Symposium on Riamet for Malaria Therapy
September 1, 1999 5 minutes read
Symposium on Riamet for Malaria Therapy
Reviewed by Maria D. Mileno, MD
Source: Promoting the Rational Use of Antimalarials in Non-immune Travelers: Riamet as Stand-by Emergency Treatment. Satellite Symposium, June 9, 1999. Participants; Hatz C, Wernsdorfer WH, van Agtmael MA, van Vugt M, Steffen R. 6th Conference of the International Society of Travel Medicine.
Riamet or co-artemether (artemether 20 mg and lumefantrine 120 mg) is a promising new oral antimalarial drug combination that combines the fast, short-acting artemether, for rapid parasite clearance, with the prolonged action of lumefantrine intended to produce radical cure of drug-resistant malaria.
An evening symposium held at the 6th Conference of the International Society of Travel Medicine, Montreal, Quebec, Canada, June 6-10, 1999 addressed the safety, efficacy, and pharmacokinetics of co-artemether in a program entitled "Co-artemether: A novel therapy to meet the global malaria challenge." In this context, a summary of new WHO guidelines for standby emergency treatment of malaria was also reviewed by Dr. Robert Steffen.
Clearly, there is a need for the development of new and more effective antimalarial agents. In China, the artemisinin compounds have been both widely and effectively used for the treatment of malaria over many years, and these agents were reviewed in the November/ December 1997 issue of TMA Update. The main advantages of the artemis-inins are their rapid action and their effectiveness against resistant malarial parasites.
Despite concerns over potential artemisinin neurotoxicity, which are clearly suggested by primate animal studies, the main disadvantage of artemisinins is the commone appearance of recrudescent infections when these agents are used as monotherapy. An important cause of this recrudescence is the short elimination half-life (1-2 hours) for this group of drugs, thus requiring prolonged treatment courses.
Lumefantrine is a synthetic molecule in the family of arylamino alcohols (thus related to quinine), which was developed by the Academy of Military Medical Sciences in Beijing (see Figure 1). It is a fluorine derivative of halofantrine.1 While lumefantrine is an effective antimalarial with distinctive blood schizonticidal activity for all Plasmodium species, including chloroquine-resistant strains of P. falciparum2, it has a slower onset of action than other antimalarial agents. Its advantages include the potential for synergism with the artemisinin compounds and low recrudescence rates when these agents are used together.3 Significant QTc prolongations (> 30 msec) seen 6-12 hours after halofantrine administration are not observed after four doses of lumefantrine in combination with artemether.4 Drug-resistance induction experiments show it is relatively easy to produce malaria resistance to lumefantrine in vivo, yet the potential for resistance does not reduce parasite drug sensitivity when lumefantrine is used in combination with artemether.
More than 2000 patients have been treated with co-artemether, in 15 trials (9 of them comparative against mefloquine, mefloquine/artesunate, quinine/Fansidar, or quinine; 6 noncomparative) conducted in China, Thailand, India, the Gambia, Tanzania, and Europe.1 Patients ranged in ages from 1-78 years, and 32.6% of those treated in Africa and Thailand were 12 years old or younger. Median parasitemia levels were 22,248 parasites/microliter. Patients had a median temperature of 38°C. Treatment protocols included a four-dose or a six-dose regimen, with the number of tablets per dose adjusted by body weight.
After 24 hours, co-artemether eliminated more than 99% of the parasites present at baseline, with an overall parasite clearance time of 36 hours (see Figure 2). Malaria symptoms resolved quickly, with a fever clearance time of 30 hours. Gametocytes were cleared rapidly compared with other antimalarials (within 4-7 days) and a rapid onset of action was seen for all doses tested. None of the patients on co-artemether developed RII or RIII treatment failure.1
With a four-dose regimen, the 28-day cure rate was 97.5% in China and 95.4% in India, but only 70.5% in Thailand. Subsequently, the six-dose regimen was tested and it resulted in cure rates that were greater than 95%, similar to the results obtained with a current standard treatment of mefloquine plus artesunate used in Thailand.1
In Africa, where high transmission rates of malaria complicate the evaluation of the long-term treatment efficacy, the seven-day cure rate was 97.3% and the 14-day cure rate was 91%. This can be contrasted with experience in Tanzania, where more than 60% of young children treated with chloroquine had resistant malaria or needed reserved antimalarial medications within the first week of therapy. Reinfections occur quickly there and even following co-artemether, more than 6% of parasite reappearances were new infections, as determined by PCR.
P. vivax infections were present in only 3.1% of all patients included in these trials. All patients on co-artemether cleared this form of malaria within 54 hours of starting treatment, and the median time to clearance of P. vivax was 23 hours. Reappearance of P. vivax was seen in 6.7% of patients on either dose regimen, mostly for patients treated in Thailand. In all, co-artemether was effective in suppressing P. vivax infections. Drugs with a longer half-life, such as mefloquine, were associated with a much later appearance of P. vivax, with a total of 18.5% showing reappearances of the parasite over a 63-day follow-up period.
In summary, co-artemether, while related to quinine and halofantrine, has no known relevant cardiac effects. Specifically, electrocardiographic QTc prolongation did not occur in any subjects, including those with the highest plasma drug levels; there was no correlation between QTc intervals and drug plasma concentrations. Co-artemether has been shown to be rapidly effective in clearing P. falciparum parasites from peripheral blood and resolving fever associated with acute malaria infections. It is superior when compared to all nonartemisinin-containing regimens. Its rapid onset of action may even prevent clinical progression to severe cerebral malaria. An additional useful property of this drug combination is the relatively rapid clearance of gametocytes, which may help reduce the reservoir of infections in countries with high malaria transmission rates.
References
1. Gathmann I, and the Co-artemether Clinical Trials Research Group. Novartis Pharma AG, Basel, Switzerland. Second European Congress on Tropical Medicine. UK Sept. 14-18, 27-32.
2. van Agtmael M, et al. Int J Antimicrob Agents 1999;12:159-169.
3. van Agtmael MA, et al. Int J Antimicrob Agents 1999;12:151-158.
4. Bindschedler M, et al. Second European Congress on Tropical Medicine. UK September 14-18, 24-26.
Concerns about clinical efficacy of the new antimalarial agent Riamet include:
a. partial clinical efficacy against P. falciparum.
b. poor clincal efficacy against P. vivax.
c. significant OTc interval prolongation due to its structural relationship to halofantrine.
d. slow onset of action for lumefantrine.
e. None of the above
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