Am. J. Trop. Med. Hyg., 50(2), 1994, pp. 187—192 Copyright 0 1994 by The American Society of Tropical Medicine and Hygiene EFFICACY AND TOLERANCE OF EXTENDED-DOSE HALOFANTRINE FOR DRUG-RESISTANT FALCIPARUM MALARIA IN THAILAND GEORGE WA11@,LERSAN LOESUTI1VIBOON, KRISADA JONGSAKUL, G. DENNIS SHANKS, COLIN K. OHRT, CHITRAPORN KARNASUTA, BRIAN SCHUSTER, AND LAWRENCE FLECKENSTEIN Department of Medicine, Armed Forces Research Institute of Medical Science (AFRIMS), Bangkok, Thailand; Surasinghanat Royal Thai Army Hospital, Aranyaprathet, Thailand; Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Washington, District of Columbia; College of Pharmacy, University of Iowa, Iowa City, Iowa Abstract. New treatments for malaria are urgently needed in areas such as Thailand where highly drug-resistant strains of Plasmodium falciparum are prevalent. Mefloquine is rapidly losing efficacy and conventional doses of halofantrine are ineffective. We there fore used pharmacokinetic simulation to design an extended-dose halofantrine regimen and tested it in 26 soldiers stationed along the Thai-Cambodian border. Halofantrine was given after meals as three doses of 500 mg each at 4-hr intervals on the first day, followed by 500 mg a day for six days (total dose 4.5 g). Twenty-six soldiers treated with quinine tetracycline for seven days (Q7T7) served as controls. There were no significant differences in efficacy between halofantrine and Q7T7 (P> 0.1) as assessed by cure rate (92% versus 85%), mean parasite clearance time (82 hr versus 81 hr), or mean fever clearance time (93 hr versus 99 hr). Halofantrine was better tolerated than Q7T7. The side effects score was lower (2 versus 11; P < 0.00 1), there were less days on which side effects occurred (2.0 days versus 5.5 days; P < 0.001), and fewer patients had adverse effects on every treatment day (4% versus 42%; P < 0.01). High-dose halofantrine is as effective and better tolerated than quinine-tetracycline for multidrug-resistant falciparum malaria. New treatments are urgently needed for drug resistant falciparum malaria. Mefloquine is but the latest in a series of antimalarials that have rapidly lost efficacy after being introduced for the treatment of malaria in the border regions of Thailand,' where drug-resistant Plasmodium fal ciparum parasites are particularly prevalent.2 Halofantrine is a promising new antimalarial, butcross-resistance withmefloquineisa poten tial problem3 and the drug is absorbed erratical ly.4 In this study, we attempted to overcome poor absorption by using a repetitive dosage reg imen and administering halofantrine with meals, which has been shown to increase its bioavail ability.5 Even when given with meals, however, the manufacturer's (SmithKline Beecham, Welwyn, Garden City, UK) recommended dose of halo fantrine (500 mg taken three times at 6-hr inter vals) cured only 50% of P. falciparum infections acquired along the Thai-Cambodian border.6 Drug levels one week after treatment were high er in the patients who were cured, suggesting that a regimen capable of producing sustained, high, blood levels might be successful. We used pharmacokimetic simulation to devise such a reg imen and them tested it in soldiers stationed along the Thai-Cambodian border. The efficacy and side effects of halofantrine were compared with those of quinine-tetracycline given for sev en days (Q7T7), the standard in-hospital treat ment for uncomplicated falciparum malaria in this region.7 Patients PATIENTS AND METHODS Study subjects were recruited from male Thai volunteer soldiers 18 years of age or older who were occupationally exposed to malaria along the Thai-Cambodian border. Patients with cere bral malaria, renal failure, hepatic impairment, shock, hemoglobinuria, or with mixed infections (e.g., P. falciparum and P. vivax) were excluded. Study volunteers were hospitalized in a non malariousareafor21 days and thenexamined one week after discharge. The reappearance of parasites in the peripheral blood within a month 187