Oral lipid-based nanoformulation of tafenoquine enhanced bioavailability and blood stage antimalarial efficacy and led to a reduction in human red blood cell loss in mice

Abstract

Paula Melariri,1 Lonji Kalombo,2 Patric Nkuna,2 Admire Dube,2,3 Rose Hayeshi,2 Benhards Ogutu,4,5 Liezl Gibhard,6 Carmen deKock,6 Peter Smith,6 Lubbe Wiesner,6 Hulda Swai2 1Polymers and Composites, Material Science and Manufacturing, Council for Scientific and Industrial Research, Port Elizabeth, South Africa; 2Polymer and Composites, Material Science and Manufacturing, Council for Scientific and Industrial Research, Pretoria, South Africa; 3School of Pharmacy, University of the Western Cape, Bellville, South Africa; 4Centre for Research in Therapeutic Sciences, Strathmore University, Nairobi, Kenya; 5Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya; 6Division of Pharmacology, University of Cape Town Medical School, Groote Schuur Hospital, Cape Town, South Africa Abstract: Tafenoquine (TQ), a new synthetic analog of primaquine, has relatively poor bioavailability and associated toxicity in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. A microemulsion formulation of TQ (MTQ) with sizes <20 nm improved the solubility of TQ and enhanced the oral bioavailability from 55% to 99% in healthy mice (area under the curve 0 to infinity: 11,368±1,232 and 23,842±872 min·µmol/L) for reference TQ and MTQ, respectively. Average parasitemia in Plasmodium berghei-infected mice was four- to tenfold lower in the MTQ-treated group. In vitro antiplasmodial activities against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum indicated no change in half maximal inhibitory concentration, suggesting that the microemulsion did not affect the inherent activity of TQ. In a humanized mouse model of G6PD deficiency, we observed reduction in toxicity of TQ as delivered by MTQ at low but efficacious concentrations of TQ. We hereby report an enhancement in the solubility, bioavailibility, and efficacy of TQ against blood stages of Plasmodium parasites without a corresponding increase in toxicity. Keywords: microemulsion, solubility, G6PD deficiency, in vivo efficacy