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CI
N
N
CI
2
HN
HN
CH 3
N CH 3 O S O N N N O CH 3 H N N N CH 3
H
O NH 2
OH CH 3 H N CH 3 CI
2
nd
Guidelines for the treatment of malaria – 2 edition
N CH 3
H 3 C
A3.6.2 Artemether
Molecular weight: 298.4
F
H 3 C H 3 C Artemether is the methyl ether of H 3 C
F F
F dihydroartemisinin. It is more lipid soluble
F
N O O than artemisinin or artesunate. It can O
O C O C O C
F O O be given as an oil-based intramuscular O
ÿ O CH 3 O CH 3 injection or orally. It is also coformu CH 3
Olated
O
H
H H H H 3 C H H with lumefantrine (previously referred to as H
HO
O
HO O O benflumetol) for combination therapy.
H H H
HN CH 3 CH 3 O CH 3
Formulations
• Capsules
CI containing 40 mg of artemether.
H 3 C H 3 C
• Tablets containing 50 mg of artemether. CH 3
O O C O O C • Ampoules of injectable solution for intramuscular injection containing 80 mg NH 2 of
HN
O O artemether in 1 ml for adults or 40 mg of artemether in 1 ml for paediatric use.
CH 3 CH 3 CI CI N
O O
H H H H In a coformulation with lumefantrine:
H 3 C H 3 C
HO H 3 C O • Tablets containing 20 mg of artemether and 120 mg of lumefantrine.
O
H H
H 3 C N
CH 3 CH 3
Pharmacokinetics OH
Peak plasma concentrations occur around 2–3 h after oral administration (38). Following
intramuscular injection, absorption is very variable, especially in children with poor
peripheral perfusion: peak plasma concentrations generally occur after around 6 h
CI
CI but absorption is slow and erratic and times to peak can be 18 h or longer in some
H H H
O
N N N CH 3 CI cases (39–41). Artemether is metabolized to dihydroartemisinin, the active metabolite.
H NH NH CH 3
H N predominates, whereas after oral
After intramuscular administration, artemether S NH 2
2
NH NH CH 3
O
CI administration dihydroartemisinin predominates. Biotransformation is mediated via
H
H
H
CH 3
O the cytochrome P450 enzyme CYP3A4. Autoinduction of metabolism is less than with
N
N
N
H artemisinin. Artemether is 95% bound to plasma proteins. The elimination half-life is
approximately 1 h, but following intramuscular administration the elimination phase
OH is prolonged because of continued absorption. No dose modifications are necessary in
O renal or hepatic impairment.
Toxicity
In all species of animals tested, intramuscular artemether and artemotil cause an
CItoxicity
H 2 C H H 3 C CH 3 unusual selective pattern of neuronal damage to certain brain stem nuclei. Neuro
OH
CH 3
O
O
HO CH 3 H N in experimental animals is related to the sustained blood concentrations that follow
O
OH
O
CH 3
OH
N
OH intramuscular administration (42), since it is much less frequent when the same doses
NH N
N 2 H H
H 3 C O
HO H NH 2 82 H HO S CH 3
OH H H OH
O OH O OH O O
H 3 C H 3 C OH N HO OH
H 3 C CH 3
N