title: Tafenoquine treatment of Plasmodium vivax malaria: suggestive evidence that CYP2D6 reduced metabolism is not associated with relapse in the Phase 2b DETECTIVE trial.
abstract: BACKGROUND
  Tafenoquine (TQ) and primaquine (PQ) are 8-aminoquinolines (8-AQ) with anti-hypnozoite activity against vivax malaria. PQ is the only FDA-approved medicine for preventing relapsing Plasmodium vivax infection and TQ is currently in phase 3 clinical trials for the same indication. Recent studies have provided evidence that cytochrome P450 (CYP) metabolism via CYP2D6 plays a role in PQ efficacy against P. vivax and have suggested that this effect may extend to other 8-AQs, including TQ. Here, a retrospective pharmacogenetic (PGx) investigation was performed to assess the impact of CYP2D6 metabolism on TQ and PQ efficacy in the treatment of P. vivax in the DETECTIVE study (TAF112582), a recently completed, randomized, phase 2b dose-ranging clinical trial. The impact of CYP2D6 on TQ pharmacokinetics (PK) was also investigated in TAF112582 TQ-treated subjects and in vitro CYP metabolism of TQ was explored. A limitation of the current study is that TAF112582 was not designed to be well powered for PGx, thus our findings are based on TQ or PQ efficacy in CYP2D6 intermediate metabolizers (IM), as there were insufficient poor metabolizers (PM) to draw any conclusion on the impact of the PM phenotype on efficacy.
  
  
  METHODS
  The impact of genetically-predicted CYP2D6 reduced metabolism on relapse-free efficacy six months post-dosing of TQ or PQ, both administered in conjunction with chloroquine (CQ), was assessed using exact statistical methods in 198 P. vivax-infected study participants comparing IM to extensive metabolizers (EM). The influence of CYP2D6 metabolizer phenotypes on TQ PK was assessed comparing median TQ area under the curve (AUC). In vitro metabolism of TQ was investigated using recombinant, over-expressed human CYP enzymes and human hepatocytes. Metabolite identification experiments were performed using liquid chromatography-mass spectrometry.
  
  
  RESULTS
  Reduction of CYP2D6 activity was not associated with an increase in relapse-rate in TQ-treated subjects (p = 0.57). In contrast, and in accordance with recent literature, CYP2D6 IMs were more common (p = 0.05) in PQ-treated subjects who relapsed (50 %) than in subjects who remained relapse-free (17 %). Further, CYP2D6 metabolizer phenotypes had no significant effect on TQ AUC, and only minimal metabolism of TQ could be detected in hepatic in vitro systems.
  
  
  CONCLUSIONS
  Together, these data provide preliminary evidence that in CYP2D6 IMs, TQ efficacy in P. vivax-infected individuals is not diminished to the same extent as PQ. As there were no PMs in either the TQ or PQ treatment arms of TAF112582, no conclusions could be drawn on potential differences in PMs. These findings suggest that differential effects of CYP2D6 metabolism on TQ and PQ efficacy could be a differentiation factor between these 8-AQs, but results remain to be confirmed prospectively in the ongoing phase 3 studies.
authors.affiliation: PAREXEL International, 2520 Meridian Parkway, Durham, NC, 27713, USA. pam.stjean@parexel.com.
authors.forename: Pamela L
authors.initials: PL
authors.lastname: St Jean
authors.affiliation: PAREXEL International, 2520 Meridian Parkway, Durham, NC, 27713, USA. zhengyu.xue@parexel.com.
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Xue
authors.affiliation: GlaxoSmithKline, Stockley Park West, Uxbridge, Middlesex, UK. nick.s.carter@gsk.com.
authors.forename: Nick
authors.initials: N
authors.lastname: Carter
authors.affiliation: GlaxoSmithKline, Stockley Park West, Uxbridge, Middlesex, UK. gavin.c.koh@gsk.com.
authors.forename: Gavin C K W
authors.initials: GC
authors.lastname: Koh
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland. duparcs@mmv.org.
authors.forename: Stephan
authors.initials: S
authors.lastname: Duparc
authors.affiliation: GlaxoSmithKline, Ware, Hertfordshire, UK. maxine.a.taylor@gsk.com.
authors.forename: Maxine
authors.initials: M
authors.lastname: Taylor
authors.affiliation: GlaxoSmithKline, Ware, Hertfordshire, UK. claire.beaumont@gsk.com.
authors.forename: Claire
authors.initials: C
authors.lastname: Beaumont
authors.affiliation: Instituto de Medicina Tropical, Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru. elmer.llanos@upch.pe.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Llanos-Cuentas
authors.affiliation: Mae Sot Hospital, Mae Sot, Tak Province, Thailand. ronnatrai@hotmail.com.
authors.forename: Ronnatrai
authors.initials: R
authors.lastname: Rueangweerayut
authors.affiliation: Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. srivicha.kru@mahidol.ac.th.
authors.forename: Srivicha
authors.initials: S
authors.lastname: Krudsood
authors.affiliation: GlaxoSmithKline, Stockley Park West, Uxbridge, Middlesex, UK. justin.a.green@gsk.com.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Green
authors.affiliation: Department of Pathology, University of Melbourne, Melbourne, VIC, Australia. jrubio@unimelb.edu.au.
authors.forename: Justin P
authors.initials: JP
authors.lastname: Rubio
mesh_terms: D000634:Aminoquinolines / Q000627:therapeutic use*; D000962:Antimalarials / Q000627:therapeutic use*; D002738:Chloroquine / Q000627:therapeutic use; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D005260:Female; D006801:Humans; D016780:Malaria, Vivax / Q000188:drug therapy* / Q000378:metabolism*; D011319:Primaquine / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; C055852:tafenoquine; D002738:Chloroquine; D019389:Cytochrome P-450 CYP2D6; D011319:Primaquine