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Background: Artemether-lumefantrine (AL) dispersible formulation was developed for the treatment of uncomplicated Plasmodium falciparum malaria in infants and children weighing 5 to <35 kg. However, there are no clinical studies with artemisinin-based combination therapy in infants <5 kg., Methods: This multicentre, open-label, single-arm study evaluated the efficacy, safety and pharmacokinetics of AL dispersible in infants aged >28 days and <5 kg of body weight, who were treated with one AL dispersible tablet (20 mg artemether/120 mg lumefantrine) given twice-daily for three days and followed up for six weeks (core follow-up) and at 12 months of age (long-term follow-up)., Results: A total of 20 patients were enrolled and completed the six-week core study follow-up. In the per protocol population, PCR-corrected cure rate at days 28 and 42 was 100% (95% CI: 79.4, 100). AL dispersible was well tolerated with reported adverse events of mild to moderate severity. Pharmacokinetic data showed that lumefantrine levels were similar, however, artemether and dihydroartemisinin levels were on average two- to three-fold greater than historical values in infants and children ≥5 kg., Conclusions: A three-day regimen of AL dispersible formulation was efficacious and generally well tolerated in infants weighing <5 kg with uncomplicated P. falciparum malaria, but artemether and dihydroartemisinin exposures could not be supported by the preclinical safety margins for neurotoxicity. Hence, dosing recommendations cannot be made in infants <5 kg as implications for toxicity are unknown., Trial Registration: Clinicaltrials.gov NCT01619878.

Background: Artemether-lumefantrine (Coartem; AL) is a standard of care for malaria treatment as an oral six-dose regimen, given twice daily over three days with one to four tablets (20/120 mg) per dose, depending on patient body weight. In order to reduce the pill burden at each dose and potentially enhance compliance, two novel fixed-dose tablet formulations (80/480 mg and 60/360 mg) have been developed and tested in this study for bioequivalence with their respective number of standard tablets., Methods: A randomized, open-label, two-period, single-dose, within formulation crossover bioequivalence study comparing artemether and lumefantrine exposure between the novel 80/480 mg tablet and four standard tablets, and the novel 60/360 mg tablet and three standard tablets, was conducted in 120 healthy subjects under fed conditions. Artemether, dihydroartemisinin, and lumefantrine were measured in plasma by HPLC/UPLC-MS/MS. Pharmacokinetic (PK) parameters were determined by non-compartmental analyses., Results: Adjusted geometric mean AUClast for artemether were 345 and 364 ng·h/mL (geometric mean ratio (GMR) 0.95; 90% CI 0.89-1.01) and for lumefantrine were 219 and 218 μg·h/mL (GMR 1.00; 90% CI 0.93-1.08) for 80/480 mg tablet versus four standard tablets, respectively. Corresponding Cmax for artemether were 96.8 and 99.7 ng/mL (GMR 0.97; 90% CI 0.89-1.06) and for lumefantrine were 8.42 and 8.71 μg/mL (GMR 0.97; 90% CI 0.89-1.05). For the 60/360 mg tablet versus three standard tablets, adjusted geometric mean AUClast for artemether were 235 and 231 ng·h/mL (GMR 1.02; 90% CI 0.94-1.10), and for lumefantrine were 160 and 180 μg·h/mL (GMR 0.89; 90% CI 0.83-0.96), respectively. Corresponding Cmax for artemether were 75.5 and 71.5 ng/mL (GMR 1.06; 90% CI 0.95-1.18), and for lumefantrine were 6.64 and 7.61 μg/mL (GMR 0.87; 90% CI 0.81-0.94), respectively. GMR for Cmax and AUClast for artemether and lumefantrine for all primary comparisons were within the bioequivalence acceptance criteria (0.80-1.25). In addition, secondary PK parameters also met bioequivalence criterion., Conclusion: Both of the novel artemether-lumefantrine tablet formulations evaluated are bioequivalent to their respective standard Coartem tablet doses. These novel formulations are easy to administer and may improve adherence in the treatment of uncomplicated malaria caused by Plasmodium falciparum., Clinical Trial Registration Number: CTRI/2011/12/002256.

Background: Artemisinin-based combination therapy, including artemether-lumefantrine (AL), is currently recommended for the treatment of uncomplicated Plasmodium falciparum malaria. The objectives of the current analysis were to compare the efficacy and safety of AL across different body weight ranges in African children, and to examine the age and body weight relationship in this population., Methods: Efficacy, safety and pharmacokinetic data from a randomized, investigator-blinded, multicentre trial of AL for treatment of acute uncomplicated P. falciparum malaria in infants and children in Africa were analysed according to body weight group., Results: The trial included 899 patients (intent-to-treat population 886). The modified intent-to-treat (ITT) population (n = 812) comprised 143 children 5 to < 10 kg, 334 children 10 to < 15 kg, 277 children 15 to < 25 kg, and 58 children 25 to < 35 kg. The 28-day PCR cure rate, the primary endpoint, was comparable across all four body weight groups (97.2%, 98.9%, 97.8% and 98.3%, respectively). There were no clinically relevant differences in safety or tolerability between body weight groups. In the three AL body weight dosing groups (5 to < 15 kg, 15 to < 25 kg and 25 to < 35 kg), 80% of patients were aged 10-50 months, 46-100 months and 90-147 months, respectively., Conclusion: Efficacy of AL in uncomplicated falciparum malaria is similar across body weight dosing groups as currently recommended in the label with no clinically relevant differences in safety or tolerability. AL dosing based on body weight remains advisable.

The pharmacokinetic and pharmacodynamic properties of a new pediatric formulation of artemether-lumefantrine, dispersible tablet, were determined within the context of a multicenter, randomized, parallel-group study. In an exploratory approach, we compared a new pediatric formulation with the tablet formulation administered crushed in the treatment of African children with uncomplicated Plasmodium falciparum malaria. Patients were randomized to 3 different dosing groups (weights of 5 to <15 kg, 15 and <25 kg, and 25 to <35 kg). Treatment was administered twice daily over 3 days. Plasma concentrations of artemether and its active metabolite, dihydroartemisinin (DHA), were determined at 1 and 2 h after the first dose of dispersible (n = 91) and crushed (n = 93) tablets. A full pharmacokinetic profile of lumefantrine was reconstituted on the basis of 310 (dispersible tablet) and 315 (crushed tablet) plasma samples, collected at 6 different time points (1 sample per patient). Dispersible and crushed tablets showed similar artemether and DHA maximum concentrations in plasma (C(max)) for the different body weight groups, with overall means of 175 ± 168 and 190 ± 168 ng/ml, respectively, for artemether and 64.7 ± 58.1 and 63.7 ± 65.0 ng/ml, respectively, for DHA. For lumefantrine, the population C(max) were 6.3 μg/ml (dispersible tablet) and 7.7 μg/ml (crushed tablet), whereas the areas under the concentration-time curves from time zero to the time of the last quantifiable plasma concentration measured were 574 and 636 μg · h/ml, respectively. For both formulations, descriptive quintile analyses showed no apparent association between artemether/DHA C(max) and parasite clearance time or between the lumefantrine C(max) and the occurrence of adverse events or corrected QT interval changes. The results suggest that the dispersible tablet provides adequate systemic exposure to artemether, DHA, and lumefantrine in African children with uncomplicated P. falciparum malaria.

Background: Efforts to ease administration and enhance acceptability of the oral anti-malarial artemether-lumefantrine (A-L) crushed tablet to infants and children triggered the development of a novel dispersible tablet of A-L. During early development of this new formulation, two studies were performed in healthy subjects, one to evaluate the palatability of three flavours of A-L, and a second one to compare the bioavailability of active principles between the dispersible tablet and the tablet (administered crushed and intact)., Methods: Study 1 was performed in 48 healthy schoolchildren in Tanzania. Within 1 day, all subjects tasted a strawberry-, orange- and cherry-flavoured oral A-L suspension for 10 seconds (without swallowing) in a randomized, single-blind, crossover fashion. The palatability of each formulation was rated using a visual analogue scale (VAS). Study 2 was an open, randomized crossover trial in 48 healthy adults given single doses of A-L (80 mg artemether + 480 mg lumefantrine) with food. The objectives were to compare the bioavailability of artemether, dihydroartemisinin (DHA) and lumefantrine between the dispersible tablet and the tablet administered crushed (primary objective) and intact (secondary objective)., Results: Study 1 showed no statistically significant difference in VAS scores between the three flavours but cherry had the highest score in several ratings (particularly for overall liking). Study 2 demonstrated that the dispersible and crushed tablets delivered bioequivalent artemether, DHA and lumefantrine systemic exposure (area under the curve [AUC]); mean ± SD AUC0-tlast were 208 ± 113 vs 195 ± 93 h.ng/ml for artemether, 206 ± 81 vs 199 ± 84 h.ng/ml for DHA and 262 ± 107 vs 291 ± 106 h x μg/ml for lumefantrine. Bioequivalence was also shown for peak plasma concentrations (Cmax) of DHA and lumefantrine. Compared with the intact tablet, the dispersible tablet resulted in bioequivalent lumefantrine exposure, but AUC and Cmax values of artemether and DHA were 20-35% lower., Conclusions: Considering that cherry was the preferred flavour, and that the novel A-L dispersible tablet demonstrated similar pharmacokinetic performances to the tablet administered crushed, a cherry-flavoured A-L dispersible tablet formulation was selected for further development and testing in a large efficacy and safety study in African children with malaria.

Objectives: Artemether-lumefantrine (AL) is first-line treatment for uncomplicated malaria in many African countries. Concomitant food consumption may affect absorption of lumefantrine but data in the most important target population, i.e. children, are lacking. Therefore, we evaluated the effect of food intake on oral lumefantrine bioavailability in African children with malaria., Methods: In a randomised, investigator-blinded, multicentre phase III efficacy trial, 899 infants and children with acute uncomplicated Plasmodium falciparum malaria received six doses of AL according to body weight over 3 days either as crushed tablets (Coartem) or as dispersible tablets. Single blood samples were obtained for lumefantrine plasma concentration determination in a subset of 621 patients, and a two-compartment pharmacokinetic model was constructed., Results: The mean observed lumefantrine plasma concentration for crushed tablet and dispersible tablet, respectively, was 100% and 55% higher with a concomitant meal at the time of dose intake than when taken alone. Similarly, consumption of milk (the most common meal) increased model-estimated lumefantrine bioavailability by 57% (90% CI: 29-96%) with crushed tablets and 65% (90% CI: 28-109%) with dispersible tablets compared to no food. The 28-day PCR-corrected cure rate (primary study endpoint) in the evaluable population was 582/587 [99.1% (95% CI: 98.0-99.7%)] and was not related to food intake., Conclusions: AL was highly efficacious. Concomitant food intake increased lumefantrine absorption in children with malaria.

Artemether and lumefantrine (AL), the active constituents of Coartem exhibit complementary pharmacokinetic profiles. Artemether is absorbed quickly; peak concentrations of artemether and its main active metabolite, dihydroartemisinin (DHA) occur at approximately two hours post-dose, leading to a rapid reduction in asexual parasite mass and a prompt resolution of symptoms. Lumefantrine is absorbed and cleared more slowly (terminal elimination half-life 3-4 days in malaria patients), and accumulates with successive doses, acting to prevent recrudescence by destroying any residual parasites that remain after artemether and DHA have been cleared from the body. Food intake significantly enhances the bioavailability of both artemether and lumefantrine, an effect which is more apparent for the highly lipophilic lumefantrine. However, a meal with only a small amount of fat (1.6 g) is considered sufficient to achieve adequate exposure to lumefantrine. The pharmacokinetics of artemether or lumefantrine are similar in children, when dosed according to their body weight, compared with adults. No randomized study has compared the pharmacokinetics of either agent in pregnant versus non-pregnant women. Studies in healthy volunteers and in children with malaria have confirmed that the pharmacokinetic characteristics of crushed standard AL tablets and the newly-developed Coartem Dispersible tablet formulation are similar. Studies to date in healthy volunteers have not identified any clinically relevant drug-drug interactions; data relating to concomitant administration of HIV therapies are limited. While dose-response analyses are difficult to undertake because of the low rate of treatment failures under AL, it appears that artemether and DHA exposure impact on parasite clearance time while lumefantrine exposure is associated with cure rate, consistent with their respective modes of action. In conclusion, knowledge of the pharmacokinetic profiles of artemether and lumefantrine is increasing within a range of settings, including infants and children. However, additional data would be warranted to better characterize artemether and lumefantrine pharmacokinetics in patients with hepatic impairment, in pregnant women, and in patients undergoing HIV/AIDS chemotherapy.

Background: Combination treatments, preferably containing an artemisinin derivative, are recommended to improve efficacy and prevent Plasmodium falciparum drug resistance. Our aim was to show non-inferiority of a new dispersible formulation of artemether-lumefantrine to the conventional crushed tablet in the treatment of young children with uncomplicated malaria., Methods: We did a randomised non-inferiority study on children weighing 5-35 kg with uncomplicated P falciparum malaria in Benin, Kenya, Mali, Mozambique, and Tanzania. The primary outcome measure was PCR-corrected 28-day parasitological cure rate. We aimed to show non-inferiority (with a margin of -5%) of dispersible versus crushed tablet. We constructed an asymptotic one-sided 97.5% CI on the difference in cure rates. A computer-generated randomisation list was kept centrally and investigators were unaware of the study medication administered. We used a modified intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00386763., Findings: 899 children aged 12 years or younger were randomly assigned to either dispersible (n=447) or crushed tablets (n=452). More than 85% of patients in each treatment group completed the study. 812 children qualified for the modified intention-to-treat analysis (n=403 vs n=409). The PCR-corrected day-28 cure rate was 97.8% (95% CI 96.3-99.2) in the group on dispersible formulation and 98.5% (97.4-99.7) in the group on crushed formulation. The lower bound of the one-sided 97.5% CI was -2.7%. The most common drug-related adverse event was vomiting (n=33 [7%] and n=42 [9%], respectively). No signs of ototoxicity or relevant cardiotoxicity were seen., Interpretation: A six-dose regimen of artemether-lumefantrine with the new dispersible formulation is as efficacious as the currently used crushed tablet in infants and children, and has a similar safety profile.

The efficacy and safety of artemether-lumefantrine for the treatment of malaria in nonimmune populations are not well defined. In this study, 165 nonimmune patients from Europe and non-malarious areas of Colombia with acute, uncomplicated falciparum malaria or mixed infection including P. falciparum were treated with the six-dose regimen of artemether-lumefantrine. The parasitologic cure rate at 28 days was 96.0% for the per protocol population (119/124 patients). Median times to parasite clearance and fever clearance were 41.5 and 36.8 hours, respectively. No patient had gametocytes after Day 7. Treatment was well tolerated; most adverse events were mild to moderate and seemed to be related to malaria. There were few serious adverse events, none of which were considered to be drug-related. No significant effects on ECG or laboratory parameters were observed. In conclusion, the six-dose regimen of artemether-lumefantrine was effective and well tolerated in the treatment of acute uncomplicated falciparum malaria in nonimmune patients.

Aims: To evaluate whether the potent CYP3A4 inhibitor ketoconazole has any influence on the pharmacokinetic and electrocardiographic parameters of the antimalarial co-artemether (artemether-lumefantrine) in healthy subjects., Methods: Sixteen subjects were randomized in an open-label, two period crossover design study. Subjects received a single dose of co-artemether (day 1) either alone or in combination with multiple oral doses of ketoconazole (400 mg on day 1 followed by 200 mg o.d. for 4 additional days). Serial blood samples were taken and assayed for artemether and its main active metabolite dihydroartemisinin (DHA), and lumefantrine., Results: The pharmacokinetics of artemether, its metabolite DHA, and lumefantrine were influenced by the presence of ketoconazole. AUC(0, infinity ) was increased from 320 to 740 ng ml-1 h (ratio 2.4, 90% CI 2.00, 2.86) for artemether, from 331 to 501 ng ml-1 h (ratio 1.7, 90% CI 1.40, 1.98) for DHA, and from 207 to 333 micro g ml-1 h (ratio 1.7, 90% CI 1.23, 2.21) for lumefantrine in the presence of ketoconazole. Cmax also increased in similar proportions for the three compounds (ratio 2.2 (90% CI 1.78, 2.83), 1.4 (90% CI 1.12, 1.74), and 1.3 (90% CI 0.96, 1.64), respectively). The terminal elimination half-life was increased for artemether (2.5 vs 1.9 h, 90% CI 1.12, 1.72) and DHA (3.1 vs 2.1 h, 90% CI 0.02, 3.36), but remained unchanged for lumefantrine (88 vs 95 h, 90% CI 0.81, 1.04). These increases in exposure to the antimalarial combination were much smaller than observed with food intake (up to 16 fold), and were not associated with increased side-effects or changes in electrocardiographic parameters. The study medications were well tolerated., Conclusions: The concurrent administration of ketoconazole with co-artemether led to modest increases in artemether, DHA, and lumefantrine exposure in healthy subjects. Dose adjustment of co-artemether is probably unnecessary in falciparum malaria patients when administered in association with ketoconazole or other potent CYP3A4 inhibitors.

Forty-two healthy Caucasian subjects were randomized in a double-blind, parallel three-group study (14 subjects per group) to investigate potential electrocardiographic and pharmacokinetic interactions between the antimalarials artemether-lumefantrine (six-dose regimen of Riamet over 3 days) and quinine (2-h intravenous infusion of 10 mg/kg body weight, not exceeding 600 mg in total, 2 h after the last dose of Riamet). The study medications were all safe and well tolerated after all treatments. Neither the pharmacokinetics of lumefantrine nor the pharmacokinetics of quinine was influenced by the presence of the other drug. Plasma levels of artemether and dihydroartemisinin appeared to be lower following the combined treatment Riamet + quinine, but this was not considered to be clinically relevant. Riamet alone had no effect on QTc interval. Infusion of quinine alone caused a transient prolongation of QTc interval, which was consistent with the known cardiotoxicity of quinine, with this effect being slightly but significantly greater when quinine was infused after Riamet. It would thus appear that the inherent risk of QTc prolongation of IV quinine was enhanced by prior administration of Riamet. However, these occasional QTc prolongations, which were small in magnitude and not correlated with plasma concentrations of any of the compounds, were not considered to be of clinical importance. In conclusion, overlapping therapy with artemether-lumefantrine and IV quinine in the treatment of patients with complicated or multidrug-resistant Plasmodium falciparum malaria may result in a modest increased risk of QTc prolongation, but this is far outweighed by the potential therapeutic benefit.

The efficacy-safety and pharmacokinetics of the six-dose regimen of artemether-lumefantrine (Coartem/Riamet; Novartis Pharma AG, Basel, Switzerland) were assessed in a randomized trial in 219 patients (> or = 12 years old) with acute, uncomplicated Plasmodium falciparum malaria in Thailand. One hundred and sixty-four patients received artemether-lumefantrine and 55 received the standard treatment combination of mefloquine-artesunate. Both drugs induced rapid clearance of parasites and malaria symptoms. The 28-day cure rates were 95.5% (90% confidence interval [CI] = 91.7, 97.9%) for artemether-lumefantrine and 100% (90% CI = 94.5, 100%) for mefloquine-artesunate. This high-dose regimen of artemether-lumefantrine was very well tolerated, with very good compliance. The most frequent adverse events were headache, dizziness, nausea, abdominal pain, dyspepsia, vomiting, and skin rash. Overall, only 2% of patients in both groups showed QTc prolongations but without any cardiac complication, and no differences were seen between patients with and without measurable baseline plasma levels of quinine or mefloquine. Plasma levels of artemether, dihydroartemisinin, and lumefantrine were consistent with historical data for the same dose regimen, and were higher, particularly for lumefantrine, than those previously observed with the four-dose regimen, explaining the greater efficacy of the six-dose regimen in a drug-resistant setting. These results confirm the excellent safety and efficacy of the six-dose regimen of artemether-lumefantrine in the treatment of multidrug-resistant P. falciparum malaria.

The serum/plasma protein binding and blood distribution of artemether and lumefantrine was studied in vitro. The techniques used were the erythrocyte partitioning and ultrafiltration methods with 1499%, respectively. Under physiological protein concentrations, the distribution in blood showed that 33% of artemether was bound to alpha(1)-acid glycoprotein, 17% to albumin, 12% to high density lipoproteins (HDL), 9.3% to low density lipoproteins (LDL) and 12% to very low density lipoproteins (VLDL), with binding capacities (nKa) of 3.2 x 10(5), 6.2 x 10(3), 2.1 x 10(5), 1.7 x 10(6) and 2.0 x 10(7) lmol(-1), respectively. 77% of lumefantrine was bound to HDL, 7.3% to LDL and 6.6% to VLDL, with binding capacities of 2.7 x 10(7), 2. 6 x 10(7) and 2.4 x 10(8) lmol(-1), respectively. A negligible fraction of lumefantrine was bound to albumin and alpha(1)-acid glycoprotein. The fraction in erythrocytes was around 10% for both artemether and lumefantrine.