Malarone (atovaquone and proguanil hydrochloride): a review of its clinical development for treatment of malaria. Malarone Clinical Trials Study Group.

Abstract

Abstract. The continuing spread of drug-resistant malaria emphasizes the need for new antimalarial drugs. Atovaquone is a broad-spectrum antiprotozoal drug with a novel mechanism of action, via inhibition of parasite mitochondrial electron transport, and a favorable safety profile. Early studies with atovaquone alone for treatment of malaria demonstrated good initial control of parasitemia but an unacceptable rate of recrudescent parasitemia. Parasites isolated during recrudescence after treatment with atovaquone alone were resistant to atovaquone in vitro. The combination of atovaquone and proguanil is synergistic in vitro, and clinical studies demonstrated enhanced efficacy of the combination compared to either drug alone for treatment of malaria. Malarone, a fixed-dose combination of 250 mg of atovaquone and 100 mg of proguanil hydrochloride, is available in many countries for treatment of acute, uncomplicated malaria caused by Plasmodium falciparum. At the recommended dose (in adults, four tablets once a day for three days), the overall cure rate was Ͼ 98% in more than 500 patients with falciparum malaria. In four randomized, controlled clinical trials, treatment with atovaquone and proguanil hydrochloride was significantly more effective than mefloquine (Thailand), amodiaquine (Gabon), chloroquine (Peru and the Philippines) or chloroquine plus pyrimethamine/sulfadoxine (Philippines). In clinical trials where the comparator drug was highly effective, treatment with atovaquone and proguanil hydrochloride was equally effective. Parasites isolated during recrudescence after treatment with the combination of atovaquone and proguanil were not resistant to atovaquone in vitro. The most commonly reported adverse events in clinical trials (abdominal pain, anorexia, nausea, vomiting, diarrhea and coughing) occurred with similar frequency in patients treated with a comparator drug. Malarone is a safe and effective new agent for treatment of malaria.

Effectiveness of Antimalarial Drugs

“…The fixed combination of atovaquone-chloroguanide, which affects mitochondrial electron transport and folate metabolism in asexual blood stages, represents true combination therapy. 112 Combined antimalarial therapies include old and new drugs -old drugs in new combinations (chloroquine and sulfadoxine-pyrimethamine), an old drug combined with a new drug (amodiaquine and artesunate), and new drugs in combination (lumefantrine and artemether). 113,114 Combination therapy that includes artemisinin appears to be potent and particularly useful in endemic regions; extracted from the weed Artemesia annua, the artemisinins (primarily artemether, artesunate, and dihydroartemisinin) were developed in China during the 1960s.…”

Antimalarial 4(1H)-pyridones bind to the Q i site of cytochrome bc 1

“…Despite this success, incidence of chloroquine, artemisinin, and multidrug resistant strains of the Plasmodium parasite and of Plasmodium falciparum, the most lethal strains of malaria, have been reported and appear to be rising (5)(6)(7). Individual compounds used in monotherapy frequently suffer resistance, resulting in the need for expensive combinatorial treatments (8)(9)(10). This situation calls for new, cost-effective, drugs that can contribute toward more effective treatment and eventual eradication.…”

“…Cytochrome bc 1 (ubiquinol: cytochrome c oxidoreductase; complex III) is a major drug target for the treatment and prevention of malaria, and in the treatment of toxoplasmosis (8,11). Cytochrome bc 1 is a dimeric multisubunit electron transport protein embedded in the inner-mitochondrial membrane (12)(13)(14).…”

Modified Fixed-Ratio Isobologram Method for Studying In Vitro Interactions between Atovaquone and Proguanil or Dihydroartemisinin against Drug-Resistant Strains of Plasmodium falciparum

“…Synergism, indifference (addition), and antagonism are the expected outcomes of drug-drug interactions. The antimalarial Malarone (GlaxoSmithKline) is a recently introduced combination regimen for the treatment (18,19) and prophylaxis (14,23) of falciparum malaria. It has been previously reported that the synergistic interaction between the components of Malarone, atovaquone (ATV) and proguanil (PG), is reduced to an indifferent interaction in ATV-resistant Plasmodium yoelii parasites (25).…”