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.

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.

Figures

Fig. 1

Clinical outcome by treatment and CYP2D6 status. Relapse frequency is the percentage (%) of subjects who experienced a relapse, with error bars representing the standard error of the mean. Odds ratios (ORs) and 95 % confidence intervals (95 % CI) were from analyses comparing the relapse frequency of reduced metabolizers (IMs) with that of extensive metabolizers (EMs) within each treatment group. Exact logistic regression was used to derive ORs, except for the TQ high dose arm (TQ 300 mg/TQ 600 mg), in which Fisher’s Exact test was used with a correction of 0.05 to each cell as there were no IM subjects who relapsed. One-sided p values (p) are displayed (see “Methods” section)

Fig. 2

Box whisker plot of TQ AUC by CYP2D6 status. The box whisker plots are displayed separately for the TQ high dose arm (TQ 300 mg/TQ 600 mg) and TQ low dose (TQ 50 mg/TQ 100 mg) arms, respectively. The median AUC is represented by the thick horizontal line, while the lower and upper box edges (‘hinges’) represent the quartiles (the 25th and 75th percentiles). The interquartile range (IQR) is the distance between the first and third quartiles. The upper (lower) whisker extends from the upper (lower) hinge to the highest (lowest) value that is within 1.5 *IQR of the hinge

Fig. 3

Summary of TQ-related components detected in incubations of TQ with recombinant human CYP Supersomes. TQ-related compounds detected in 5 and 10 μM incubations of TQ with recombinant human CYP enzymes (Supersomes™), hepatocytes and appropriate controls (retention time and protonated molecular ion observed by UPLC-MS in parenthesis). The Carboxy-TQ derivative observed after prolonged incubation is circled