title: Assessment of the prophylactic activity and pharmacokinetic profile of oral tafenoquine compared to primaquine for inhibition of liver stage malaria infections.
abstract: BACKGROUND
  As anti-malarial drug resistance escalates, new safe and effective medications are necessary to prevent and treat malaria infections. The US Army is developing tafenoquine (TQ), an analogue of primaquine (PQ), which is expected to be more effective in preventing malaria in deployed military personnel.
  
  
  METHODS
  To compare the prophylactic efficacy of TQ and PQ, a transgenic Plasmodium berghei parasite expressing the bioluminescent reporter protein luciferase was utilized to visualize and quantify parasite development in C57BL/6 albino mice treated with PQ and TQ in single or multiple regimens using a real-time in vivo imaging system (IVIS). As an additional endpoint, blood stage parasitaemia was monitored by flow cytometry. Comparative pharmacokinetic (PK) and liver distribution studies of oral and intravenous PQ and TQ were also performed.
  
  
  RESULTS
  Mice treated orally with three doses of TQ at 5 mg/kg three doses of PQ at 25 mg/kg demonstrated no bioluminescence liver signal and no blood stage parasitaemia was observed suggesting both drugs showed 100% causal activity at the doses tested. Single dose oral treatment with 5 mg TQ or 25 mg of PQ, however, yielded different results as only TQ treatment resulted in causal prophylaxis in P. berghei sporozoite-infected mice. TQ is highly effective for causal prophylaxis in mice at a minimal curative single oral dose of 5 mg/kg, which is a five-fold improvement in potency versus PQ. PK studies of the two drugs administered orally to mice showed that the absolute bioavailability of oral TQ was 3.5-fold higher than PQ, and the AUC of oral TQ was 94-fold higher than oral PQ. The elimination half-life of oral TQ in mice was 28 times longer than PQ, and the liver tissue distribution of TQ revealed an AUC that was 188-fold higher than PQ.
  
  
  CONCLUSIONS
  The increased drug exposure levels and longer exposure time of oral TQ in the plasma and livers of mice highlight the lead quality attributes that explain the much improved efficacy of TQ when compared to PQ.
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA. qigui.li.civ@mail.mil.
authors.forename: Qigui
authors.initials: Q
authors.lastname: Li
authors.forename: Michael
authors.initials: M
authors.lastname: O'Neil
authors.forename: Lisa
authors.initials: L
authors.lastname: Xie
authors.forename: Diana
authors.initials: D
authors.lastname: Caridha
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zeng
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Brandon
authors.initials: B
authors.lastname: Pybus
authors.forename: Mark
authors.initials: M
authors.lastname: Hickman
authors.forename: Victor
authors.initials: V
authors.lastname: Melendez
mesh_terms: D000634:Aminoquinolines / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D000962:Antimalarials / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D005434:Flow Cytometry; D006207:Half-Life; D008099:Liver / Q000469:parasitology; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D010962:Plasmodium berghei / Q000187:drug effects* / Q000254:growth & development; D011319:Primaquine / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D034101:Sporozoites / Q000187:drug effects / Q000254:growth & development
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; C055852:tafenoquine; D011319:Primaquine
references.citation: J Parasitol. 1984 Oct;70(5):831-3
references.pmid: 6150971
references.citation: Am J Trop Med Hyg. 1998 May;58(5):645-9
references.pmid: 9598455
references.citation: Antimicrob Agents Chemother. 1991 Feb;35(2):277-82
references.pmid: 2024961
references.citation: J Infect Dis. 2009 Nov 1;200(9):1470-8
references.pmid: 19811100
references.citation: J Infect Dis. 1999 Oct;180(4):1282-7
references.pmid: 10479159
references.citation: Clin Infect Dis. 2004 Oct 15;39(8):1095-103
references.pmid: 15486831
references.citation: J Med Chem. 2011 Jan 13;54(1):131-42
references.pmid: 21141892
references.citation: Am J Trop Med Hyg. 2003 Nov;69(5):542-7
references.pmid: 14695093
references.citation: Malar J. 2011 Dec 09;10:350
references.pmid: 22152047
references.citation: Antimicrob Agents Chemother. 2013 Jan;57(1):417-24
references.pmid: 23129047
references.citation: Antimicrob Agents Chemother. 1998 May;42(5):1293-4
references.pmid: 9593172
references.citation: Parasitology. 2007 Aug;134(Pt 9):1151-62
references.pmid: 17445324
references.citation: Science. 2011 Dec 9;334(6061):1372-7
references.pmid: 22096101
references.citation: Am J Trop Med Hyg. 2002 Jul;67(1):39-43
references.pmid: 12363062
references.citation: Vaccine. 2013 Jul 25;31(34):3410-6
references.pmid: 23063834
references.citation: Am J Trop Med Hyg. 1990 Jun;42(6):532-7
references.pmid: 2164790
references.citation: Cytometry A. 2007 May;71(5):297-307
references.pmid: 17279569
references.citation: Antimicrob Agents Chemother. 2010 Feb;54(2):792-8
references.pmid: 19995933
references.citation: J Infect Dis. 1992 Apr;165(4):764-8
references.pmid: 1532406
references.citation: Trans R Soc Trop Med Hyg. 2002 Nov-Dec;96(6):683-4
references.pmid: 12625150
references.citation: Methods Mol Biol. 2013;923:429-43
references.pmid: 22990796
references.citation: Ann Trop Med Parasitol. 1993 Dec;87(6):547-52
references.pmid: 8122915
references.citation: J Infect Dis. 2004 Oct 15;190(8):1456-63
references.pmid: 15378438
references.citation: Clin Infect Dis. 2003 Mar 1;36(5):541-9
references.pmid: 12594633
references.citation: Expert Opin Investig Drugs. 2007 May;16(5):705-15
references.pmid: 17461742
references.citation: Am J Trop Med Hyg. 1992 Feb;46(2):169-82
references.pmid: 1539752
references.citation: PLoS One. 2009 Nov 18;4(11):e7881
references.pmid: 19924309
references.citation: Trans R Soc Trop Med Hyg. 1994 Nov-Dec;88(6):691-2
references.pmid: 7886774
references.citation: Nat Protoc. 2007;2(7):1811-8
references.pmid: 17641649
references.citation: Parasite Immunol. 2012 Dec;34(12):562-9
references.pmid: 23171040
references.citation: PLoS One. 2013 Apr 11;8(4):e60820
references.pmid: 23593316
references.citation: Clin Infect Dis. 2001 Dec 15;33(12):1968-74
references.pmid: 11700577