treatment of Plasmodium falciparum malaria: a randomized controlled trial. Clin Infect Dis (2005) 40:1777–84.[CrossRef][Web of Science][Medline]

27 . World Health Organization. Scaling up home based management of malaria. (2004) Geneva, Switzerland.


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