Universidad Peruana Cayetano Heredia

Tafenoquine treatment of Plasmodium vivax malaria: suggestive evidence that CYP2D6 reduced metabolism is not associated with relapse in the Phase 2b DETECTIVE trial

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dc.contributor.author St-Jean, Pamela-L.
dc.contributor.author Xue, Zhengyu
dc.contributor.author Carter, Nick
dc.contributor.author Koh, Gavin-C. K. W.
dc.contributor.author Duparc, Stephan
dc.contributor.author Taylor, Maxine
dc.contributor.author Beaumont, Claire
dc.contributor.author Llanos Cuentas, Elmer Alejandro
dc.contributor.author Rueangweerayut, Ronnatrai
dc.contributor.author Krudsood, Srivicha
dc.contributor.author Green, Justin-A.
dc.contributor.author Rubio, Justin-P.
dc.date.accessioned 2019-02-06T14:48:06Z
dc.date.available 2019-02-06T14:48:06Z
dc.date.issued 2016
dc.identifier.uri https://hdl.handle.net/20.500.12866/5165
dc.description.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. Conclusion: 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. en_US
dc.language.iso eng
dc.publisher BioMed Central
dc.relation.ispartofseries Malaria Journal
dc.rights info:eu-repo/semantics/restrictedAccess
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
dc.subject Aminoquinolines/therapeutic use en_US
dc.subject Antimalarials/therapeutic use en_US
dc.subject Chloroquine/therapeutic use en_US
dc.subject Cytochrome P-450 CYP2D6/metabolism en_US
dc.subject Female en_US
dc.subject Humans en_US
dc.subject Malaria, Vivax/drug therapy/metabolism en_US
dc.subject Primaquine/therapeutic use en_US
dc.subject Treatment Outcome en_US
dc.title Tafenoquine treatment of Plasmodium vivax malaria: suggestive evidence that CYP2D6 reduced metabolism is not associated with relapse in the Phase 2b DETECTIVE trial en_US
dc.type info:eu-repo/semantics/article
dc.identifier.doi https://doi.org/10.1186/s12936-016-1145-5
dc.subject.ocde https://purl.org/pe-repo/ocde/ford#3.03.07
dc.subject.ocde https://purl.org/pe-repo/ocde/ford#3.03.08
dc.relation.issn 1475-2875


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