Artemether/lumefantrine fixed-dose combination comprises a fixed ratio of 1:6 parts of artemether and lumefantrine, respectively. The site of antiparasitic action of both components is the food vacuole of the malarial parasite, where they are thought to interfere with the conversion of haem, a toxic intermediate produced during haemoglobin breakdown, to the nontoxic haemozoin, malaria pigment. Lumefantrine is thought to interfere with the polymerisation process, while artemether generates reactive metabolites as a result of the interaction between its peroxide bridge and haem iron. Both artemether and lumefantrine have a secondary action involving inhibition of nucleic acid- and protein synthesis within the malarial parasite. Artemether/lumefantrine has been reported to have potent activity in terms of clearing gametocytes.
Pharmacokinetic characterisation of artemether/lumefantrine is limited by the lack of an intravenous formulation, and the very high interand intra-subject variability of artemether and lumefantrine plasma concentrations and derived pharmacokinetic parameters (AUC, Cmax).
Artemether is absorbed fairly rapidly and dihydroartemisinin, the active metabolite of artemether, appears rapidly in the systemic circulation with peak plasma concentrations of both compounds reached about 2 hours after dosing. Mean Cmax and AUC values of artemether ranged between 60.0–104 ng/ml and 146–338 ng·h/ml, respectively, in fed healthy adults after a single dose of 80 mg artemether/480 mg lumefantrine. Mean Cmax and AUC values of dihydroartemisinin ranged between 49.7–104 ng/mL and 169-308 ng·h/ml, respectively. Absorption of lumefantrine, a highly lipophilic compound, starts after a lag-time of up to 2 hours, with peak plasma concentration (mean between 5.10– 9.80 µg/ml) about 6–8 hours after dosing. Mean AUC values of lumefantrine ranged between 108 and 243 µg·h/ml. Food enhances the absorption of both artemether and lumefantrine: in healthy volunteers the relative bioavailability of artemether was increased more than two-fold, and that of lumefantrine sixteen-fold compared with fasted conditions when artemether/lumefantrine was taken after a high-fat meal.
Food has also been shown to increase the absorption of lumefantrine in patients with malaria, although to a lesser extent (approximately two-fold), most probably due to the lower fat content of the food ingested by acutely ill patients. The food interaction data indicate that absorption of lumefantrine under fasted conditions is very poor (assuming 100% absorption after a high-fat meal, the amount absorbed under fasted conditions would be <10% of the dose). Patients should therefore be encouraged to take the medication with a normal diet as soon as food can be tolerated.
Artemether and lumefantrine are both highly bound to human serum proteins in vitro (95.4% and 99.7%, respectively). Dihydroartemisinin is also bound to human serum proteins (47–76%).
Artemether is rapidly and extensively metabolised (substantial first-pass metabolism) both in vitro and in humans. Human liver microsomes metabolise artemether to the biologically active main metabolite dihydroartemisinin (demethylation), predominantly through the isoenzyme CYP3A4/5. This metabolite has also been detected in humans in vivo.
Glucuronidation of dihydroartemisinin is predominately catalysed by UGT1A9 and UGT2B7.
Dihydroartemisinin is further converted to inactive metabolites.
The pharmacokinetics of artemether in adults is time-dependent. During repeated administration of artemether/lumefantrine, plasma artemether levels decreased significantly, while levels of the active metabolite (dihydroartemisinin) increased, although not to a statistically significant degree. The ratio of day 3/day 1 AUC for artemether was between 0.19 and 0.44, and was between 1.06 and 2.50 for dihydroartemisinin. This suggests that there was induction of the enzyme responsible for the metabolism of artemether. Artemether and dihydroartemisinin were reported to have a mild inducing effect on CYP3A4 activity.
Lumefantrine is N-debutylated, mainly by CYP3A4, in human liver microsomes. In vivo in animals (dogs and rats), glucuronidation of lumefantrine takes place directly and after oxidative biotransformation. In humans, the exposure to lumefantrine increases with repeated administration of artemether/lumefantrine over the 3-day treatment period, consistent with the slow elimination of the compound. Systemic exposure to the metabolite desbutyl-lumefantrine, for which the in vitro antiparasitic effect is 5 to 8 fold higher than that for lumefantrine, was less than 1% of the exposure to the parent drug. Desbutyl-lumefantrine data is not available specifically for an African population. In vitro, lumefantrine significantly inhibits the activity of CYP2D6 at therapeutic plasma concentrations.
Artemether and dihydroartemisinin are rapidly cleared from plasma with a terminal half-life of about 2 hours. Lumefantrine is eliminated very slowly with an elimination half-life of 2 to 6 days. Demographic characteristics such as sex and weight appear to have no clinically relevant effects on the pharmacokinetics of artemether/lumefantrine.
Limited urinary excretion data are available for humans. In 16 healthy volunteers, neither lumefantrine nor artemether was found in urine after administration of artemether/lumefantrine, and only traces of dihydroartemisinin were detected (urinary excretion of dihydroartemisinin amounted to less than 0.01% of the artemether dose).
In animals (rats and dogs), no unchanged artemether was detected in faeces and urine due to its rapid and extensive first-pass metabolism, but numerous metabolites (partly identified) have been detected in faeces, bile and urine. Lumefantrine was excreted unchanged in faeces and with traces only in urine. Metabolites of lumefantrine were eliminated in bile/faeces.
No specific dose proportionality studies were performed. Limited data suggest a dose-proportional increase of systemic exposure to lumefantrine when doubling the artemether/lumefantrine dose. No conclusive data is available for artemether.
Systemic exposure to lumefantrine, artemether and dihydroartemisinin was similar following administration of artemether/lumefantrine as dispersible tablets and crushed tablets in healthy adults.
Systemic exposure to lumefantrine was similar following administration of artemether/lumefantrine dispersible tablets and intact tablets in healthy adults. However, exposure to artemether and dihydroartemisinin was significantly lower (by 20-35%) for the dispersible than for the intact tablet. These findings are not considered to be clinically relevant for the use of the dispersible tablets in the paediatric population since adequate efficacy of artemether/lumefantrine dispersible tablets was demonstrated in this population. The dispersible tablet is not recommended for use in adults.
No specific pharmacokinetic studies have been performed in elderly patients. However, there is no information suggesting that the dosage in patients over 65 years of age should be different than in younger adults.
In paediatric malaria patients, mean Cmax (CV%) of artemether (observed after first dose of artemether/lumefantrine) were 223 (139%), 198 (90%) and 174 ng/ml (83%) for body weight groups 5-<15, 15-<25 and 25-<35 kg, respectively, compared to 186 ng/ml (67%) in adult malaria patients. The associated mean Cmax of DHA were 54.7 (108%), 79.8 (101%) and 65.3 ng/mL (36%), respectively compared to 101 ng/ml (57%) in adult malaria patients. AUC of lumefantrine (population mean, covering the six doses of artemether/lumefantrine) were 577, 699 and 1150 µg•h/ml for paediatric malaria patients in body weight groups 5-<15, 15-<25 and 25-<35 kg, respectively, compared to a mean AUC of 758 µg•h/ml (87%) in adult malaria patients. The elimination half-lives of artemether and lumefantrine in children are unknown.
Study B2306 showed that the Cmax of artemether and DHA in infants with uncomplicated P. falciparum malaria weighing <5 kg and older than 28 days of age who were treated with artemether/lumefantrine dispersible tablets, was on average 2- to 3-fold higher than that in pediatric patients with a body weight ≥5 kg and children up to 12 years of age treated with the same dose of artemether/lumefantrine tablets. The mean Cmax of lumefantrine was similar to that observed in pediatric patients with a body weight ≥5 kg.
Pharmacokinetics of artemether, DHA and lumefantrine in the Japanese population was found to be consistent with other populations.
No specific pharmacokinetic studies have been performed either in patients with hepatic or renal insufficiency or elderly patients. The primary clearance mechanism of both artemether and lumefantrine may be affected in patients with hepatic impairment. In patients with severe hepatic impairment, a clinically significant increase of exposure to artemether and lumefantrine and/or their metabolites cannot be ruled out. Therefore, caution should be exercised in dosing patients with severe hepatic impairment. Based on the pharmacokinetic data in 16 healthy subjects showing no or insignificant renal excretion of lumefantrine, artemether and dihydroartemisinin, no dose adjustment for the use of artemether/lumefantrine in patients with renal impairment is advised.
The main changes observed in repeat-dose toxicity studies were associated with the expected pharmacological action on erythrocytes, accompanied by responsive secondary haematopoiesis.
Studies in dogs and rats have shown that intramuscular injections of artemether resulted in brain lesions. Changes observed mainly in brainstem nuclei included chromatolysis, eosinophilic cytoplasmic granulation, spheroids, apoptosis and dark neurons. Lesions were observed in rats dosed for at least 7 days and dogs for at least 8 days, but lesions were not observed after shorter intramuscular treatment courses or after oral dosing. The estimated artemether 24 h AUC after 7 days of dosing at the no observed effect level is approximately 7-fold greater or more than the estimated artemether 24 h AUC in adult humans. The hearing threshold was affected at 20 dB by oral artemether administration to dogs at a dose of about 29 times the highest artemether clinical dose (160 mg/day) based on body surface area comparisons. Most nervous system disorder adverse events in the studies of the 6-dose regimen were mild in intensity and resolved by the end of the study.
Artemether and lumefantrine were not genotoxic/clastogenic based on in vitro and in vivo testing.
Carcinogenicity studies were not conducted.
Embryotoxicity was observed in rat and rabbit reproductive toxicity studies conducted with artemether, a derivative of artemisinin. Artemisinins are known to be embryotoxic. Lumefantrine alone caused no sign of reproductive or development toxicity at doses up to 1,000 mg/kg/day in rats and rabbits, doses which are at least 10 times higher than the daily human dose based on body surface area comparisons.
Reproductive toxicity studies performed with the artemether-lumefantrine combination caused maternal toxicity and increased post-implantation loss in rats and rabbits.
Artemether caused increases in post-implantation loss and teratogenicity (characterised as a low incidence of cardiovascular and skeletal malformations) in rats and rabbits. The embryotoxic artemether dose in the rat yields artemether and dihydroartemisinin exposures similar to those achieved in humans based on AUC.
Artemether-lumefantrine administration yielded altered sperm motility, abnormal sperm, reduced epididymal sperm count, increased testes weight, and embryotoxicity; other reproductive effects (decreased implants and viable embryos, increased preimplantation loss) were also observed. The no adverse effect level for fertility was 300 mg/kg/day. The relevance to this finding in humans is unknown.
A study investigated the neurotoxicity of oral artemether in juvenile rats. Mortality, clinical signs and reductions in body weight parameters occurred most notably in younger rats. Despite the systemic toxicity noted, there were no effects of artemether on any of the functional tests performed and there was no evidence of a direct neurotoxic effect in juvenile rats.
Very young animals are more sensitive to the toxic effect of artemether than adult animals. There is no difference in sensitivity in slightly older animals compared to adult animals. Clinical studies have established the safety of artemether and lumefantrine administration in patients weighing 5 kg and above.
In toxicity studies in dogs at doses >600 mg/kg/day, there was some evidence of prolongation of the QTc interval (safety margin of 1.3-fold to 2.2-fold for artemether using calculated free Cmax), at higher doses than intended for use in man. In vitro hERG assays showed a safety margin of >100 for artemether and dihydroartemisinin. The hERG IC50 was 8.1 µM for lumefantrine and 5.5 µM for its desbutyl metabolite.
Based on the available non-clinical data, a potential for QTc prolongation in the human cannot be discounted.
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