title: 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: 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.
authors.affiliation: Polymers and Composites, Material Science and Manufacturing, Council for Scientific and Industrial Research, Port Elizabeth, South Africa.
authors.forename: Paula
authors.initials: P
authors.lastname: Melariri
authors.affiliation: Polymer and Composites, Material Science and Manufacturing, Council for Scientific and Industrial Research, Pretoria, South Africa.
authors.forename: Lonji
authors.initials: L
authors.lastname: Kalombo
authors.affiliation: Polymer and Composites, Material Science and Manufacturing, Council for Scientific and Industrial Research, Pretoria, South Africa.
authors.forename: Patric
authors.initials: P
authors.lastname: Nkuna
authors.affiliation: Polymer and Composites, Material Science and Manufacturing, Council for Scientific and Industrial Research, Pretoria, South Africa ; School of Pharmacy, University of the Western Cape, Bellville, South Africa.
authors.forename: Admire
authors.initials: A
authors.lastname: Dube
authors.affiliation: Polymer and Composites, Material Science and Manufacturing, Council for Scientific and Industrial Research, Pretoria, South Africa.
authors.forename: Rose
authors.initials: R
authors.lastname: Hayeshi
authors.affiliation: Centre for Research in Therapeutic Sciences, Strathmore University, Nairobi, Kenya ; Centre for Clinical Research, Kenya Medical Research Institute, Nairobi, Kenya.
authors.forename: Benhards
authors.initials: B
authors.lastname: Ogutu
authors.affiliation: Division of Pharmacology, University of Cape Town Medical School, Groote Schuur Hospital, Cape Town, South Africa.
authors.forename: Liezl
authors.initials: L
authors.lastname: Gibhard
authors.affiliation: Division of Pharmacology, University of Cape Town Medical School, Groote Schuur Hospital, Cape Town, South Africa.
authors.forename: Carmen
authors.initials: C
authors.lastname: deKock
authors.affiliation: Division of Pharmacology, University of Cape Town Medical School, Groote Schuur Hospital, Cape Town, South Africa.
authors.forename: Peter
authors.initials: P
authors.lastname: Smith
authors.affiliation: Division of Pharmacology, University of Cape Town Medical School, Groote Schuur Hospital, Cape Town, South Africa.
authors.forename: Lubbe
authors.initials: L
authors.lastname: Wiesner
authors.affiliation: Polymer and Composites, Material Science and Manufacturing, Council for Scientific and Industrial Research, Pretoria, South Africa.
authors.forename: Hulda
authors.initials: H
authors.lastname: Swai
mesh_terms: D000284:Administration, Oral; D000634:Aminoquinolines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D004912:Erythrocytes / Q000469:parasitology*; D006801:Humans; D008288:Malaria; D051379:Mice; D049329:Nanostructures / Q000008:administration & dosage / Q000737:chemistry; D010962:Plasmodium berghei / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects*
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; C055852:tafenoquine
keywords: G6PD deficiency; in vivo efficacy; microemulsion; solubility