First-time-in-humans safety and pharmacokinetics of WR 238605, a new antimalarial.

Abstract

Abstract. WR 238605 is an 8-aminoquinoline drug currently under development for prophylaxis and treatment of malaria. Preclinical studies have demonstrated that it has greater efficacy and less toxicity compared with primaquine. In this first-time-in-human randomized, double-blind, placebo-controlled study designed to evaluate the safety, tolerance and pharmacokinetics, WR 238605 was administered to 48 men in single oral doses ranging from four to 600 mg (base). It was well tolerated, with gastrointestinal disturbances as possible side effects. Linear kinetics were demonstrated at these doses. WR 238605 has a long absorption phase and is slowly metabolized, with a t max of 12 hr and an elimination half-life of 14 days. These safety, efficacy and pharmacokinetic properties make this drug an excellent candidate for further testing as a prophylactic, radical curative, and terminal eradication drug.Malaria is a leading cause of morbidity and mortality in third-world countries. 1 About 2.4 billion people, almost half the world's population, live in malaria-endemic areas. The annual incidence of malaria is estimated to be in the range of 100-300 million cases. Of these, approximately 1.0-1.5 million die. 2 Plasmodium falciparum is considered the most important malaria parasite because of its high morbidity and mortality, especially in nonimmune individuals such as children, international travelers, and U.S. Armed Forces deployed overseas. Plasmodium vivax malaria, although less often fatal, still carries significant morbidity as well as the problem of relapses. 3 Primaquine is the only available drug active against exoerythrocytic (persistent tissue) stages of P. vivax or P. ovale. However, primaquine has a low therapeutic index. 4,5 The most serious toxicity is acute hemolysis, which occurs in individuals who are genetically deficient in glucose-6-phosphate dehydrogenase (G6PD). Other adverse effects include abdominal pain, cramps, anorexia, nausea, vomiting, leukocytosis, leukopenia, and methemoglobinemia. Headaches, interference with visual accommodation, pruritus, hypertension, and arrhythmias have also occasionally been reported with primaquine therapy. More recently, primaquine has been shown to be better tolerated when administered with food. 6-8 However in the standard regimen for the radical cure of P. vivax malaria, primaquine's short half-life necessitates daily administration, often resulting in poor compliance, which may lead to treatment failures. Furthermore, recent reports of refractory or tolerant strains have surfaced, and these strains may become more of a problem in the future. 3,9 Safer, more effective, and longer acting antimalarial drugs for causal prophylaxis, terminal eradication, and radical cure are needed.WR 238605 succinate ((Ϯ)-8-[(4-amino-1-methylbutyl) amino]-2,6-dimethoxy-4-methyl-5-(3-trifluoromethylphenoxy) quinoline succinate) is an 8-aminoquinoline developed by the Walter Reed Army Institute of Research (WRAIR) in search of a safer, more effective, and longer-acting primaquine repl...

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“…Gametocytes from the NF54 pfs16 , NF54 pfs48/45 , and NF54 mal8p1.16 reporter lines were exposed to compounds at concentrations corresponding to 0.5×, 1×, and 5× the mean IC 50 value obtained against asexual blood stage parasites. IC 50 values (Table 1) were <70 nM for all compounds tested, with the exception of the prophylactic antiliver stage agents primaquine and tafenoquine, which were far less active against asexual stages (IC 50 values of 1.3 and 4.4 μM, respectively).…”

“…We also examined the gametocytocidal potency of the clinical candidate tafenoquine, a 5-phenoxy derivative of primaquine that is less toxic and has a longer plasma half-life (14 d vs. 5-6 h, respectively) (48,50). In our assays, tafenoquine was comparable with primaquine in showing gametocytocidal activity (primarily against early stages), albeit at high concentrations (2.2-22 μM) (Fig.…”

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