A Phase Ii Dose-Ranging Study of Sitamaquine for the Treatment of Visceral Leishmaniasis in India

Abstract

This randomized, open label, multicenter study assessed the dose-response and safety profile for oral sitamaquine in 120 Indian subjects with visceral leishmaniasis (VL). Patients aged 5-64 years (mean age 21.2 years) received one of four sitamaquine doses (1.5, 1.75, 2.0, or 2.5 mg kg(-1) day(-1)) daily for 28 days. At Day 180 in the intent-to-treat population, final cure (primary efficacy outcome) was achieved in 92 of 106 (87%) patients overall and 25 of 31 (81%), 24 of 27 (89%), 23 of 23 (100%), and 20 of 25 (80%) patients at doses of 1.5, 1.75, 2.0, or 2.5 mg kg(-1) day(-1) sitamaquine, respectively. Sitamaquine was generally well tolerated. The most common adverse events during the active treatment phase were vomiting (8% [10 of 120]), dyspepsia (8% [9 of 120]) and cyanosis (3% [4 of 120]). Nephrotic syndrome (3% [3 of 120]) and glomerulonephritis (2% [2 of 120]) were also reported and require further investigation. Oral sitamaquine demonstrated efficacy in Indian VL and was well tolerated.

Primaquine revisited six decades after its discovery

“…This drug is already in clinical assays for the oral treatment of visceral leishmaniasis [41], with phase II trials in India and Kenya being quite encouraging [229,230]. Physicochemical analysis of the interaction of sitamaquine with phospholipid monolayers and sterols at the air-water interface showed interactions only to occur in the presence of anionic phospholipids.…”

Pharmacokinetics of Oral Sitamaquine Taken with or without Food and Safety and Efficacy for Treatment of Visceral Leishmaniais: A Randomized Study in Bihar, India

“…Two initial phase II clinical studies of 1.5−3.0 mg/kg/day of sitamaquine for 28 days in India and Africa showed maximal efficacy with 1.75 or 2 mg/kg/day. 16,17 Clinical symptoms resolved rapidly in both studies. 16,17 In the study in India, day 14 splenic aspirates were parasite negative in 96 (82%) of 117 patients overall and in 26 (93%) of 28 patients in the cohort receiving 2.0 mg/kg/day.…”

“…16,17 Clinical symptoms resolved rapidly in both studies. 16,17 In the study in India, day 14 splenic aspirates were parasite negative in 96 (82%) of 117 patients overall and in 26 (93%) of 28 patients in the cohort receiving 2.0 mg/kg/day. 16 These data suggested that a shorter therapy course may be possible.…”

“…16,17 In the study in India, day 14 splenic aspirates were parasite negative in 96 (82%) of 117 patients overall and in 26 (93%) of 28 patients in the cohort receiving 2.0 mg/kg/day. 16 These data suggested that a shorter therapy course may be possible. 16,17 Some renal adverse events were reported; most occurred after day 21, generally in the groups receiving higher doses (> 2.0 mg/kg/day).…”

Drug Resistance in Leishmaniasis

“…In recent years four new potential therapies have been introduced for visceral leishmaniasis (Table 1). These include an amphotericin B liposome formulation registered in the United States and Europe (AmBisome) (14,105); oral miltefosine (142) which has been registered in India and is now in phase IV trial; a parenteral formulation of aminosidine (paromomycin) (150) currently completing phase III clinical trials in India (www.iowh.org) and on trial in East Africa (www.dndi .org); and oral sitamaquine (previously WR6026), which has completed phase II trials in India, Kenya, and Brazil (50,84,159) and is in development with GlaxoSmithKline (http://science.gsk.com/about/disease.htm). Treatment of CL has also improved through the introduction of topical formulations of paromomycin (8,55,138) and other drugs, including the immunomodulator imiquimod (6,67).…”