Pharmacokinetics of oral sitamaquine taken with or without food and safety and efficacy for treatment of visceral leishmaniais: a randomized study in Bihar, India

Abstract

This randomized, open-label study of patients in India with visceral leishmaniasis (VL) investigated the effect of food on sitamaquine and desethyl-sitamaquine pharmacokinetics. Patients were randomized to receive oral sitamaquine, 2 mg/kg/day, once a day for 21 days across four cohorts (n = 41) (fasted/fed, fed/fasted, fed/fed, and fasted/fasted) over two periods (days 1-10 and 11-21), or intravenous amphotericin B (AmB), 1 mg/kg every other day for 30 days (n = 20). Mean day 21 pharmacokinetics across the four cohorts were sitamaquine, area under curve (AUC)((0-τ)) = 6,627-8,903 ng.hr/mL, AUC((0-16)) = 4,859-6,633 ng.hr/mL, maximum plasma concentration (C(max)) = 401-570 ng/mL, apparent terminal half-life (t(1/2)) = 18.3-22.8 hr, time to reach C(max) (t(max)) = 3.5-6 hr; and desethyl-sitamaquine, AUC((0-τ)) = 2,307-3,163 ng.hr/mL, C(max) = 109-154 ng/mL, t(1/2) = 23.0-27.9 hr, t(max) = 2-10 hr, with no significant food effect. On-therapy adverse events were observed for sitamaquine in 4 (10%) of 41 patients and for AmB in 17 (85%) of 20 patients. The final clinical cure (day 180) was 85% (95% confidence interval = 70.8-94.4%) for sitamaquine and 95% (95% confidence interval = 75.1-99.9) for AmB. Sitamaquine can be taken regardless of food intake, was generally well tolerated, and showed potential efficacy in patients with visceral leishmaniasis.

Conflict of interest statement

Disclosure: GlaxoSmithKline conducted the study and collected and analyzed data. All authors had access to the primary data and take responsibility for data reporting accuracy and completeness. The corresponding authors had responsibility for the final decision to submit for publication. Shyam Sundar has received support for clinical trials and travel funds to attend scientific meetings from Paladin Labs, Institute for One World Health, GlaxoSmithKline, Bharat Serum and Vaccine Ltd., Drugs for Neglected Diseases Initiative, National Institute of Allergy and Infectious Diseases, National Institutes of Health, World Health Organization, and the European Commission. Prabhat K. Sinha has received support from the Institute for One World Health, GlaxoSmithKline, Drugs for Neglected Diseases Initiative, World Health Organization, Médecins Sans Frontières (Barcelona) for clinical trials and travel funds to attend scientific meetings. Susan A. Dixon, Renata Buckley, Ann K. Miller, and Khadeeja Mohamed are employees of GlaxoSmithKline as noted in the affiliations. Mahir Al-Banna is a contractor employed by GlaxoSmithKline as noted in the affiliations.

Figures

Figure 1.

Study design.

Figure 2.

Day 21 mean plasma concentration−time curves for sitamaquine and desethyl-sitamaquine on a log−linear scale.

Figure 3.

Laboratory parameters throughout the study for which there were clinically important differences between treatment groups: A, methemoglobin level (mean ± SE); B, serum creatinine level (mean ± SE); C, creatinine clearance (mean ± SE); and D, urine total protein:creatinine ratio (mean ± SE).

Figure 4.

Erythrocytes per high-power field in urine of patients (individual patient profiles) for A, sitamaquine and B, amphotericin B.