Pharmacological data of Artemether

Artemether (12024-p)

Artemether (BAN, rlNN)

Dihydroarthemether Methyl Ether; Dihydroqinghaosu Methyl

Ether;o-Methyldihydroartemisinin;SM-224.(3R,5aS,6R,8aS,9R,10S,12R,12aR)-Decahydro-10-methoxy-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3,j]-1,2-benzodioxepin.

C₁₆H₂₆O₅ = 298.4.

CAS — 71963-77-4.

Adverse Effects and Precautions

Treatment with Artemether and its derivatives appears to be generally well tolerated, although there have been reports of mild gastrointestinal disturbance, dizziness, tinnitus, neutropenia, elevated liver enzyme values, and ECG abnormalities including prolongation of the QT interval.

Evidence of severe neurotoxicity has been seen in animals given high doses.

General reference to adverse effects associated with Artemether derivatives.

1. Price R, et al. Adverse effects in patients with acute falciparum malaria treated with Artemether derivatives. Am J Trop Med Hyg 1999; 60: 547-55.

Effects on the heart. Bradycardia was reported in 10 of 34 patients who received Artemether orally for 4 days.¹

1. Karbwang J,et al. Comparison of oral Artemether and mefloquine in acute uncomplicated falciparum malaria. Lancet 1992; 340: 1245-8.

Effects on the nervous system. Neurotoxicity has been reported in animals given artemotil.¹ an in vitro study² has shown that dihydroatemisinin, the metabolite common to all Artemether derivatives currently used, is neurotoxic. There has been a report ³ of acute cerebellar dysfunction manifesting as ataxia and slurred speech in a patient who took a 5-day course of articulate by mouth.

1. Brewer TG, et al. Neurotoxicity in animals due to Artemether and Artemether. Trans R Soc Trop Med Hyg 1994; 88 (suppl 1): 33-6.

2. Wesche DL, et al. Neurotoxicity of arthemether analogs in vitro. Antimicrobial Agents Chemother 1994; 38: 1813-19.

3. Miller LG, Panosian CB. Ataxia and slurred speech after artesunate treatment for falciparum malaria. N Engl J Med 1997; 336: 1328.

Pregnancy. Artesunate or Artemether was used to treat multidrug resistant falciparum malaria in 83 pregnant women in Thailand; of 73 pregnancies resulting in live births none showed evidence of any congenital abnormality.¹ sixteen of the women had received artesunate during the first trimester; of these, 12 had normal deliveries, 1 was lost to study, and 3 had spontaneous abortions.

No undue adverse effects on the neonates occurred in a study² involving 45 women treated for multidrug-resistant malaria during their second or third trimester of pregnancy with Artemether or Artemether plus mefloquine.

1. McGreevy R, et al. Arthemether derivatives in the treatment of falciparum malaria in pregnancy. Trans R Soc Trop Med Hyg 1998; 92: 430-3.

2. Sowunmi A, et al. Randomized trial of Artemether versus Artemether and mefloquine for the treatment of chloroqwuine/sufadoxine[sic]-pyrimethamine-resistant flaciparum malaria during pregnancy. J Obstet Gynaecol 1998; 18: 322-7.

Interactions

Grapefruit juice. The oral bioavailability of artemether may be increased by concomitant administration of grapefruit juice.

1. van Agtmael MA, et al. The effect of grapefruit juice on the time dependent decline of artemether plasma levels in healthy subjects. Clin Phamacol Ther 1999; 66: 322-7.

Pharmacokinetics

Peak plasma concentrations have been achieved in about 3 hours after oral administration of artemether, in about 6 hours after intramuscular injection of artemether, and in about 11 hours after rectal administration of artemisinin. Arthemetherand its derivatives are all rapidly hydrolyzed to the active metabolite dihydroartemisinin. Reported elimination half-lives have been about 45 minutes after intravenous administration of artesunate, about 4 hours after rectal artemisinin, and about 4 to 11 hours after intramuscular or oral artemether. There is very little published data on the pharmacokinetics of artemotil, but its elimination half-life appears to be longer than that of artemether.

Reviews.

1. White NJ, et al. Clinical pharmacokinetics and pharmacodynamics of artemether-lumefantrine. Clin Pharmacokinet1999; 37: 105-25.

2. Navaratnam V, et al. Pharmacokinetics of artemisinin-type compounds. Clin Pharmacokinet 2000; 39: 255-70.

Uses and Administration

Arthemetheris a sesquiterpene lactone isolated from Artemisia annua, a herb that has traditionally been used in China for the treatment of malaria, it is a potent and rapidly acting blood schizontocide active against Plasmodium vivax and against both chloroquine-sensitive and chloroquine-resistant strains of P. falciparum.

Arthemetherand its derivatives are used usually in combination with other antimalarials for the treatment of malaria resistant to conventional drugs.

The following doses are those suggested by WHOM for the treatment of malaria in areas of multidrug resistance. For oral administration in uncomplicated falciparum malaria, Artemether or sodium artesunate may be given as a 3-day course. The dose of arthemetheris 25 mg per kg body-weight on the first day with 12.5 mg per kg on the second and third days. For artesunate, the initial dose is 5 mg per kg on the first day with 2.5 mg per kg on days two and three. In both case a single dose of mefloquine 15 mg per kg (or occasionally 25 mg per kg if necessary) is given on the second day to affect clinical cure.

For oral treatment of uncomplicated flaciparum malaria, artemether is given in combination with lumefantrine, over a period of 60 hours in a dose of 80 mg administered at diagnosis and repeated after 8, 34, 36, 48 and 60 hours (total dose 480 mg). If the oral arthemether compounds have to be used alone they should be given for a minimum of 5 days.

For parenteral administration is server malaria, artemether or artesunate are employed. The loading dose of artemether is 3.2 mg per kg body-weight intramuscularly, followed by 1.6 mg per kg daily for a artesunate maximum of 6 days. The loading dose of artesunate is 2.4 mg per kg intravenously, followed at 12 and 24 hours by a dose of 1.2 mg per kg, and then 1.2 mg per kg daily for a maximum of 6 days. For both drugs the patients should be transferred to oral therapy as soon as possible. Additionally a single oral dose of mefloquine should be given to effect clinical cure.

Reviews

1. de Vries PJ, Dien TK. Clinical pharmacology and therapeutic potential of arthemether and its derivatives in the treatment of malaria. Drugs 1996; 52: 818-36.

2. Mclntosh HM, Olliaro P. Artemether derivatives for treating uncomplicated malaria (updated 20 February 2001). Available in The Cochrane Library; Issue 4. Oxford: Update Software; 2001.

3. Mclntosh HM, Olliaro P. Artemether derivatives for treating severe malaria (updated 29 August 2001). Available in The Cochrane Library; Issue 4. Oxford: Update Software; 2001.

Administration of Artemether derivatives.

To overcome the poor solubility of arthemetherin water a number of dosage forms and routes of administration have been tried. Also several more potent derivatives with more suitable pharmaceutical properties have been developed.^1-3 notably the methyl ether derivative, artemether, and the ethyl ether derivative, artemotil, which are more lipid soluble; the sodium salt of the hemisuccinate ester, sodium artesunate, which is soluble in water but appears to heave poor stability in aqueous solutions; and sodium artelinate which is both soluble and stable in water. Other derivatives which have been studied include artefline. Several preparation of Artemether derivatives are available either commercially or for studies organized by bodies such as WHO.³ These include oral formulations of artemether, artesunate, Artemether itself, and dihydroartemisinin; intramuscular formulations of artemotil, artemether, and artesunate, intravenous formulations of artelinic acid and artesunate; and suppositories of Artemether and artesunate.

1. Titulaer HAC, et al. Formulation and pharmacokinetics of Artemether and its derivative. Int J Pharmaceutics 1991; 69: 83-92.

2. WHO. WHO model prescribing information: drugs are used in parasitic diseases. 2^nd ed. Geneva: WHO, 1995.

3. Olliaro PL, Trigg PI. Status of antimalarial drugs under development. Bull WHO 1995; 73: 565-71.

Malaria

Arthemetherand its derivatives have been shown in many studies to be effective in the treatment of both acute uncomplicated and sever malaria, the overall management of which is caused further on p.428. In an attempt to delay the developed of resistance to these compounds, WHO has recommended that their use be restricted to the treatment of malaria in areas of documented multidrug resistance and that they should not be used at all for prophylaxis; in practice, however, they appear to be more widely used. Recrudescence rates are high when Artemether compounds are given alone and they should therefore, when possible, be given with another antimalarial such as mefloquine in order to affect a clinical cure.

In acute uncomplicated malaria the drugs are usually given by mouth. Those used have been artemisinin, artemether or artesunate usually with mefloquine additionally. Artemether is also used with lumefantrine. The combination of artesunate with pyrimethamine-sulfadoxine is under investigation for use as first-line treatment in areas of chloroquine resistance. Artemotile may be given intramuscularly in acute malaria.

Parenteral therapy is generally necessary in sever malaria and good result in multidrug-resistant areas have been obtained with artemether, artemotil, or rtesunate intramuscular, usually followed by oral mefloquine. Artesunate has also been given intravenously. Rectal administration of artemisini, followed by oral mefloquine, has been successful.

Alternatives to standard treatment of cerebral malaria with intravenous quinine have been sought, partly because of the problems associated with giving intravenous infusions in the field. Several studies have shown intramuscular artemether to be effective, but the wisdom of such use when there is no multidrug resistance has been severely questioned. Also, although artemether has compared favorably with quinine in the treatment of severe (including cerebral) falciparum malaria, in other studies artemether, although an effective alternative to quinine, was either associated with slightly longer coma-recovery times or did not reduce mortality significantly compared with quinine.