Document text
Principal Investigator: BABU L TEKWANI
Organization: SOUTHERN RESEARCH INSTITUTE
Fiscal Year: 2019
Award: $742,840
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
Development of dormant hypnozoites in the hepatic tissues, which may cause malaria relapse weeks to
months after the initial infection, poses the major challenge for treatment & control of vivax malaria. 8-
Aminoquinolines (8-AQs) are the only antimalarial drugs active against Plasmodium vivax hypnozoites. However,
the utility of 8-AQs has been limited due to a dose-limiting hemolytic toxicity in individuals with glucose-6-
phosphate dehyrogenase (G6PD) deficiency. G6PD deficiency affects more than 400 million people worldwide
Lipid/polymeric nanoparticle formulations have recently been shown to have significant oral bioavailability. This
approach, along with targeted delivery to the hepatic tissues may be applied for improving therapeutic index of
8-AQs. The goal of this project would be to develop stable lipid nanoparticles [solid lipid nanoparticles (SLNs) or
nanostructured lipid carriers (NLCs)] loaded with primaquine or NPC1161B, which can permeate across the
intestinal epithelia, reach the blood circulation and distribute in the tissues intact following oral administration.
Targeted and non-targeted nano-carrier formulations (polymeric, lipid based and micellar) of PQ and
NPC1161B will be prepared and optimized for pharmaceutical properties. Lipid-based nanoparticles will be
prepared by high-pressure homogenization technique using glyceryl stearate, glyceryl distearate, glyceryl
behenate, miglyol and other GRAS listed, biocompatible and biodegradable lipids, and their combinations. The
formulations will be evaluated with respect to drug loading, loading efficiency, particle size and size distribution,
zeta potential, resistance to lipolysis, in vitro drug release rates, physical and chemical stability, uptake and
metabolism by primary human hepatocytes. In vivo pharmacokinetics and tissue distribution in rodents will
assess the liver/blood ratios of the drugs and characterize their metabolism and plasma/liver pharmacokinetics.
The formulations with desired PK and metabolism profiles would be progressed to in vivo efficacy in rodent
malaria blood and liver stage causal prophylaxis models. In vivo hemotoxicity will be evaluated in the recently
developed humanized NOD-SCID mouse model engrafted with human G6PD deficient blood.
Targeted orally bioavailable nano-carrier formulations of PQ and NPC1161B will reduce total dose of the
drug required for complete efficacy, which presumably would translate to "a higher total dose of active metabolite
in parasitized liver cells" required to clear vivax hypnozoites. Reduced exposure of erythrocytes to the drug or
the metabolites would improve therapeutic index of these drugs and allow their safe use in G6D deficient
individuals. This would also allow application of these drugs for public health and malaria control programs.
Terms: <ASGP-R><Abnormal Assessment of Metabolism><Address><Affect><Aminoquinolines><Anti-Malarials><Antimalarial Agents><Antimalarial Drugs><Antimalarials><Asialoglycoprotein Receptor><Asialoorosomucoid Receptor><Asialoorosomucoid-Binding Protein><Assay><Bioassay><Bioavailability><Bioavailable><Biologic Assays><Biologic Availability><Biological Assay><Biological Availability><Blood><Blood Circulation><Blood Plasma><Blood Reticuloendothelial System><Blood erythrocyte><Bloodstream><Body Tissues><Circulation><Clinical><Development><Dose><Dose-Limiting><Drug Delivery><Drug Delivery Systems><Drug Efflux><Drug Kinetics><Drug Targeting><Drug or chemical Tissue Distribution><Drugs><Early-Stage Clinical Trials><Erythrocytes><Erythrocytic><Evaluation><Formulation><Generations><Glucose-6-Phosphate><Goals><Hemolysis><Hepatic Cells><Hepatic Parenchymal Cell><Hepatic Tissue><Hepatocyte><Human><In Vitro><Individual><Infection><Intermediary Metabolism><Lead><Ligands><Lipids><Lipolysis><Liver><Liver Cells><Lytotoxicity><Malaria><Marrow erythrocyte><Medical><Medication><Metabolic Processes><Metabolic Studies><Metabolism><Metabolism Studies><Methods><Modeling><Modern Man><NOD/SCID mouse><Nanostructures><Octadecanoates><Oral><Oral Administration><Oral Drug Administration><P vivax><P. vivax><Paludism><Parasites><Particle Size><Pb element><Pharmaceutic Preparations><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacokinetics><Pharmacologic Substance><Pharmacological Substance><Phase 1 Clinical Trials><Phase I Clinical Trials><Phenotype><Physiologic Availability><Plasma><Plasma Serum><Plasmodium Infections><Plasmodium vivax><Plasmodium vivax Malaria><Polymers><Population><Pre-Clinical Model><Preclinical Models><Preparation><Primaquine><Property><Prophylactic treatment><Prophylaxis><Public Health><Red Blood Cells><Red Cell><Relapse><Resistance><Reticuloendothelial System, Serum, Plasma><Rodent><Rodent Model><Rodentia><Rodents Mammals><Safety><Solid><Stearates><System><Techniques><Testing><Therapeutic><Therapeutic Index><Tissue Distribution><Tissues><Toxic effect><Toxicities><Translating><Vivax Malaria><analog><anti-malarial agents><anti-malarial drugs><base><biocompatibility><biomaterial compatibility><blood corpuscles><chemical stability><clinical development><controlled release><cytotoxicity><developmental><drug release kinetics><drug release rate><drug/agent><efficacy testing><erythrolysis><first in man><first-in-human><global health><heavy metal Pb><heavy metal lead><hepatic body system><hepatic organ system><improved><in vitro Assay><in vivo><in vivo evaluation><in vivo testing><intestinal epithelium><intraoral drug delivery><lipid nanoparticle><malaria infection><malaria-infected><malarial infection><member><metabolic abnormality assessment><mouse model><murine model><nano carrier><nano particle><nano particulate><nano-sized particle><nano-structures><nanocarrier><nanoparticle><nanoparticulate><nanosized particle><phase 1 trial><phase I protocol><pressure><programs><resistant><site targeted delivery><targeted delivery><tool><uptake><zeta potential>