Malarone (R) (atovaquone and proguanil hydrochloride): A review of its clinical development for treatment of malaria

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 elec tron transport, and a favorable safety profile. Early studies with atovaquo ne alone for treatment of malaria demonstrated good initial control of para sitemia but an unacceptable rate of recrudescent parasitemia. Parasites iso lated during recrudescence after treatment with atovaquone alone were resis tant 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(TM), a fixed-dose combination of 250 mg of atovaquone and 100 mg o f proguanil hydrochloride, is available in many countries for treatment of acute, uncomplicated malaria caused by Plasmodium falciparum. At the recomm ended dose tin adults, four tablets once a day for three days), the overall cure rate was > 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 (T hailand), amodiaquine (Gabon), chloroquine (Peru and the Philippines) or ch loroquine plus pyrimethanline/sulfadoxine (Philippines). In clinical trials where the comparator drug was highly effective, treatment with atovaquone and proguanil hydrochloride was equally effective. Parasites isolated durin g recrudescence after treatment with the combination of atovaquone and prog uanil were not resistant to atovaquone in vitro. The most commonly reported adverse events in clinical trials (abdominal pain, anorexia, nausea, vomit ing, diarrhea and coughing) occurred with similar frequency in patients tre ated with a comparator drug. Malarone is a safe and effective new agent for treatment of malaria.