Efficacy and pharmacokinetic evaluation of a novel anti-malarial compound (NP046) in a mouse model
Department of Medicine, Division of Clinical Pharmacology, University of Cape Town, Observatory 7925, Cape Town, South Africa; PAREXEL International Clinical Research Organization, Private Bag X09, Brandhof, Bloemfontein, South Africa; Department of Chemistry, University of the Free State, PO Box 339, Bloemfontein, South Africa; Research Development, University of the Free State, PO Box 339, Bloemfontein, South Africa
Background: Even though malaria is a completely preventable and treatable disease, it remains a threat to human life and a burden to the global economy due to the emergence of multiple-drug resistant malaria parasites. According to the World Malaria Report 2013, in 2012 there were an estimated 207 million malaria cases and 627,000 deaths. Thus, the discovery and development of new, effective anti-malarial drugs are required. To achieve this goal, the Department of Chemistry at the University of the Free State has synthesized a number of novel amino-alkylated chalcones and analogues, which showed in vitro anti-malarial activity against both chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains. The lead compound (NP046) was selected for a comprehensive pharmacokinetic (PK) and in vivo efficacy evaluation in a mouse model. Methods: In vivo efficacy: Water solutions of NP046 were administered orally at 50 and 10 mg/kg using oral gavage and IV at 5 and 1 mg/kg via the dorsal penile vein to Plasmodium berghei (ANKA strain) infected male C57BL/6 mice (n = 5), once a day for four days. Blood samples were collected via tail bleeding in tubes containing phosphate buffer saline (PBS) on day five to determine the % parasitaemia by flow cytometry. In vivo PK: NP046 solutions in water were administered orally (50 and 10 mg/kg) and IV (5 mg/kg) to male C57BL/6 mice (n = 5). Blood samples were collected via tail bleeding into heparinized tubes and analysed using a validated LC-MS/MS assay. Data obtained from the concentration-time profile was evaluated using Summit PK software to determine the PK parameters of NP046. Results: NP046 inhibited parasite growth for the oral and IV groups. Better parasite growth inhibition was observed for the IV group. The PK evaluation of NP046 showed low oral bioavailability (3.2% and 6% at 50 mg/kg and 10 mg/kg dose, respectively and a moderate mean half-life ranging from 3.1 to 4.4 hours. Conclusion: Even though the oral bioavailability of NP046 is low, its percentage parasite growth inhibition is promising, but in order to improve the oral bioavailability, structure-activity-relationship (SAR) optimization studies are currently being conducted. © 2015 Abay et al.
antimalarial agent; chloroquine; hydrocortisone; np 046; reserpine; unclassified drug; animal experiment; antimalarial activity; area under the curve; Article; blood sampling; controlled study; drug bioavailability; drug clearance; drug efficacy; drug penetration; flow cytometry; in vivo study; lipophilicity; liquid chromatography; male; maximum plasma concentration; mouse; nonhuman; pharmacokinetics; plasma concentration-time curve; Plasmodium berghei; Plasmodium berghei infection; tandem mass spectrometry; time to maximum plasma concentration
MRC, South African Medical Research Council