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

Abstract

BackgroundTafenoquine (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.MethodsThe 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.ResultsReduction 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.ConclusionTogether, 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-016-1145-5) contains supplementary material, which is available to authorized users.

Molecular and immunological analyses of confirmed Plasmodium vivax relapse episodes

“…This failure was not related to a reduced ability to metabolise 8-aminoquinolines by cytochrome P450 as a result of CYP2D6 polymorphisms, reflecting previous observations showing similar clearance rates for intermediate and extensive metabolisers [34]. This suggests that some P. vivax lines circulating in Thailand might not be fully susceptible to the standard dose of primaquine (15 mg for 14 days from day 2), which should prompt reconsideration of the suitability of this dosage; all the more urgently should emergent chloroquine-resistant parasites [35] spread further.…”

Primaquine pharmacology in the context of CYP 2D6 pharmacogenomics: Current state of the art

“…metabolism has yet to be established in humans and is currently being actively investigated (St Jean, et al, 2016).. That being said, there is a need for the discovery and development of new safer antimalarial agents that treat relapsing strains of malaria and do not require CYP 2D6 metabolism for activity. Such drugs would be invaluable tools in the fight against malaria.…”

Genetic Polymorphism of human CYP2D6 gene coding region from vivax malaria cases in Yunnan Province, China

“…Although decreased enzyme activity in the heterogeneity of CYP2D6 is speculated to lead to failed therapy of primaquine to kill hypnozoite of P. vivax [9,17,[35][36][37], the correlation between different genotypes and the relapse of P. vivax is poorly understood. In this study, we found that the genotypes with combined mutations at c. 408, c. 886 and c. 1457 were most closely related to the relapse of vivax malaria (OR = 5.615, P < 0.05) ( Table 3), and that mutation at c. 886…”