In vitro drug interactions between Tafenoquine and current antimalarials in Plasmodium falciparum parasites

Open Access
Author:
Kemirembe, Karen
Graduate Program:
Entomology
Degree:
Master of Science
Document Type:
Master Thesis
Date of Defense:
November 12, 2015
Committee Members:
  • Liwang Cui, Thesis Advisor
Keywords:
  • Plasmodium falciparum
  • tafenoquine
  • malaria
  • gametocyte
  • drug interaction
  • 8-aminoquinoline
  • isobologram
  • ACT
  • Plasmodium vivax
Abstract:
Background: According to the 2014 World Malaria Report, about half of all countries with ongoing malaria transmission are co-endemic for Plasmodium vivax and P. falciparum malaria parasites. The 8-aminoquinoline, tafenoquine (TFQ), a primaquine (PMQ) derivative, is currently in late-stage clinical development for the radical cure of P. vivax, administered as a single 300 mg dose following a 3-day chloroquine (CQ) regimen; currently only PMQ is licensed for this. Because CQ resistance is spreading in P. vivax, there is an on-going shift to artemisinin combination therapy (ACT) in place of CQ. Drug interactions between TFQ and ACTs, as with CQ, will therefore occur in vivo. Since P. vivax and P. falciparum mixed infections are common and P. vivax in vitro culture is unstable, drug interactions between TFQ and ACTs in asexual and sexual stage gametocytes of P. falciparum are investigated in this study. Methods: A SYBR Green I drug susceptibility assay for asexual parasites, and a flow cytometry- based method for gametocytes, resulting in fractional inhibitory concentrations and corresponding isobolograms were used to determine decreased (antagonistic) or enhanced (synergistic) drug efficacy of ACT-partner drugs in the presence of TFQ at fixed ratios based on published in vivo peak plasma concentrations. Six ACT-partner drugs namely amodiaquine (AMQ), lumefantrine (LMF), mefloquine (MFQ), naphthoquine (NQ), piperaquine (PPQ) and pyronaridine (PND), as well as CQ are investigated against CQ or artemisinin (ART) resistant or sensitive asexual parasites and a transgenic green fluorescent α-tubulin IIGFP [PlasmoDB: PF3D7_042230] gametocyte line. Results: ACT-partner drugs were mostly synergistic in asexual parasites regardless of genetic background when combined with TFQ, whereas differential interactions were observed in gametocytes.